A secondary amine amide organocatalyst for the asymmetric nitroaldol reaction of α-ketophosphonates

Article abstract of DOI:10.1002/chem.200801958

A study was conducted for the asymmetric nitroaldol reaction of α-ketophosphonates by using a secondary amine amide organocatalyst. The study used a series of chiral secondary amine amides and synthesized it with α-ketophosphonates with nitromethane used as the solvent at 0°C. The nitroaldol reaction can be used for preparing nitrogen-containing compounds in the organic synthesis. It was observed during the study the α- ketophosphonates can be converted into optically active β-amino-α- hydroxy phosphonates, that further can be used as biological activity intermediates for inhibition of renin of HIV protease. The study also found that secondary amines like diethylamine or piperidine can promote the nitroaldol reaction of α-ketophosphonate at 0°C.

Full text of DOI:10.1002/chem.200801958

DOI: 10.1002/chem.200801958
A Secondary Amine Amide Organocatalyst for the Asymmetric Nitroaldol
Reaction of a-Ketophosphonates
Xiaohong Chen,[a] Jun Wang,[a] Yin Zhu,[a] Deju Shang,[a] Bo Gao,[a] Xiaohua Liu,[a]
Xiaoming Feng,*[a, b] Zhishan Su,[a] and Changwei Hu*[a]
The nitroaldol (Henry) reaction is a fundamental synthet-
ic tool for the construction of nitrogen-containing com-
pounds in the organic synthesis.[1] Transformation of Henry
reaction adducts, such as reduction to amines or oxidation
(i.e., Nef reaction) to carbonyl compounds, could yield a va-
riety of useful synthetic intermediates.[2] Over the past sever-
al years, many efficient catalytic asymmetric versions of this
reaction have been developed.[3] However, compared with
the substantial progress made with aldehydes,[4] few efficient
catalysts have been developed for the asymmetric nitroaldol
reactions of ketones.[5] The only example using a-keto-
phosphonates as the acceptor was reported by Zhaoꢀs
group.[5h] The products could be converted into optically
active b-amino-a-hydroxy phosphonates, which are of signif-
icant biological activity intermediates, such as the inhibition
of renin and HIV protease.[6]
To the best of our knowledge, chiral organocatalysts uti-
lized in direct nitroaldol reactions mainly contain cinchona
alkaloids derivatives, guanidine and thiourea to form the ni-
tromethide intermediates.[3] Until now, no secondary amine
has yet been reported as an efficient catalyst. Thus, the
search for an effective catalyst system based on secondary
amines is very interesting. However, the literature revealed
that less steric hindered organic bases, such as triethylamine
or diethylamine, could not be incorporated in the nitroaldol
reactions of aryl-substituted a-ketophosphonates.[7a,b] The
poor performance of the catalyst and extremely low yield
was ascribed to the serious rearrangement of the aryl-substi-
À
À
tuted nitroaldol product (as well as potential C C or C P
bond cleavages) initiated by the deprotonation of the prod-
uct under the reaction conditions.[7c–e] Excitingly, during the
course of our studies, it was found that secondary amines,
such as diethylamine or piperidine, could efficiently promote
the nitroaldol reaction of a-ketophosphonate 3a in THF at
08C, to give the desired product in high yields (Table 1, en-
tries 1–2). It might be that the appropriate solvent and low
reaction temperature efficiently suppressed further transfor-
mation of the product. Encouraged by this result, we fo-
cussed on the development of an asymmetric version of the
secondary amine catalyzed asymmetric nitroaldol reaction
of a-ketophosphonate.
Accordingly, a series of excellent chiral secondary amine
amides[8] 1a–g (Figure 1) was synthesized and evaluated in
the reaction of a-ketophosphonate 3a with nitromethane
using THF as the solvent at 08C (Table 1). The l-pipecolic
acid derivative 1b with a (R,R)-1,2-diphenylethylenediamine
backbone was superior to l-proline-derived 1a and gave the
desired product 4a in 54% yield with 56% ee (Table 1,
entry 4 vs 3). Only 11% ee were obtained using (R,R)-1,2-
diaminocyclohexane as chiral diamine backbone (Table 1,
entry 5). Moreover, for the achiral ethylenediamine 1d
backbone, rather poor results were obtained (10% yield and
9% ee; Table 1, entry 6), which suggested that the chiral di-
amine backbone moiety is of great importance. Trace
amounts of product with low enantioselectivity (35%) were
obtained when two nitrogen hydrogen atoms of the piperi-
dine moiety in catalyst 1b were replaced by methyl groups
(Table 1, entry 7). Furthermore, only 28% ee were obtained
with 1 f derived from (S,S)-1,2-diphenylethylenediamine and
l-pipecolic acid (Table 1, entry 8 vs 4), indicating that
matched chirality between diamine and piperidine was very
important for the high catalytic efficiency. When mono-
amide 1g was synthesized to catalyze this reaction, mostly
racemic product was obtained (Table 1, entry 9 vs 4), which
implied that the cooperation of the C2-symmetric two amino
[a] X. Chen, J. Wang, Y. Zhu, D. Shang, Dr. B. Gao, Dr. X. Liu,
Prof. Dr. X. Feng, Dr. Z. Su, Prof. Dr. C. Hu
Key Laboratory of Green Chemistry & Technology
Ministry of Education, College of Chemistry, Sichuan University
Fax : (+86)28-8541-8249
E-mail: xmfeng@scu.edu.cn
[b] Prof. Dr. X. Feng
State Key Laboratory of Oral Diseases
Sichuan University
Chengdu 610041 (P. R. China)
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.200801958.
10896
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Chem. Eur. J. 2008, 14, 10896 – 10899

COMMUNICATION
Table 1. Optimization of reaction conditions.
Table 2. Phenols screened in this reaction.
[b]
Entry[a]
Additive
pKa
Yield [%][c]
ee [%][d]
1
2
3
4
phenol (2a)
9.9
64
76
83
88
82
88
96
80
4-nitrophenol (2b)
2,4-dinitrophenol (2c)
2,4,6-trinitrophenol (2d)
7.14
4.01
1.02
Entry[a] X ([mol%])
Solvent [mL] T [8C] Yield [%][h] ee [%][i]
[a] Unless noted otherwise, the reactions were carried out with 0.1 mmol
a-ketophosphonate 3a, 0.3 mL nitromethane, 5 mol% 1b, 6 mol% addi-
tive and 1.8 mL tBuOMe/PhOMe (2/1) at À208C for 80 h. [b] Relative
1
2
3
4
5
6
7
8
Et2NH (10)
piperidine (10) 0.1
0.1
0
0
0
0
0
0
0
0
0
0
0
0
À20
À20
À20
À20
76
80
40
54
43
10
trace
56
72
47
64
68
54
52
38
66
0
0
1a (10)
1b (10)
1c (10)
1d (10)
1e (10)
1 f (10)
1g (10)
1b (10)
1b (10)
1b (10)
1b (10)
1b (5)
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
1.8
1.8
11
56
11
9
35
28
5
66
60
63
65
66
78
84
[10]
pKa in water. [c] Isolated yield. [d] Determined by chiral HPLC.
Table 3. Substrate scope for the enantioselective nitroaldol reaction of a-
ketophosphonates with nitromethane.
9
10[b]
11[c]
12[d]
13[d,e]
14[d,e]
15[d,f]
16[d,f,g]
Entry[a]
1
R1
R2
Product
Yield [%][b,c]
86
ee [%][d]
1b (5)
1b (5)
Me
4a
94
2
3
4
5
Et
iPr
Et
4b
4c
4d
4e
83
73
88
90
96
92
99
99
[a] Unless noted otherwise, the reactions were carried out with 3a
(0.1 mmol), nitromethane (0.1 mL), 10 mol% catalyst in THF at 08C for
24 h. [b] tBuOMe as solvent. [c] PhOMe as solvent. [d] tBuOMe/PhOMe
(2/1) as solvent. [e] The reaction time was 48 h. [f] The reaction time was
80 h. [g] 0.3 mL nitromethane was used. [h] Isolated yield. [i] Determined
by chiral HPLC.
Me
6
7
Et
Me
4 f
4g
93
90
96(R)[e]
97
8
Et
4h
92
91
amide units played a crucial role for the asymmetric induc-
tion.
A solvent survey revealed that tBuOMe showed higher ee
while PhOMe provided higher yield (Table 1, entries 10–11).
9
10
Et
Me
4i
4j
73
76
98
92
11
12
Et
Me
4k
4l
67
68
95
93
13
14
Et
Me
4m
4n
85
78
97
92
15
16
Et
Me
4o
4p
88
86
91
90
17
18
Et
Me
4q
4r
80
81
91
90
19
20
Et
Me
4s
4t
81
83
96
93
21
22
Et
Me
4u
4v
66
73
84
86
Figure 1. Catalysts evaluated in this study.
23
24
Et
Et
4w
4x
54
95
88
99
The best result could be obtained in a 2:1 mixture of
tBuOMe and PhOMe (68% yield and 63% ee; Table 1,
entry 12).[9] When the temperature was decreased to À208C,
the enantioselectivity was slightly increased to 65% ee
(Table 1, entry 13). Furthermore, the catalyst loading could
be reduced to 5 mol% without affecting the enantioselectiv-
ity (Table 1, entry 14). When the concentration of the sub-
strate was decreased, the enantioselectivity was dramatically
improved to 78% ee but the reactivity was further reduced
(Table 1, entry 15). Fortunately, when the amount of nitro-
methane was increased, the reactivity and enantioselectivity
25
26
Et
Me
4y
4z
90
90
91
84
[a] Unless noted otherwise, the reactions were carried out with 0.1 mmol
a-ketophosphonate 3, 0.3 mL nitromethane, 5 mol% 1b, 6 mol% 2c and
1.8 mL tBuOMe/PhOMe (2/1) at À208C for 1–4.5 days. [b] Isolated yield.
[c] For detailed reaction time, see Supporting Information. [d] Deter-
mined by chiral HPLC. [e] Determined by X-ray diffraction analysis.[11]
were greatly improved (66% yield and 84% ee; Table 1,
entry 16).
Chem. Eur. J. 2008, 14, 10896 – 10899
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X. Feng, C. Hu et al.
To further optimize the results, some achiral additives
were screened. Phenols were found to be positive effect to
the reaction (for details, see Supporting Information). When
2,4-dinitrophenol (2c) was used as additive, both the yield
and enantioselectivity were improved drastically (83% yield
and 96% ee; Table 2, entry 3). The slightly less acidic
phenol (2a) or 4-nitrophenol (2b) gave lower yields and ee
which elongates the carbonyl bond of the substrate in TS1
(1.287 vs 1.285 ꢂ).[9] A hydrogen bond is observed between
the phosphorus oxygen and the amide moiety in TS1, which
greatly contributes to the stability of the transition state.
Therefore, TS1 is evidently the favorable transition state
which leads to the formation of major R product, which is in
accordance with the experimental results.
(Table 2, entries 1,
2 vs 3),
while the stronger acidic 2,4,6-
trinitrophenol (2d) exhibited
high reactivity and low enantio-
selectivity (80% ee; Table 2,
entry 4 vs 3). Extensive screen-
ing showed that the optimal re-
action conditions were 5 mol%
organocatalyst 1b, 0.1 mmol a-
ketophosphonate 3a, 0.3 mL ni-
tromethane in 1.8 mL tert-butyl
methyl ether together with ani-
sole (2:1 ratio), 6 mol% 2c as
additive at À208C. Additional-
ly, this process was tolerant to
air and moisture.
Under the optimized reaction
conditions, a wide range of a-
ketophosphonates were investi-
gated (Table 3). Aryl-substitut-
ed a-ketophosphonates with
Figure 2. The calculated transition state of Henry reaction of para-chlorophenyl a-ketophosphonate 3 f with ni-
tromethane catalyzed by 1b–2c. The geometries were optimized at the level of HF/3-21g*. The relative ener-
gies [kcalmolÀ1] are with HF/3-21 g* in brackets. TS1 favored (R)-product, TS2 favored (S)-product.
varying ester alkyl groups, such as Me, Et and iPr, were
found to be tolerable in this reaction and good results were
obtained (Table 3, entries 1–3). Also, benzoylphosphonates
with different substituents on the aromatic ring could give
the desired nitroaldol products in good to excellent results.
Substrates with either electron-donating, such as methyl,
methoxyl and tert-butyl substituents or electron-withdrawing
including halogen substituents, reacted smoothly with nitro-
methane to give moderate to high yields with excellent
enantioselectivities (Table 3, entries 4–20). Moreover, the
disubstituted aromatic, heteroaromatic and aliphatic a-keto-
phosphonates could also be converted to the desired prod-
ucts with good to excellent enantioselectivities (Table 3, en-
tries 21–26). In addition, the absolute configuration of prod-
uct 4 f was determined to be R through X-ray diffraction
analysis.[11]
A preliminary study on the mechanism of this direct ni-
troaldol reaction of a-ketophosphonate has been investigat-
ed by theoretical calculations. As shown in Figure 2 for the
two transition states, one of the piperidine moiety is proton-
ated by the acidic additive 2c, which activates the a-keto-
phosphonate via hydrogen bonding; the other deprotonates
the hydrogen atom from nitromethane to protonate itself,
which stabilizes the nitromethide by an intermolecular hy-
drogen bond.[12] According to the computational results, the
energy of TS1 is lower than that of TS2 by ꢀ3.7 kcalmolÀ1.
Furthermore, the hydrogen bond between the carbonyl
group of the substrate and the piperidine moiety of the cata-
lyst 1b in TS1 is shorter than that in TS2 (1.588 vs 1.791 ꢂ),
In conclusion, we have developed an efficient secondary
amine amide catalyst system for the asymmetric nitroaldol
reaction of a-ketophosphonates under mild conditions. In
the presence of 5 mol% organocatalyst 1b, excellent enan-
tioselectivities (up to 99% ee) and moderate to high yields
were achieved for most substrates. Additionally, a theoreti-
cal study on the transition states revealed that this secon-
dary amine amide catalyst could be involved in hydrogen-
bond interactions, which is important for the reactivity and
enantioselectivity of this reaction.
Experimental Section
Typical experimental procedure: A solution of catalyst 1b (2.17 mg, 5
mol%) and nitromethane (0.3 mL) in tBuOMe and PhOMe (1.8 mL, 2:1
ratio) was stirred for 10 min at ambient temperature. After it was cooled
to À208C, a-ketophosphonate 3a (24 mL, 0.1 mmol) and 2c (1.2 mg,
6 mol%) were added successively. The mixture was stirred at À208C for
80 h and quenched with satd. NH4Cl (2 mL). The aqueous layer was ex-
tracted with ethyl acetate (10 mLꢃ2). The combined organic layers were
washed with satd. NaHCO3, brine, dried over anhydrous Na2SO4, and
concentrated in vacuo. The crude product was purified by flash chroma-
tography by using EtOAc/PE to afford 4a as a white solid.
Acknowledgements
We appreciate the National Natural Science Foundation of China (Nos.
20732003 and 20702033) and the Ministry of Education (No.
10898
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Asymmetric Nitroaldol Reactions
COMMUNICATION
20070610019) for financial support. We also thank Sichuan University
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Keywords: aldol reaction
reaction · organocatalysis
· amides · amines · Henry
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Received: September 22, 2008
Published online: November 6, 2008
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10899