Highly enantioselective henry reactions in water catalyzed by a copper tertiary amine complex and applied in the synthesis of (S)-N-trans-feruloyl octopamine

Article abstract of DOI:10.1002/chem.201002915

It's in the water! A new copper tertiary amine complex was prepared and applied in asymmetric Henry reactions in water and in the short synthesis of (S)-N-trans-feruloyl octopamine. This catalytic system provided an approach to the enantioselective Henry reaction of aldehydes with hydroxyl substituents (see graphic).

Full text of DOI:10.1002/chem.201002915

DOI: 10.1002/chem.201002915
Highly Enantioselective Henry Reactions in Water Catalyzed by a Copper
Tertiary Amine Complex and Applied in the Synthesis of (S)-N-trans-
FerulACTHNURTGNEUoGN yl Octopamine
Guoyin Lai, Fengfeng Guo, Yueqin Zheng, Yang Fang, Haigang Song, Kun Xu,
Sujing Wang, Zhenggen Zha,* and Zhiyong Wang*[a]
Water, known as a safe, harmless, cheap, and environmen-
tally benign solvent, has attracted continuous attention in
the field of organic synthesis.[1] In addition to the potential
advantages of replacing organic solvents, water shows spe-
cial properties as the reaction medium. Synthetic aqueous
chemistry may help us to understand details of some biolog-
ical phenomena.[1b,g] Development of aqueous asymmetric
reactions could avoid tedious procedures of removing water
from reactions carried out in organic solvents. Moreover,
some special substrates, such as compounds commercially
available as aqueous solutions or proton-containing com-
pounds, may react smoothly in aqueous media.[1b] Many
obtained in good yields and enantiomeric excess (ee).[3] En-
zymatic catalysis has been employed for Henry reactions.
These reactions were catalyzed by hydroxynitrile lyase in a
biphasic aqueous system and the desired products were ob-
tained with moderate yields and ee values.[4] Despite these
impressive contributions, reports on the use of aldehydes as
substrates are limited and the enantioselectivities still need
to be improved. Therefore, the development of new, more
efficient, and environmentally benign catalysts for the afore-
mentioned reaction in water is still desired and challenging.
We have been focusing on investigating aqueous organic re-
actions.[5] The asymmetric reaction in water is one of our
main aims. Previously, we have reported an asymmetric
Henry reaction catalyzed by copper Schiff base 1.[2m] Herein,
we developed a highly enantioselective Lewis acid catalyzed
nitroaldol reaction with water as the solvent. Excellent
yields (99%) and ee values (99%) were achieved for a wide
range of aldehydes.
Considering the broad application of proline derivates in
aqueous aldol reactions[1e,6] and based on ligand 1, we de-
signed proline derivates 2a–2c, which were used in the
asymmetric Henry reaction in water (Scheme 1). With li-
gands 2a–2c in hand, the addition of nitromethane 4 to ben-
zaldehyde 3a in water was chosen as a model reaction. Ini-
tially, copper acetate was employed as the Lewis acid to co-
ordinate in situ with ligands 2a, 2b, and 2c and afford the
corresponding catalysts. As shown in Table 1, ligand 2c was
prominent in providing nitroalcohol 5a in 51% yield and
À
challenges remain in catalytic asymmetric C C bond forma-
tion in water, especially for asymmetric transition-metal cat-
alysis, although considerable progress has been made in this
area.[1f]
Enantioselective Henry reactions have been extensively
À
studied since 1992 due to the importance of C C bond for-
mation.[2a] Although several Lewis acid complexes and orga-
nocatalysts have exhibited high activities and stereoselectivi-
ties for these transformations,[2–4] successful examples in
water are quite limited. Recently, the bifunctional guani-
dine–thiourea catalyst was reported in a biphasic system of
water and toluene in which the corresponding products were
[a] G. Lai, F. Guo, Y. Zheng, Y. Fang, H. Song, K. Xu, Dr. S. Wang,
Dr. Z. Zha, Prof. Dr. Z. Wang
Hefei National Laboratory for Physical Sciences at Microscale
CAS Key Laboratory of Soft Matter Chemistry
and Department of Chemistry
University of Science and Technology of China, Hefei
Anhui, 230026 (P.R. China)
Fax : (+86)551-3603185
E-mail: zgzha@ustc.edu.cn
zwang3@ustc.edu.cn
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201002915.
Scheme 1. Structures of the ligands used in this study. Bn=benzyl.
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COMMUNICATION
Table 1. Optimization of reaction conditions.[a]
Table 2. Asymmetric Henry reactions of nitromethane with various alde-
hydes.[a]
Yield[b] [%]
ee[c] [%]
Entry
Ligand
PTC[b]
X
t [h]
Yield[c] [%]
ee[d] [%]
Entry
R
3
5
t [h]
1
2
3
4
5
6
7
8
2a
2b
2c
2c
2c
2c
2c
2c
2c
2c
2c
2c
2c
2c
2c
none
none
OAc
OAc
OAc
OAc
OAc
OAc
OTf[j]
Cl
NO3
Br
Br
Br
Br
36
36
36
36
36
36
36
36
36
36
12
12
12
12
24
23
35
51
42
41
60
37
56
40
61
97
96
99
96
97
12
69
76
80
58
81
75
90
90
93
82
80
90
92
98
1
2
3
4
5
6
7
8
C6H5
3a
3b
3c
3d
3e
3 f
3g
3h
3i
5a
5b
5c
5d
5e
5 f
5g
5h
5i
24
12
12
12
12
24
36
24
36
48
48
48
48
48
48
48
48
48
48
72
72
48
48
97
99
98
98
96
94
87
89
89
87
86
87
83
88
93
85
82
85
87
81
87
84
95
98
95
94
96
98
97
99
98
98
98
98
99
95
92
96
98
91
92
93
94
97
97
95
4-NO2C6H4
3-NO2C6H4
2-NO2C6H4
4-ClC6H4
3-ClC6H4
2-ClC6H4
4-BrC6H4
2-BrC6H4
4-MeC6H4
3-MeC6H4
2-MeC6H4
4-MeOC6H4
3-MeOC6H4
2-MeOC6H4
1-naphthyl
2-furyl
none
PVP[j]
SDS[j]
Bu4NBr
Bu4NBr
Bu4NBr
Bu4NBr
Bu4NBr
Bu4NBr
Bu4NBr
Bu4NBr
Bu4NBr
Bu4NBr
9
10
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
3j
5j
11[e]
12[f]
13[g]
14[g,h]
15[g,h,i]]
3k
3 L
3m
3n
3o
3p
3q
3r
3 s
3t
3u
3v
3w
5k
5 L
5m
5n
5o
5p
5q
5r
5 s
5t
5u
5v
5w
Br
Br
[a] Reactions were carried out with 3a (0.25 mmol), 2 (10 mol%), and
CuX2, nitromethane (10 equiv), and water (1 mL) at 258C unless other-
wise noted. [b] 10 mol%. [c] Isolated yield. [d] Determined by chiral
HPLC. [e] Na2CO3 (10 mol%) was added. [f] K2CO3 (10 mol%) was
added. [g] Cs2CO3 (10 mol%) was added. [h] 4-tert-butylphenol
(10 mol%) was added. [i] Reaction performed at 08C. [j] Some abbrevia-
tions: PVP=polyvinyl pyrrolidone, SDS=sodium dodecyl sulfate, and
OTf=triflate.
Ph
ACHTUGNTERN(NUNG CH2)2
Cy
iPr
iBu
(E)-cinnamyl
pentyl
[a] Reactions were carried out with aldehyde (0.25 mmol) and nitrome-
thane (10 equiv), water (1 mL), 2c (10 mol%), CuBr2, Cs2CO3, 4-tert-bu-
tylphenol, and Bu4NBr at 08C. [b] Isolated yield. [c] Determined by
chiral HPLC.
76% ee (compare entries 1–3 in Table 1). Various phase-
transfer catalysts (PTCs) were then tested (Table 1, en-
tries 4–6) because this reaction was performed in water.
From this survey, Bu4NBr emerged as a promising PTC can-
didate (Table 1, entry 6). Afterwards, different copper salts
were tested to see if the counterions of the copper ion have
any influence on the reaction. As expected, the counterions
affected the enantioselectivity remarkably (Table 1, en-
tries 6–10). Among the copper salts, CuBr2 proved to be the
best choice, providing 5a in 93% ee (Table 1, entry 10).
However, the reaction yield was low (61%) in spite of the
selectivity. Different carbonates were then employed to ac-
celerate the reactions (Table 1, entries 11–13). It was found
that Cs2CO3 was the best base to give the corresponding
product with an excellent yield of 99% and only a slightly
decreased ee value (Table 1, entry 13). To increase the ee
value, 4-tert-butylphenol was added to the reaction mixture
as an achiral ligand.[2t] As a result, the ee value was en-
hanced to 92% with a slightly decreased yield to 96%
(Table 1, entry 14). Finally, the reaction temperature was op-
timized. Good results were obtained at 08C with a reaction
time of 24 h; this afforded 5a in 97% yield and 98% ee
(Table 1, entry 15). Therefore, the optimal reaction condi-
tions were as follows: CuBr2 as the Lewis acid, 2c as the
chiral ligand, Bu4NBr as the PTC, Cs2CO3 as the base, 4-
tert-butylphenol as an additive, water as the solvent, and the
reaction was carried out at 08C.
ety of aldehydes were employed as substrates in this reac-
tion to afford the corresponding nitroaldol products in high
yields and excellent enantioselectivities; above 95% ee in
most cases. Although aromatic aldehydes with ortho sub-
stituents (Table 2, entries 4, 7, 9, 12, and 15) showed slightly
better enantioselectivity than those with para (Table 2, en-
tries 2, 5, 8, 10, and 13) or meta substituents (Table 2, en-
tries 3, 6, 11, and 14), the steric hindrance and electronic
nature of the aromatic ring had little influence on the enan-
tioselectivities (Table 2, entries 1–17). When 3p, with a
naphthyl substituent, was employed as a substrate the reac-
tion ran smoothly to give 5p with 98% ee (Table 2,
entry 16). The heteroaromatic aldehyde 3q gave the corre-
sponding product with excellent yield and ee (Table 2,
entry 17). The reaction could be performed with branched
aliphatic compounds or unbranched aldehydes with 92–
97% ee (Table 2, entries 18–23). Among them, the a,b-unsa-
turated aldehyde 3v was also an acceptable substrate, exclu-
sively giving the 1,2-addition product 5v in 84% yield and
97% ee (Table 2, entry 22). Large-scale reactions with low
catalyst loading (1 mol%) were tested. For example, the re-
action with 3o was carried out on a 6 mmol scale with
1 mol% of catalyst loading in H2O (5 mL). After the reac-
tion was performed, at 08C for 120 h, product 5o was isolat-
ed in good yield (1.06 g, 90% yield) with 98% ee. These re-
Under the optimal conditions, the generality of the reac-
tion substrates was investigated. As shown in Table 2, a vari-
Chem. Eur. J. 2011, 17, 1114 – 1117
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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1115

Z. Zha, Z. Wang et al.
sults clearly indicated that this protocol has a broad general-
ity in this enantioselective Henry reaction.
This method also showed the following additional special
advantages:
1) The ligand, a tertiary amine, could easily be recovered in
high yields by a simple treatment with dilute HCl/satu-
rated NaHCO3 and was then recycled.[7]
2) Acetaldehyde (commercially available as a 40% solution
in water) reacted smoothly with nitromethane with satis-
fying results (Scheme 2a).
Scheme 3. Synthesis of (S)-N-trans-feruloyl octopamine (6). Reagents
and conditions: a) 3aa (2 mmol) and nitromethane (10 equiv), water
(10 mL), 2c (5 mol%), CuBr2, Cs2CO3, 4-tert-butylphenol, and Bu4NBr;
08C, 144 h; 63% yield, and 94% ee; b) 1) Pd/C (10%), H2, THF;
2) ferulic acid (8), Et3N, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide
(EDCI), 1-hydroxybenzotriazole (HOBt), and THF.
tion substrates, simple manipulation, mild reaction condi-
tions, and excellent reaction efficiency prove the potential
industrial use of this reaction. Further studies on other cata-
lytic asymmetric reactions in water catalyzed by 2c are in
progress in our group.
Scheme 2. Application of this catalytic system to some special substrates.
Reagents and reaction conditions: a) aldehyde (0.25 mmol), nitro-
ACHTUNGTRENNUNGmethane (10 equiv), water (1 mL); 2c (10 mol%), CuBr2, Cs2CO3, 4-tert-
butylphenol, and Bu4NBr; 08C, 72 h.
3) Aldehydes with hydroxyl groups could be used to avoid
protecting and deprotecting steps (Schemes 2 and 3).[1b,f]
4) 4-Hydroxyaldehyde (3aa) was directly used as the start-
ing material for the synthesis of (S)-N-trans-feruloyl oc-
topamine (6).
Experimental Section
Nitromethane (2.5 mmol) was added to
a mixture of ligand 2c
(0.025 mmol), CuBr2 (0.025 mmol), Cs2CO3 (0.025 mmol), 4-tert-butylphe-
nol (0.025 mmol), and Bu4NBr (0.025 mmol) at room temperature. The
mixture was allowed to stir for 1 h and water (1 mL) was added. The re-
sulting mixture was stirred for another hour and then cooled to 08C for
1 h before 3a (26.5 mg, 0.25 mmol) was added. After 24 h the mixture
was quenched with dilute HCl (0.5 mL, 1m) and then extracted with
ethyl acetate (3ꢁ2 mL). The organic phase was washed with saturated
NaHCO3 and brine, dried with Na2SO4, and evaporated in vacuo. Purifi-
cation of the residue by column chromatography afforded the desired
Henry product 5a (40.5 mg) in 97% yield. The ee value was determined
by HPLC on a chiralcel OD-H column (98% ee). Saturated NaHCO3
was added dropwise to the combined aqueous phase until pH 8 was
reached. The mixture was extracted with EtOAc (3ꢁ2 mL). The organic
layer was dried over Na2SO4 and evaporated in vacuo. The residue was
purified by flash column chromatography (EtOAc/petroleum ether 1:6
v/v) to afford the pure ligand 2c (8.9 mg, 84% recovered).
Compound 6 is a useful natural product.[8] Recently, it
was proven to be much more potent in inducing the death
of the cancerous white blood cells than the enantiomer (R)-
N-trans-feruloyl ocptopamine.[9] We attempted to utilize our
catalytic system to synthesize 6 without any protecting or
deprotecting steps (Scheme 3).
As shown in Scheme 3, compound (S)-5aa (63% yield,
94% ee), obtained from the Henry reaction between 4-hy-
droxybenzaldehyde (3aa; 2 mmol scale) and nitromethane,
was readily converted to the intermediate (S)-octopamine
(7) by catalytic hydrogenation. Subsequent amidation of 7
and ferulic acid (8) gave product 6 with 90% ee. The overall
yield of these hydrogenation and amidation steps was 64%.
In conclusion, we have developed a Lewis acid catalyzed
asymmetric Henry reaction in water. Synthetically valuable
b-nitroalcohols were obtained in good yields and with high
ee values. Furthermore, acetaldehyde (commercially avail-
able as an aqueous solution) and hydroxyl-substituted alde-
hydes could also be suitable substrates. The utilities of this
reaction were demonstrated in the synthesis of (S)-N-trans-
feruloyl octopamine (6). The broad generality of the reac-
Acknowledgements
We are grateful to the National Nature Science Foundation of China
(20932002, 20972144, 90813008, and 20772188).
Keywords: amines
·
anticancer agents
·
asymmetric
synthesis · Henry reactions · water chemistry
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Chem. Eur. J. 2011, 17, 1114 – 1117

Copper-Catalyzed Henry Reactions
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Received: October 9, 2010
Published online: December 14, 2010
Chem. Eur. J. 2011, 17, 1114 – 1117
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