Copper complex of aminoisoborneol schiff base Cu2(SBAIB-d) 2: An efficient catalyst for direct catalytic asymmetric nitroaldol (henry) reaction

Article abstract of DOI:10.1002/adsc.201200337

A new bifunctional copper complex of the aminoisoborneol Schiff base - Cu₂(SBAIB-d)₂ - has been developed for the effective direct catalytic asymmetric Henry reaction. One mol% of this catalyst produces the expected Henry products in high yields (up to 99%) with excellent enantioselectivities (up to 98% ee). The utility of the present catalyst was also extended to the Henry reaction with nitroethane and 1-nitropropane that furnished the corresponding products in moderate to high yields (up to 99%) with moderate to high enantioselectivities of syn (up to 98% ee) and anti (up to 98% ee) diastereomers. The highlights of this catalytic system are easy manipulation, air and moisture tolerance, the need for 1 mol% of an easily synthesizable catalyst and the high enantioselectivities achieved for a wide range of substrates. Copyright

Full text of DOI:10.1002/adsc.201200337

FULL PAPERS
DOI: 10.1002/adsc.201200337
Copper Complex of Aminoisoborneol Schiff Base
Cu2A(SBAIB-d)2: An Efficient Catalyst for Direct Catalytic
Asymmetric Nitroaldol (Henry) Reaction
CHTUNGTRENNUNG
Ramalingam Boobalan,a Gene-Hsian Lee,b and Chinpiao Chena,*
a
Department of Chemistry, National Dong Hwa University, Soufeng, Hualien 974, Taiwan, Republic of China
Fax : (+886)-3-836-0475; e-mail: chinpiao@mail.ndhu.edu.tw
Instrumentation Center, College of Science, National Taiwan University, Taipei 106, Taiwan, Republic of China
b
Received: April 20, 2012; Published online: && &&, 0000
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201200337.
Abstract: A new bifunctional copper complex of the syn (up to 98% ee) and anti (up to 98% ee) diaste-
aminoisoborneol Schiff base – Cu2ACTHNUTRGEN(UNG SBAIB-d)2 – has reomers. The highlights of this catalytic system are
been developed for the effective direct catalytic easy manipulation, air and moisture tolerance, the
asymmetric Henry reaction. One mol% of this cata- need for 1 mol% of an easily synthesizable catalyst
lyst produces the expected Henry products in high and the high enantioselectivities achieved for a wide
yields (up to 99%) with excellent enantioselectivities range of substrates.
(up to 98% ee). The utility of the present catalyst
was also extended to the Henry reaction with nitro-
ethane and 1-nitropropane that furnished the corre- Keywords: asymmetric catalysis; copper(II) com-
sponding products in moderate to high yields (up to plexes; enantioselectivity; Henry reaction; Schiff
99%) with moderate to high enantioselectivities of bases
Introduction
synthesis,[11] their applications in the Henry reaction
have not attracted considerable attention because of
The direct nitroaldol (Henry) reaction is one of the the formation of nitroaldol products in moderate to
À
most renowned C C bond formation reactions in the good ee. Figure 1 shows the structures of various salen
organic synthesis. The resultant bifunctional b-hydrox- and Schiff base ligands and their metal complexes
ynitroalkane product is a highly versatile synthon for used in the Henry reaction.
the synthesis of numerous functionally varying com-
Among Wangꢀs b-amino alcohol Schiff base-Cu
pounds such as 1,2-amino alcohols, a-hydroxy ke- complexes 1–4,[12a,c] the 2.5 mol% of complex 4[12c]
tones, a-amino ketones, a-hydroxycarboxylic acid and showed moderate to good ee in EtOH. Pedroꢀs N,N-li-
various pharmaceuticals.[1] Since Shibasakiꢀs asymmet- gands Schiff bases,[3i] and iminopyridines 5 and 6 were
ric variant of this reaction,[2] numerous efforts have the most promising ligand with Cu
ACHTUNTRGENUNG(OAc)2·2H2O at
been devoted to the development of a catalytic asym- À658C using 11 mol%, however, only a maximum of
metric Henry reaction by various metal catalysts in- 85% chiral induction was achieved. The bisthiophene
cluding copper,[3] zinc,[4] chromium,[5] cobalt,[6] bimetal Schiff base 7 was reported to give a mere 17% ee in
catalysts,[7] rare-earth metals,[8] with structurally vary- this reaction.[3j] The Cu(I) complex of phosphine-
ing chiral ligands, organocatalysts[9] as well as by bio- Schiff base ligand 8 also yielded the corresponding
catalysts.[10] In terms of chiral ligands, Shibasakiꢀs product with only 80% ee.[12b] Other Schiff bases 9,[12d]
BINOL complex,[2] Evansꢀ BOX complex,[3b] Pedroꢀs 11,[12e] and 12[12g] were found to be inefficient ligands
N,N-ligand (especially aminopyridine),[1d] Lanꢀs bisi- for the Henry reaction. Although the recently report-
midazoline,[3q]
Wanꢀs
bissulfonamide-diamine,[3r] ed chiral Cu(II) complex of paracyclopane Schiff base
Wangꢀs recently reported tertiary amino alcohol,[3u] 10 has shown good ee,[12f] its substrate scope was limit-
and Trostꢀs dinuclear zinc-amino alcohol[4a] are some ed only to 2-nitrobenzaldehye. Interestingly, amino or
of the most successful ligands for the Henry reaction. diamino compounds, formed by reduction of these
Although salen and Schiff base ligands are considered Schiff bases, became excellent catalysts for the Henry
as one of the most privileged ligands in asymmetric reaction; for example, Pedroꢀs N,N-diamine (amino-
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Figure 1. The structure of Schiff bases, salen ligands and its metal complexes used in the asymmetric Henry reaction.
pyridine) ligand[1d] and the recently reported[3u] triden- catalyst results in breakthrough in prolonged failures
tate proline alcohol ligand. Compared to Schiff bases, and circumvents the limitations. Herein, this study de-
various metal complexes (Co,[6] Cr,[5] Cu[3g,7b]) of salen scribes a practically very simple, highly efficient asym-
ligands 13–17 showed enhanced chiral induction; metric Henry reaction by using bifunctional Cu2
however, they did have limitations such as absence of
a strong chiral induction for m- and p-substituted ben-
zaldehydes, demand for an inert atmosphere, and
ACHTUNGTERN(NUNG SBAIB)2 for numerous aldehydes and nitroalkanes.
a low reaction temperature. The development of Results and Discussion
highly efficient and simple asymmetric catalysts is one
of our goals.[13] With our present state of understand- Preparation of Copper Complex Cu
ing, we envisioned that the bifunctional copper com-
2ACHTUNGTNER(NUNG SBAIB)2
plex of Schiff bases of aminoisoborneol [Cu2 Considering the wide application of copper metal in
(SBAIB)2] (Scheme 1) would overcome this pro- the Henry reaction, we synthesized seven copper
ACHTUNGTRENNUNG
longed inefficiency of Schiff base ligands for the complexes 18–24 from camphor-based ligands. The
Henry reaction. The strong steric hindrance in the Schiff bases of aminoisoborneol [SBAIB] 18a–24a
exo-aminoisoborneol backbone is considered to play were prepared as shown in Scheme 1. These
a pivotal role for high chiral induction, in contrast to (+)-SBAIB ligands can be prepared easily from (1R)-
most of the reported b-amino alcohol Schiff bases camphor in high yields, among these (+)-SBAIB-
that do not possess such a huge steric hindrance when a 18a showed a good to excellent chiral induction in
forming metal complexes.
the asymmetric phenylacetylene addition reaction to
Although many catalytic systems have been devel- various aldehydes.[13c] The proposed structure of these
oped for the Henry reaction, many still have draw- complexes was verified by the X-ray crystal structure
backs such as the need of high catalyst loading, low of Cu2[(+)-SBAIB-d]2 21 (Figure 2).
reaction temperature, inert atmosphere to achieve
high enantioselectivity, and, the limitation in the sub-
strate scope of aldehydes as well as nitroalkanes other
than nitromethane. Therefore, always finding a new
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Copper Complex of Aminoisoborneol Schiff Base Cu2ACTHNUTRGEN(UNG SBAIB-d)2: An Efficient Catalyst
Scheme 1. Synthesis of copper complex of Schiff base ligands (SBAIB).
conditions. Various solvents were screened for this re-
action with 2.5 mol% 21 (Table 1, entries 8–14).
Among these solvents tert-butyl alcohol emerged as
a promising solvent resulting in high yield (97%) and
ee (86%) in 36 h reaction time. Then the higher
mol% of catalyst 21 was tested and we found that
there was no improvement for yield and ee of 2-nitro-
1-(4-nitrophenyl)ethanol 25 (Table 1, entries 15–17).
An immediate addition of aldehyde to the catalytic
system has only afforded a lower yield and ee
(Table 1, entry 18) in 36 h. When the amount of
MeNO2 was increased to 20 volumes (with respect to
aldehyde 25a) with t-BuOH (20 volumes), a higher ee
(91%) with the yield of 97% was obtained (Table 1,
entry 21), conversely, when it was decreased from 10
equivalents, lower ees were observed (Table 1, en-
tries 19 and 20). To enhance the enantioselectivity,
the 20:20 volume ratio of MeNO2 and t-BuOH was
changed into 10:30, 30:10, and 40:0. However, the re-
sults (Table 1, entries 22–24) showed lower ee com-
pared to the 20:20 solvent volume ratio result.
Figure 2. X-ray crystal structure of Cu2ACTHNUGTRNEU(GN SBAIB-d)2, 21
[CCDC 865431; these data can be obtained free of charge
from The Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif].
The mol% of ligand 21 was decreased to study any
amplification in ee (Table 1, entries 25 and 26). As ex-
pected, both 1 mol% as well as 0.5 mol% 21 yielded
the best results (93% ee), better than any of the earli-
Optimization of the Reaction Conditions
With the seven Cu complexes 18–24 in hand, the opti- er conditions with ligand 21, however, the reaction
mization of the Henry reaction was started with 4-ni- time for the latter was long (Table 1 entry 26). Then
trobenzaldehyde 25a and nitromethane in ethanol the reaction temperature was optimized, a lower ee
with 2.5 mol% of the Cu complex. Cu2ACTHNUTRGENUN(G SBAIB-d)2 21 was resulted for both higher and lower temperatures
was found to be the best catalyst among the seven Cu (Table 1, 27 and 28). Finally the total volume of the
complexes (Table 1, entries 1–7). The reaction was reaction solvent (40 volumes) was decreased to 20
carried out by addition of aldehyde 25a to the 3 h volumes (10:10 MeNO2/t-BuOH) (Table 1, entry 29),
pre-stirred mixture of Cu complex and nitromethane also the reaction with the achiral base additive trie-
in ethanol at room temperature under atmospheric thylamine (5 mol%) (Table 1, entry 30) was studied,
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Table 1. Catalyst screening and optimization.[a]
Entry
Ligand [mol%]
MeNO2 [equiv.][b]
Solvent [vol][c]
Temp. [8C]
Time [h]
Yield [%][d]
ee [%][e]
1
2
3
4
5
6
7
8
18 (2.5)
19 (2.5)
20 (2.5)
21 (2.5)
22 (2.5)
23 (2.5)
24 (2.5)
21 (2.5)
21 (2.5)
21 (2.5)
21 (2.5)
21 (2.5)
21 (2.5)
21 (2.5)
21 (5)
21 (10)
21 (20)
21 (2.5)[f]
21 (2.5)
21 (2.5)
21 (2.5)
21 (2.5)
21 (2.5)
21 (2.5)
21 (1)
10
10
10
10
10
10
10
10
10
10
10
10
10
10
10
10
EtOH (40)
EtOH (40)
EtOH (40)
EtOH (40)
EtOH (40)
EtOH (40)
EtOH (40)
MeOH (40)
i-PrOH (40)
t-BuOH (40)
THF (40)
r.t.
r.t.
r.t.
r.t.
rt
36
36
36
36
36
36
36
36
36
36
42
42
42
42
36
36
36
36
36
36
42
40
40
40
40
60
30
76
40
3
99
99
34
48
28
72
43
50
86
97
21
27
trace
trace
50
74
83
80
10
50
98
98
88
37
>99
97
98
57
96
99
13
16
51
62
38
41
45
33
82
86
68
54
NA
NA
78
71
81
81
80
78
91
87
90
79
93
93
90
91
91
2
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
40
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
DCM (40)
ACN (40)
DMF (40)
t-BuOH (40)
t-BuOH (40)
t-BuOH (40)
t-BuOH (40)
t-BuOH (40)
t-BuOH (40)
t-BuOH (20)
t-BuOH (30)
t-BuOH (10)
nil
t-BuOH (20)
t-BuOH (20)
t-BuOH (20)
t-BuOH (20)
t-BuOH (10)
t-BuOH (20)
10
10
1.5
5
20 (vol)
10 (vol)
30 (vol)
40 (vol)
20 (vol)
20 (vol)
20 (vol)
20 (vol)
10 (vol)
20 (vol)
21 (0.5)
21 (1)
21 (1)
10
r.t.
r.t.
21 (1)
21 (1)[g]
[a]
All the reactions were carried out in an 8-mL vial with 50 mg of 25a (1 equiv.) under atmospheric air.
MeNO2 used as purchased without further drying.
All the solvents were used as purchased without further drying.
Yield refers to the chromatographically pure compounds.
The ee was determined by chiral HPLC on Chiralcel OD-H column.
Aldehyde was added immediately to 21 in tBuOH/MeNO2.
5 mol% triethylamine was used as additive.
[b]
[c]
[d]
[e]
[f]
[g]
but the results were not promising, especially with Enantioselective Henry Reaction of Various
triethylamine a mere 2% ee was obtained for the cor- Aldehydes
responding product despite the very short (3 h) reac-
tion time.
The scope of the ligand was then explored under the
Therefore, entry 25 (>99% yield and 93% ee) in optimized condition. The results are shown in Table 2.
Table 1 was chosen as an the optimized conditions Numerous aldehydes were screened, which enabled
and are as follows: an addition of aldehyde 25a to the preparation of the corresponding b-nitro alcohols in
pre-stirred solution of catalyst Cu2[(+)-SBAIB-d]2 21 excellent yield (up to 99%) with very high enantiose-
(1 mol%) in 40 volumes of solvent (20:20 MeNO2/t- lectivity (up to 98%).
BuOH) at room temperature under atmospheric con-
ditions.
The electron-withdrawing and electron-donating
substituents on aromatic aldehydes had a significant
effect on the reaction rate; generally, the former had
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Table 2. Enantioselective Henry reaction of nitromethane with various aldehydes.
Entry
R[a]
Product
Time [h]
Yield [%][b]
ee [%][c]
Sign/Conf.[d]
1
2
3
4
5
6
7
8
4-NO2C6H4 25a
3-NO2C6H4 26a
2-NO2C6H4 27a
4-CH3C6H4 28a
3-CH3C6H4 29a
2-CH3C6H4 30a
4-CH3OC6H4 31a
3-CH3OC6H4 32a
2-CH3OC6H4 33a
4-FC6H4 34a
3-FC6H4 35a
2-FC6H4 36a
4-ClC6H4 37a
3-ClC6H4 38a
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
61
62
63
40
38
37
96
96
80
96
96
85
90
96
90
96
96
86
96
96
84
69
69
96
96
96
96
86
96
96
96
96
96
100
96
96
96
96
96
96
96
96
99
94
99
83
86
96
85
89
96
96
93
98
91
84
97
93
90
98
96
88
93
90
91
89
96
52
76
86
88
69
56
72
42
88
65
86
96
91
86
93
91
97
92
94
92
93
93
93
95
95
97
94
96
98
90
94
98
91
91
91
91
92
89
90
89
88
92
96
93
92
88
90
81
83
77
96
82
76
+/S
+/S
À/S
+/S
+/S
+/S
+/S
+/S
+/S
+/S
+/NA
+/S
+/S
+/S
+/S
+/S
+/S
+/S
+/S
+/NA
+/NA
+/S
+/S
+/S
+/NA
+/NA
+/S
+/S
+/S
+/S
+/S
+/S
À/S
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
2-ClC6H4 39a
4-BrC6H4 40a
3-BrC6H4 41a
2-BrC6H4 42a
4-CNC6H4 43a
3-CNC6H4 44a
4-EtOCOC6H4 45a
Ph 46a
4-t-BuC6H4 47a
4-PhC6H4 48a
2-PhC6H4 49a
4-BnOC6H4 50a
3,5-(CH3O)2C6H3 51a
2-naphthyl 52a
1-naphthyl 53a
furfuryl 54a
2-thiophenyl 55a
E-cinnamyl 56a
a-Me-E-cinnamyl 57a
Me2CHCH2 58a
cyclohexyl 59a
PhCH2 60a
À/S
+/S
À/S
PhCH2CH2 61a
n-heptyl 62a
n-decyl 63a
À/S
+/S
+/S
[a]
All the reactions were carried out in an 8-mL vial with 50 mg of aldehyde (1 equiv.) with 1 mol% 21.
Yield refers to the chromatographically pure compounds.
The ee was determined by chiral HPLC on various chiral columns, see the Supporting Information for more details.
The absolute configuration of the products was determined on the basis of sign of specific rotation and its peaks order in
the chiral HPLC.
[b]
[c]
[d]
a higher reaction rate for this catalytic system. ortho- in high enantioselectivity (Table 2, entries 11, 20, 21,
Substituted aromatic aldehydes exhibited a slightly 25, and 26, respectively) with high yields except for 4-
higher enantioselectivity compared to meta- and para- benzyloxybenzaldehyde (50a), which showed a moder-
substituted benzaldehydes (Table 2, entries 3, 12, 15, ate yield in 96 h. The polycyclic aromatic aldehydes
and 18). New substrates for the Henry reaction such (1- and 2-naphthaldehydes, Table 2, entries 28 and 29)
as 3-fluoro- (35a), 3-cyano- (44a), 3-ethoxycarbonyl- also yielded highly enantioenriched products. Gratify-
(45a), 2-phenyl- (49a) and 4-benzyloxybenzaldehyde ingly, the heteroaromatic aldehydes, furfural (54a)
(50a) also yielded the corresponding Henry products and 2-thiophenecarboxaldehyde (55a), also showed
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Table 3. Enantioselective Henry reaction with 20 mol% water.
Entry
Aldehyde[a]
Product
Time [h]
Yield [%][b,d]
ee [%][c,d]
Sign/Conf.[e]
1
2
3
25a
26a
27a
25
26
27
40
38
38
96 (99)
95 (94)
99 (99)
92 (93)
91 (91)
96 (97)
+/S
+/S
À/S
[a]
The reactions were carried out with aldehydes (0.33 mmol), 21 (0.0033 mol, 1 mol%) and H2O (0.066 mmol, 20 mol%).
Yield refers to the chromatographically pure compounds.
The ee was determined by chiral HPLC on Chiralcel OD-H column.
The values in brackets are the results of the Henry reactions without water (Table 2, entries 1, 2, and 3).
The absolute configuration of the products was determined on the basis of sign of specific rotation and its peaks order in
the chiral HPLC.
[b]
[c]
[d]
[e]
very high chiral inductions with moderate yields reomers in moderate yield (62%) with moderate de
(Table 2, entries 30, and 31). Although the yields were for anti (66:34). Achiral additives (bases and phenols)
moderate to good for a,b-unsaturated aldehydes have been known to influence the yield, ee, and de in
(Table 2, entries 32, and 33), they displayed good the Henry reaction.[14] We initially carried out the re-
enantioselectivity in their products. We were delight- action with various achiral bases as additives (not
ed to find good to excellent enantioselectivities and shown), nevertheless, none of them yielded a promis-
yields for various unbranched and branched aliphatic ing result. Therefore, we then screened several phe-
aldehydes (Table 2, entries 34–39). As the best result nolic additives for the reaction between nitroethane
for aliphatic aldehydes, the Henry product 61 (96% and either p- and m-nitrobenzaldehyde (25a and 26a,
yield and 96% ee) was obtained for 3-phenylpropio- respectively) (Table 4, entries 5–9). Although no en-
naldehyde 61a (Table 2, entry 37). All the Henry hancement in de occurred, we were pleased to find
products synthesized using catalyst 21 possess the S a good yield (92%) and ee (syn 25b/anti 25c; 80/93)
configuration as compared with the literature.
for the aldehyde 25a with 10 mol% of 4-methoxyphe-
Although the optimized conditions for this reaction nol [4-MeOC6H4OH] as an additive (Table 4, entry 9).
used commercially available t-BuOH without further However, when applying 10 mol% 4-MeOC6H4OH to
drying, to test the effect of water, studies were con- the reaction of a slightly electron-rich aldehyde, 2-
ducted with 20 mol% of water. Interestingly, the ob- methylbenzaldehyde (30a), (Table 4, entry 10), the
tained results were considerably promising (Table 3). diastereomeric mixture syn 30b/anti 30c was obtained
The effect of water is significantly low as the enantio- in only a moderate yield (60%) with moderate ee
selectivity and yield of the corresponding products re- (syn/anti; 89:80). To amplify the yield and ee, various
mained almost same as for products obtained without mole amounts of 4-MeOC6H4OH were screened
water. This became credible evidence that the current (Table 4, entries 11–14). Consequently, 50 mol% 4-
catalytic system is tolerable for moisture, is practically MeOC6H4OH afforded the Henry product in an ex-
very simple, and can be achieved without any precau- cellent yield (99%) with excellent ee of syn 30b
tion for exclusion of moisture.
(94%) and anti 30c (91%) (Table 4, entry 12).
Under these optimized conditions then various al-
dehydes were explored (Table 4, entries 15–21).
Yields and ees were in the range of good to excellent;
however, for the 2-fluorobenzaldehyde product 36b/
Nitroaldol (Henry) Reaction with Other Nitroalkanes
The scope of the nitroaldol (Henry) reaction with ni- 36c (Table 4, entry 19) only a moderate yield (51%)
troalkanes other than nitromethane remains limited was obtained. As a best result 98% ee was obtained
for many catalytic systems in the literature. Therefore, for syn diastereomer 33b of the 2-methoxybenzalde-
the feasibility of this catalytic system for other nitroal- hyde product. For the anti isomer, both 2-methyl-
kanes was studied. When the optimized conditions (30a) and 2-bromobenzaldehyde (42a) yielded the
were used for nitroethane, yields in the range of low best result (91% ee).
to moderate with low diastereoselectivity and moder-
Thereafter, when 10 mol% benzoic acid [PhCO2H]
ate ee were obtained in 120 h (Table 4, entries 1–4). was used as an achiral additive, a superior ee was de-
However, ortho-nitrobenzaldehyde (27a) showed high termined for aldehyde 30a (Table 4, entry 22) com-
ee for both syn 27b (96%) and anti 27c (96%) diaste- pared to 4-MeOC6H4OH (50 mol%). A series of alde-
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2ACHTUNGERTN(NUNG SBAIB-d)2: An Efficient Catalyst
Table 4. Henry reaction with nitroethane and 1-nitropropane.[a]
Entry
RCHO
R1
Additive [mol%]
Time [h]
Yield [%][b]
anti/syn[c]
ee [%][d]
syn
anti
1
2
3
4
5
6
7
8
25a
26a
27a
46a
26a
25a
25a
25a
25a
30a
30a
30a
30a
30a
25a
26a
27a
33a
36a
42a
46a
30a
25a
26a
27a
33a
36a
42a
46a
25a
25a
26a
30a
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Et
none
none
none
none
120
120
120
120
100
96
96
96
96
120
120
120
120
120
120
120
120
120
120
120
120
120
100
100
100
100
100
100
96
28
51
62
35
85
76
74
81
92
60
99
99
99
99
86
88
90
82
51
72
99
98
88
90
94
80
98
81
82
40
58
63
53
56:44
59:41
66:34
55:45
53:47
52:48
57:43
57:43
58:42
55:45
55:45
54:46
52:48
57:43
56:44
60:40
63:37
58:42
57:43
57:43
55:45
57:43
55:45
59:41
64:36
56:44
57:43
58:42
59:41
61:39
60:40
59:41
55:45
43
76
96
68
73
55
61
80
80
89
94
94
94
93
84
80
90
98
91
95
77
94
87
85
97
98
92
65
84
81
85
85
89
63
77
96
69
74
67
78
90
93
80
84
91
90
89
86
80
94
76
86
91
74
96
98
86
97
81
87
83
83
82
82
93
91
4-NO2C6H4OH (10)
2,4-Me2C6H3OH (10)
2,4-(t-Bu)2C6H3OH (10)
3,4-Cl2C6H3OH (10)
4-MeOC6H4OH (10)
4-MeOC6H4OH (10)
4-MeOC6H4OH (25)
4-MeOC6H4OH (50)
4-MeOC6H4OH (75)
4-MeOC6H4OH (100)
4-MeOC6H4OH (50)
4-MeOC6H4OH (50)
4-MeOC6H4OH (50)
4-MeOC6H4OH (50)
4-MeOC6H4OH (50)
4-MeOC6H4OH (50)
4-MeOC6H4OH (50)
PhCO2H (10)
PhCO2H (10)
PhCO2H (10)
PhCO2H (10)
PhCO2H (10)
PhCO2H (10)
PhCO2H (10)
PhCO2H (10)
4-MeC6H4OH (10)
PhCO2H (10)
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
120
120
120
120
Et
Et
Et
PhCO2H (10)
PhCO2H (10)
[a]
Reaction conditions: catalyst 21 (1 mol%, 0.01 equiv.) in t-BuOH/R1CH2NO2 (20:20 vol) stirred for 1.5 h, additive addi-
tion, 1.5 h stirring and finally aldehyde (50 mg, 1 equiv.) addition and stirred for mentioned time.
Yield refers to the chromatographically pure compounds.
The anti/syn ratio was determined by H NMR.
The ees of syn and anti forms were determined by chiral HPLC on various chiral columns.
[b]
[c]
[d]
1
hydes was then screened with 10 mol% PhCO2H. All 10 mol% PhCO2H as an additive. These results
the aldehydes showed good yield and ee of diastereo- showed that this catalytic system is highly promising
meric mixtures (Table 4, entries 23–29). Even benzal- not only for nitromethane, but also for other nitroal-
dehyde (46a) yielded its product with a higher ee kanes in the presence of achiral additive either 4-
(Table 4, entry 29) compared to the result with 4- MeOC6H4OH (50 mol%) or PhCO2H (10 mol%).
MeOC6H4OH. However, 2-bromobenzaldehyde (42a)
showed an unreasonably moderate ee. This catalytic
system was also investigated with regard to the scope Proposed Mechanism for Chiral Induction
of the Henry reaction with nitropropane. The prod-
ucts were furnished in moderate yields with good The observed absolute configuration of the Henry
enantioselectivities (Table 4, entry 31–33) with products obtained from the reaction of aldehydes
Adv. Synth. Catal. 0000, 000, 0 – 0
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Ramalingam Boobalan et al.
FULL PAPERS
Scheme 2. Proposed mechanism for the absolute configuration of the Henry product (S)-46 obtained from benzaldehyde 46a
and nitromethane.
with nitromethane is predicted by the proposed mech- Conclusions
anism (Scheme 2). Benzaldehyde is taken as an exam-
ple. Generally, a base or counter anion is needed to In summary, this study shows that Cu2ACTHUNTRGNEU(GN SBAIB-d)2 21
generate a nitronate anion in the Henry reaction. is an efficient catalyst for the asymmetric nitroaldol
Hence the external base and the counter anion are (Henry) reaction. Synthetically valuable Henry ad-
absent in the present catalytic system; this must be ducts were produced in excellent yields with high ee
a bifunctional catalytic system. The dimeric Cu com- values for the reaction of various aldehydes with ni-
plex (based on the X-ray) could be involved in the tromethane. The merits of this catalytic system are its
mechanism as proposed. Nitronate is considered to be simplicity, mild reaction conditions, the need for as
formed by the removal of a proton by one of the little as 1 mol% of catalyst 21, an easy synthesis of
phenoxides attached to the copper to give transition catalyst in high yield, and the broad generality of the
state-1 [TS-1]. Then the second copper could act as aldehyde including aromatic, polycyclic aromatic, het-
a Lewis acid which would coordinate with carbonyl eroaromatic, a,b-unsaturated, branched, and unbr-
oxygen of aldehyde to activate the electrophilicity of ached aliphatic aldehydes. The present catalytic
the carbonyl group as in TS-2. The aldehyde could ar- system also has a high substrate scope for nitroal-
range in such a fashion where steric hindrance be- kanes other than nitromethane. Although lower des
tween methyl groups in the camphor moiety and one were obtained with nitroethane and nitropropane, ex-
of the two groups (H and Ph) in the aldehyde would cellent ee for both syn (up to 98%) and anti (up to
become less as in TS-2. Furthermore, this TS-2 ar- 98%) diastereomers were obtained when either
rangement would yield a p-p interaction between al- 50 mol% 4-MeOC6H4OH or 10 mol% PhCO2H were
dehyde phenyl group and phenyl group of Schiff base. added as an additive. Furthermore, this is the first
The opposite arrangement would have stronger steric Schiff base catalytic system that is highly effective for
hindrance and almost no p-p interaction, therefore, a wide range of substrates. Further studies of this cat-
TS-2 would be the more favorable TS. The addition alyst for other asymmetric reactions will be reported
of nitronate to the Re-face of the aldehyde and cleav- in due course.
age from the catalyst through TS-3 would then afford
(S)-46 and the regeneration of catalytic system.
8
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Copper Complex of Aminoisoborneol Schiff Base Cu2ACTHNUTRGEN(UNG SBAIB-d)2: An Efficient Catalyst
References
Experimental Section
[1] For reviews on the asymmetric Henry reaction, see:
a) F. A. Luzzio, Tetrahedron 2001, 57, 915–945; b) J.
Boruwa, N. Gogoi, P. P. Saikia, N. C. Barua, Tetrahe-
dron: Asymmetry 2006, 17, 3315–3326; c) C. Palomo,
M. Oiarbide, A. Laso, Eur. J. Org. Chem. 2007, 2561–
2574; d) G. Blay, V. Henandez-Olmos, J. R. Pedro, Syn-
lett 2011, 1195–1211.
General Procedure for Synthesis of Copper Complex
of Aminoisoborneol Schiff Base [Cu2A(SBAIB)]2
CTHUNGTRENNUNG
To a methanolic (40 vol) solution of aminoisoborneol Schiff
base [(+)-SBAIB] (1 equiv.) in a single-neck round-bottom
flask was added solid CuACHTNUTRGNE(UNG OAc)2·H2O (1.2 equiv.). The re-
sulting yellowish green reaction mixture was stirred for 2 h
at room temperature. Then solid NaOH (4 equiv.) was
added to the above solution and stirring continued for 6 h.
The resulting bluish solution was evaporated to dryness. To
this residue was added brine and followed by extraction
with benzene (4 times). The combined benzene layer was
dried over anhydrous Na2SO4, filtered, and concentrated to
obtain the corresponding copper complex as a solid product,
which was used for the asymmetric Henry reactions.
[2] H. Sasai, T. Suzuki, S. Arai, T. Arai, M. Shibasaki, J.
Am. Chem. Soc. 1992, 114, 4418–4420.
[3] References for Cu-catalyzed asymmetric Henry reac-
tion: a) C. Christensen, K. Juhl, K. A. Jorgensen, J.
Org. Chem. 2002, 67, 4875–4881; b) D. A. Evans, D.
Seidel, M. Rueping, H. W. Lam, J. T. Shaw, C. W.
Downey, J. Am. Chem. Soc. 2003, 125, 12692–12693;
c) H. Maheswaran, K. L. Prasanth, G. G. Krishna, K.
Ravikumar, B. Sridhar, M. L. Kantam, Chem.
Commun. 2006, 4066–4068; d) K. Y. Ma, J. S. You,
Chem. Eur. J. 2007, 13, 1863–1871; e) B. Qin, X. Xiao,
X. H. Liu, J. L. Huang, Y. H. Wen, X. M. Feng, J. Org.
Chem. 2007, 72, 9323–9328; f) M. Bandini, M. Benaglia,
R. Sinisi, S. Tommasi, A. Umani-Ronchi, Org. Lett.
2007, 9, 2151–2153; g) Y. Xiong, F. Wang, X. Huang,
Y. H. Wen, X. Feng, Chem. Eur. J. 2007, 13, 829–833;
h) T. Arai, M. Watanabe, A. Yanagisaka, Org. Lett.
2007, 9, 3595–3597; i) G. Blay, E. Climent, I. Fernandez,
V. Hernandez, J. R. Pedro, Tetrahedron: Asymmetry
2007, 18, 1603–1612; j) M. Bandini, F. Picinelli, S. Tom-
masi, A. Umani-Ronchi, C. Ventrici, Chem. Commun.
2007, 616–618; k) G. Blay, L. R. Domingo, V. Hernan-
dez-Olmos, J. R. Pedro, Chem. Eur. J. 2008, 14, 4725–
4730; l) K. Y. Spangler, C. Wolf, Org. Lett. 2009, 11,
4724–4727; m) G. Q. Zhang, E. Yashima, W. D.
Woggon, Adv. Synth. Catal. 2009, 351, 1255–1262; n) M.
Breuning, D. Hein, M. Steiner, V. H. Gessner, C. Stroh-
mann, Chem. Eur. J. 2009, 15, 12764–12769; o) A.
Noole, K. Lippur, A. Metsala, M. Lopp, T. Kanger, J.
Org. Chem. 2010, 75, 1313–1316; p) M. Steurer, C.
Bolm, J. Org. Chem. 2010, 75, 3301–3310; q) L. Cheng,
J. Dong, J. You, G. Gao, J. Lan, Chem. Eur. J. 2010, 16,
6761–6765; r) W. Jin, X. Li, Y. Huang, F. Wu, B. Wan,
Chem. Eur. J. 2010, 16, 8259–8261; s) I. Panov, P. Drabi-
na, Z. Padelkova. P. Simunek, M. Sedlak, J. Org. Chem.
2011, 76, 4787–4793; t) D. Didier, C. Magnier-Bouvier,
E. Schulza, Adv. Synth. Catal. 2011, 353, 1087–1095;
u) G. Lai, F. Guo, Y. Zheng, Y. Fang, H. Song, K. Xu,
S. Wang, Z. Zha, Z. Wang, Chem. Eur. J. 2011, 17,
1114–1117; v) Y. Q. Ji, G. Qi, Z. M. A. Judeh, Eur. J.
Org. Chem. 2011, 4892–4898.
General Procedure for Catalytic Enantioselective
Henry Reactions [Table 2]
A mixture of Cu2[(+)-SBAIB-d]2 21 (1 mol%, 0.01 equiv.), t-
BuOH (1 mL, 20 vol with respect to aldehyde) and MeNO2
(1 mL, 20 vol with respect to aldehyde) in a screw-capped
vial (8 mL) was stirred at room temperature for 3 h under
atmospheric conditions. Then aldehyde (50 mg, 1 equiv.) was
added to the above blue solution and stirred for the men-
tioned time. It was then quenched with 1N HCl and the vol-
atile material was evaporated by rotavapor to afford the
crude product. This was purified by column chromatography
(either 70–230 or 230–400 mesh silica gel). The resultant
product was taken for the characterization. See the support-
ing informations for spectral data and HPLC spectra of
Henry products.
General Procedure for Henry Reactions with
Nitroethane and 1-Nitropropane [Table 4, entries 12–
33]
A mixture of Cu2[(+)-SBAIB-d]2 (1 mol%, 0.01 equiv.), t-
BuOH (1 mL, 20 vol) and either EtNO2 or n-PrNO2 (1 mL,
20 vol) in a vial (8 mL) was stirred at room temperature for
1.5 h. Then the additive either 4-MeOC6H4OH (50 mol%,
0.5 equiv.) or PhCO2H (10 mol%, 0.1 equiv.) was added and
the mixture stirred for another 1.5 h. Aldehyde (50 mg,
1 equiv.) was added and the resulting reaction mixture was
stirred for the mentioned time. Afterwards, 1N HCl was
added to quench the reaction and the volatiles were evapo-
rated by rotavapor to afford the crude product. This was
then purified by column chromatography (either 70–230 or
230–400 mesh silica gel) and taken for the characterization.
[4] References for Zn-catalyzed asymmetric Henry reac-
tion: a) B. M. Trost, V. S. C. Yeh, Angew. Chem. 2002,
114, 889–891; Angew. Chem. Int. Ed. 2002, 41, 861–863;
b) C. Palomo, M. Oiarbide, A. Laso, Angew. Chem.
2005, 117, 3949–3952; Angew. Chem. Int. Ed. 2005, 44,
3881–3884; c) S. Liu, C. Wolf, Org. Lett. 2008, 10, 1831–
1834; d) A. Bulut, A. Aslan, O. Dogan, J. Org. Chem.
2008, 73, 7373–7375.
[5] References for Cr-catalyzed asymmetric Henry reac-
tion: a) R. Kowalczyk, L. Sidorowicz, J. Skarzewaski,
Tetrahedron: Asymmetry 2007, 18, 2581–2586; b) R.
Kowalczyk, P. Kwiatkowski, J. Skarzewski, J. Jurczak, J.
Acknowledgements
The authors thank Ms. L. M. Hsu, at the Instruments Center,
National Chung Hsing University, for her help in obtaining
mass spectral data, and the National Science Council of the
Republic of China, for financially supporting this research
under the contract NSC 100-2113M-259-006-MY3.
Adv. Synth. Catal. 0000, 000, 0 – 0
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Ramalingam Boobalan et al.
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Org. Chem. 2009, 74, 753–756; c) A. Zulauf, M. Mellah,
E. Schulz, J. Org. Chem. 2009, 74, 2242–2245.
[6] References for Co-catalyzed asymmetric Henry reac-
tion: a) Y. Kogami, T. Nakajima, T. Ikeno, T. Yamada,
Synthesis 2004, 1947–1950; b) J. Park, K. Lang, K. A.
Abboud, S. Hong, J. Am. Chem. Soc. 2008, 130, 16484–
16485.
[7] References for bimetal-catalyzed asymmetric Henry re-
action: a) H. Sasai, T. Tokunaga, S. Watanabe, T.
Suzuki, N. Itoh, M. Shibasaki, J. Org. Chem. 1995, 60,
7388–7389; b) S. Handa, K. Nagawa, Y. Sohtome, S.
Matsunaga, M. Shibasaki, Angew. Chem. 2008, 120,
3274–3277; Angew. Chem. Int. Ed. 2008, 47, 3230–3233;
c) T. Nitabaru, A. Nojiri, M. Kobayashi, N. Kumagai,
M. Shibasaki, J. Am. Chem. Soc. 2009, 131, 13860–
13869.
[8] Reference for rare earth metal-catalyzed asymmetric
Henry reaction: B. M. Choudary, K. V. S. Ranganath,
U. Pal, M. L. Kantam, B. Sreedhar, J. Am. Chem. Soc.
2005, 127, 13167–13171.
[9] References for organocatalysts in asymmetric Henry
reaction: a) E. J. Corey, F. Y. Zhang, Angew. Chem.
1999, 111, 2057–2059; Angew. Chem. Int. Ed. 1999, 38,
1931–1934; b) T. Ooi, K. Doda, K. Maruoka, J. Am.
Chem. Soc. 2003, 125, 2054–2055; c) Y. Sohtome, Y.
Hashimoto, K. Nagasawa, Adv. Synth. Catal. 2005, 347,
1643–1648; d) H. M. Li, B. M. Wang, L. Deng, J. Am.
Chem. Soc. 2006, 128, 732–733; e) T. Marcelli, R. N. S.
van der Haas, J. H. van Maarseveen, H. Hiemstra,
Angew. Chem. 2006, 118, 943–945; Angew. Chem. Int.
Ed. 2006, 45, 929–931; f) Y. Sohtome, Y. Hashimoto, K.
Nagasawa, Eur. J. Org. Chem. 2006, 2894–2897; g) T.
Mandal, S. Samanta, C. G. Zhao, Org. Lett. 2007, 9,
943–945; h) M. Bandini, R. Sinisi, A. Umani-Ronchi,
Chem. Commun. 2008, 4360–4362; i) K. Kanagaraj, P.
Suresh, K. Pitchumani, Org. Lett. 2010, 12, 4070–4073.
[10] References for the biocatalytic asymmetric Henry reac-
tion: a) T. Purkarthofer, K. Gruber, M. Gruber-Khadja-
wi, K. Waich, W. Skrane, D. Mink, H. Griengl, Angew.
Chem. 2006, 118, 3532–3535; Angew. Chem. Int. Ed.
2006, 45, 3454–3456; b) M. G. Khadjawi, T. Purkarthof-
er, W. Skrane, H. Griengl, Adv. Synth. Catal. 2007, 349,
1445–1450.
Z. Q. Xu, L. Liu, R. Wang, Org. Lett. 2006, 8, 2277–
2280; c) Z. B. Li, T. D. Liu, L. Pu, J. Org. Chem. 2007,
72, 4340–4343; d) E. M. McGarrigle, D. G. Gilheany,
Chem. Rev. 2005, 105, 1563–1602; e) P. J. Walsh, H. Li,
C. A. de Parrodi, Chem. Rev. 2007, 107, 2503–2545;
f) T. Niimi, T. Uchida, R. Irie, T. Katsuki, Adv. Synth.
Catal. 2001, 343, 79–88; g) H. Mizutani, S. J. Degrado,
A. H. Hoveyda, J. Am. Chem. Soc. 2002, 124, 779–781;
h) Y. Kato, M. Furutachi, Z. Chen, H. Mitsunuma, S.
Matsunaga, M. Shibasaki, J. Am. Chem. Soc. 2009, 131,
9168–9169; i) Q. Fan, L. Lin, J. Liu, Y. Huang, X. Feng,
G. Zhang, Org. Lett. 2004, 6, 2185–2188; j) Y. Yasuto-
mi, H. Suematsu, T. Katsuki, J. Am. Chem. Soc. 2010,
132, 4510–4511.
[12] References for the application of Schiff base ligands in
asymmetric Henry reaction: a) C. Gan, G. Lai, Z.
Zhang, Z. Wang, M.-M. Zhoub, Tetrahedron: Asymme-
try 2006, 17, 725–728; b) J.-J. Jianga, M. Shi, Tetrahe-
dron: Asymmetry 2007, 18, 1376–1382; c) G. Lai, S.
Wang, Z. Wang, Tetrahedron: Asymmetry 2008, 19,
1813–1819; d) J. Guo, J. Mao, Chirality 2009, 21, 619–
627; e) M. L. Ingalsbe, J. D. St. Denis, J. L. Gleason,
G. P. Savage, R. Priefer, Synthesis 2010, 98–102; f) D.
Xin, Y. Ma, F. He, Tetrahedron: Asymmetry 2010, 21,
333–338; g) G. Oztꢂrk, M. Colak, N. Demirel, Chirality
2011, 23, 374–378.
[13] References on successful asymmetric catalysts devel-
oped in our laboratory: a) X.-R. Huang, C. Chen, G.-
H. Lee, S.-M. Peng, Adv. Synth. Catal. 2009, 351, 3089–
3095; b) X.-R. Huang, X.-H. Pan, G.-H. Lee, C. Chen,
Adv. Synth. Catal. 2011, 353, 1949–1954; c) R. Booba-
lan, C. Chen, G. H. Lee, Org. Biomol. Chem. 2012, 10,
1625–1638.
[14] References for the influence of achiral additives in
asymmetric Henry reaction: a) refs.[3d,3e,3q,3o,3u]
; b) S.
Handa, K. Nagawa, Y. Sohtome, S. Matsunaga, M. Shi-
basaki, Angew. Chem. 2008, 120, 3274–3277; Angew.
Chem. Int. Ed. 2008, 47, 3230–3233; c) T. Arai, R. Ta-
kashita, Y. Endo, M. Watanabe, A. Yanagisawa, J. Org.
Chem. 2008, 73, 4903–4906; d) H. Y. Kim, K. Oh, Org.
Lett. 2009, 11, 5682–5685; e) S. Selvakumar, D. Sivasan-
karan, V. K. Singh, Org. Biomol. Chem. 2009, 7, 3156–
3162; f) W. Jin, X. Li, B. Wan, J. Org. Chem. 2011, 76,
484–491; g) Y. Zhou, J. Dong, F. Zhang, Y. Gong, J.
Org. Chem. 2011, 76, 588–600.
[11] Selected references for application of Schiff base and
salen ligands in asymmetric synthesis: a) Z. B. Li, L.
Pu, Org. Lett. 2004, 6, 1065–1068; b) C. Chen, L. Hong,
10
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FULL PAPERS
Copper Complex of Aminoisoborneol Schiff Base
11
Cu2ACHTUNGTRENNUNG(SBAIB-d)2: An Efficient Catalyst for Direct Catalytic
Asymmetric Nitroaldol (Henry) Reaction
Adv. Synth. Catal. 2012, 354, 1 – 11
Ramalingam Boobalan, Gene-Hsian Lee, Chinpiao Chen*
Adv. Synth. Catal. 0000, 000, 0 – 0
ꢁ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
11
ÞÞ
These are not the final page numbers!