Enantioselective Henry reaction catalyzed by CuII salt and bipiperidine

Article abstract of DOI:10.1021/jo902664v

(Chemical Equation Presented) A complex derived from the enantiomeric bipiperidine and copper(II) acetate hydrate is an efficient catalyst for the enantioselective Henry reaction. The easy availability of both catalyst components, mild reaction conditions

Full text of DOI:10.1021/jo902664v

pubs.acs.org/joc
bisoxazolines,3 bisoxazolidines,4 boron-bridged bisoxazo-
Enantioselective Henry Reaction Catalyzed by CuII
Salt and Bipiperidine
lines,5 C2-symmetric diamines,6 pyridine derivatives,7 chiral
Schiff bases,8 sparteine,9 sulfonyldiamine,10 and hetero-
organic ligands11 catalyze an asymmetric nitroaldol
(Henry) reaction.12 It is very difficult to find a common
feature for the above-mentioned nitrogen-containing com-
pounds. Thus, several very different diamines have been
tested for the asymmetric induction ability.
Artur Noole, Kristin Lippur, Andrus Metsala,
~
Margus Lopp, and Tonis Kanger*
Department of Chemistry, Tallinn University of Technology,
Akadeemia tee 15, 12618 Tallinn, Estonia
We have investigated four types of enantiomeric ligands
(compounds 1-4) for the copper-catalyzed asymmetric
Henry reaction (Figure 1).
Of these compounds, bimorpholines (1 and 2) and bipi-
peridines 4 are already known as efficient organocatalysts in
aldol and Michael reactions, respectively.13
kanger@chemnet.ee
Received December 16, 2009
All these ligands are constructed similarly, by linking
two heterocyclic rings, but they differ from each other
in the number of coordinative sites in the molecule and
the flexibility of the structure. Flexible C2-symmetric
(2S,20S)-2,20-bimorpholines 1 and (3S,30S)-3,30-bimor-
pholines 2 bear four donor atoms, but the electron-donat-
ing ability of the nitrogen atom is reduced by the close
location of the electronegative oxygen atoms. A different
position of the bridging bond between two heterocycles
changes the accessibility of donor atoms by the metal. The
replacement of oxygen atoms in rings by methylene groups
leads to bipiperidine derivatives 4 which can be prepared
much more easily than the corresponding morpholines.
Racemic bipiperidine 4a is straightforwardly derived from
the commercially available dipyridyl in one chemical
step.14 Piperidinylpyridine 3 and bipiperidine 4 deriva-
tives differ from the bimorpholines in terms of a reduced
number of coordinative sites in the molecule. In addition,
the nitrogen atoms in piperidinylpyridine 3 are chemically
different, and furthermore, the two rings are structurally
totally different: one is a flat aromatic pyridine ring and
the other a flexible saturated piperidine ring. The steric
hindrance surrounding the electron-donating center in all
ligands can be easily modified by changing substituents
R1-R4.
A complex derived from the enantiomeric bipiperidine
and copper(II) acetate hydrate is an efficient catalyst for
the enantioselective Henry reaction. The easy availability
of both catalyst components, mild reaction conditions,
high yield, and good to excellent enantioselectivity make
the catalyst useful for everyday practice.
TheHenry (nitro-aldol) reaction is a well-knowntoolfor the
building of a C-C bond.1 Since the pioneering work of
Shibasaki,2 where the heterobimetallic catalyst was used,
various versions of metal-catalyzed asymmetric Henry reac-
tions have been described. Copper has a special place among
the metals used as catalysts because it is a cheap, low toxicity
metal and has been widely used in organic synthesis. The
excellent chelating properties of that metal allow coordi-
nation of it with bidentate as well as with polydentate ligands.
Copper complexes with various ligands, which include
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DOI: 10.1021/jo902664v
r
Published on Web 01/22/2010
J. Org. Chem. 2010, 75, 1313–1316 1313
2010 American Chemical Society

Noole et al.
JOCNote
TABLE 1. Screening of Catalysts for the Asymmetric Henry Reaction
entry catalyst aldehyde (R=) time (h) yielda (%) eeb (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
1a
1b
1c
2
p-NO2
p-NO2
p-NO2
o-NO2
o-NO2
p-NO2
p-NO2
p-NO2
o-NO2
o-NO2
o-NO2
o-NO2
o-NO2
o-NO2
18
18
90
21
24
22
6
46
43
91
92
90
93
67
83
81
28
58
91
83
17
0
0
11
69
54
20
35
13
53c
63c
55
55
41
85
3a
3b
3c
3d
4a
4a
4b
4b
4c
4c
18
3
FIGURE 1. Bimorpholines 1 and 2, piperidinylpyridine 3, and
bipiperidine 4.
111d
4
93d
2
The synthesis of bimorpholine derivatives (1 and 2)15,16
and (2S,20S)-bipiperidine 414 was described by us previously.
Ligand 3a was derived from bipyridyl, followed by its mono-
quaternization, selective reduction of one pyridine ring, and
separation of enantiomers via crystallization with tartaric
acid.17 The synthesis of the new ligands 3c and 3d is described
in the Supporting Information.
70d
aIsolated yield after column chromatography. bDetermined by chiral
HPLC. cThe ee of the ligand was 90%. dThe reaction was performed at
-25 °C.
TABLE 2. Optimization of the Reaction Conditions for the Asymmetric
Henry Reaction in MeOH
With the set of ligands in hand, we screened their selectivity
and reactivity in the Henry reaction. The addition of nitro-
methane (10 equiv) to nitrobenzaldehyde (ortho or para
isomer) in the presence of 5 mol % of Cu(OAc)2 H2O and 5
mol % of ligand at room temperature was chosen as a model
reaction. Our preliminary experiments revealed that alcohols
are the best solvents for the reaction. The obtained results are
presented in Table 1. We observed that the 2,20-bimorpholine-
derived catalysts 1a-c were all nonselective (Table 1, entries
1-3). The piperidinylpyridine derivatives 3a-d were found to
be more selective and also more reactive, affording the product
in high yield within ∼24 h (Table 1, entries 5-8). The highest
selectivity at room temperature was obtained using N-isopro-
pyl-3,30-bimorpholine 2 (Table 1, entry 4). However, reactions
with synthetically more easily available bipiperidine derivatives
4 also gave quite satisfactory enantioselectivities (for the
screening), but the corresponding complexes were found to
be much more reactive (Table 1, entries 9, 11, and 13). We
assumed that the reaction using that ligand at a lower tem-
perature should proceed at a reasonable rate and with in-
creased enantioselectivity. The substituent at the nitrogen atom
in 4 has a significant influence on the selectivity of the Henry
reaction at lower temperature (-25 °C) (Table 1, entries 10, 12,
and 14). The most selective ligand bipiperidine 4c was selected
as potential ligand for further studies.
L/M
(mol %)
additive
(mol %)
temp
(°C)
time
(h)
yielda
(%)
eeb
(%)
entry
1
2
3
4
5
6
5
5
5
5
5
10
rt
-10
-25
-25
-25
-25
2
25
70
19
22
39
83
52
17
68
17
79
41
77
85
79
Et3N (5)
Et3N (5)
Et3N (5)
87c
81c
aIsolated yield after column chromatography. bDetermined by chiral
HPLC. c5 equiv of nitromethane was used.
enantioselectivity and the temperature of the reaction (Table 2,
entries 1-3). Although a considerably high enantiomeric purity
of the product was obtained at -25 °C, the reaction was
unreasonably slow at that temperature (Table 2, entry 3).
Basic additives are known to accelerate the Henry reac-
tion.18 Indeed, the use of 5 mol % of Et3N increased the rate
of the reaction, and the product was formed in a 68% yield
within 19 h at -25 °C. However, the additive caused lower
stereoselectivity (Table 2, entry 4). A compromise between
reactivity and selectivity was found by reducing the amount
of nitromethane to 5 equiv and increasing the amount of the
catalyst to 10 mol %. Thus, the reaction under those optimal
conditions (5 equiv of nitromethane, 5 mol % of Et3N,
10 mol % of catalyst at -25 °C in MeOH) afforded the
product in a high yield and ee (79% and 81%, respectively)
with a reasonable reaction time (Table 2, entry 6).
Next, the scope of the reaction was examined. Several
aromatic aldehydes provided β-nitro alcohols in very high
yields and ee in the reaction with nitromethane, catalyzed by
(S,S)-bipiperidine 4c or its enantiomer ent-4c complex with
copper(II) acetate (Table 3). Comparing MeOH and EtOH
as the reaction media, we observed that EtOH is clearly a
preferable solvent, affording products in shorter reaction
time and higher enantiomeric purity than running a reaction in
The optimization of the reaction conditions was carried
out with iPr-bipiperidine 4c, copper(II) acetate hydrate
(in 1:1 molar ratio), and o-nitrobenzaldehyde, in the presence
or absence of the basic additive in MeOH (Table 2).
The obtained results revealed a clear correlation between
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M.; Kriis, K.; Kanger, T.; Alexakis, A. Synthesis 2007, 1729–1732.
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Pehk, T.; Lopp, M. Tetrahedron: Asymmetry 2007, 18, 137–141. (b) Lippur,
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K.; Elmers, C.; Kailas, T.; Muurisepp, A.-M.; Pehk, T.; Kanger, T.; Lopp,
M. Synth. Commun. 2010, 40, 266–281.
(17) Cheng, Y.-Q.; Bian, Z.; Qing Kang, C.-Q.; Guo, H. Q.; Gao, L.-X.
Tetrahedron: Asymmetry 2008, 19, 1572–1575.
(18) Blay, G.; Domingo, L. R.; Hernandez-Olmos, V.; Pedro, J. R.
Chem.—Eur. J. 2008, 14, 4725–4730.
1314 J. Org. Chem. Vol. 75, No. 4, 2010

Noole et al.
JOCNote
TABLE 3. Henry Reaction of Aldehydes and Nitromethane Catalyzed by Cu(OAc)2 H2O and Ligand 2 or 4c Complex
nitromethane
(equiv)
temp
(oC)
time
(h)
yieldb
(%)
ee
(%)
entry
aldehydea
benzaldehyde
benzaldehyde
ligand
solvent
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
4c
ent-4c
4c
ent-4c
4c
ent-4c
4c
ent-4c
4c
ent-4c
4c
ent-4c
4c
ent-4c
4c
ent-4c
2
5
10
5
10
5
10
5
10
5
10
5
10
5
10
5
10
5
MeOH
EtOH
MeOH
EtOH
MeOH
EtOH
MeOH
EtOH
MeOH
EtOH
MeOH
EtOH
MeOH
EtOH
MeOH
EtOH
MeOH
EtOH
-25
-25
-25
-25
-25
-25
-25
-25
-25
-25
-25
-25
-25
-25
-25
-25
-25
-25
40
19
39
23
47
20
72
42
43
6
24
22
49
7
96
70
48
24
93
97
79
91
60
97
26
93
94
97
92
90
67
70
52
43
80
94
94 (R)
96 (S)
81 (R)
83 (S)
71 (R)
71 (S)
81 (R)
93 (S)
85 (R)
95 (S)
85 (R)
93 (S)
80 (R)
88 (S)
84 (R)
92 (S)
83 (S)
76 (S)
o-nitrobenzaldehyde
o-nitrobenzaldehyde
p-nitrobenzaldehyde
p-nitrobenzaldehyde
p-methoxybenzaldehyde
p-methoxybenzaldehyde
p-bromobenzaldehyde
p-bromobenzaldehyde
2-naphthylaldehyde
2-naphthylaldehyde
trans-cinnamaldehyde
trans-cinnamaldehyde
cyclohexanecarbaldehyde
cyclohexanecarbaldehyde
o-nitrobenzaldehyde
o-nitrobenzaldehyde
2
10
aReaction conditions in MeOH: Cu(OAc)2 H2O (10 mol %), ligand (10 mol %), Et3N (5 mol %), CH3NO2 (5 equiv), -25 °C. In EtOH: Cu(OAc)2
H2O (10 mol %), ligand (10 mol %), Et3N (5 mol %), CH3NO2 (10 equiv), -25 °C. bIsolated yield after column chromatography.
TABLE 4. Henry Reaction of Aldehydes and Nitroethane Catalyzed by
MeOH. Even deactivated anisaldehyde afforded, in EtOH, a
complete conversion in a highly stereoselective manner, and the
product was isolated in an almost quantitative yield and high ee
(Table 3, entry 8). Stereoselectivities are not considerably
influenced by the electronic and steric character of substituents
in the aromatic ring, and enantiomeric purities were moderate
to high (71-96%). A longer reaction time was needed for
aliphatic aldehydes. Thus, cyclohexane carbaldehyde gave the
corresponding nitro alcohol only approximately in 50% of the
yield within ∼90 h (Table 3, entries 15, 16). R,β-Unsaturation at
formyl group does not hinder the reaction. Thus, cinnamalde-
hyde reacted smoothly in EtOH (Table 3, entry 14). Enantio-
meric purities of aliphatic β-nitro alcohols were high (in the best
case, 92%, Table 3, entry16).
A comparison of bimorpholine 2 (Table 3, entries 17 and 18)
and bipiperidine ligand 4c (Table 3, entries 3 and 4) revealed that
their catalytic properties are very similar. However, the easier
synthetic availability of the latter ligand makes it more practical.
In the reaction of other nitroalkyl compounds besides
nitromethane with aldehydes, two contiguous stereocenters
are formed simultaneously. Although a copper-catalyzed
enantioselective Henry reaction is well-documented, there
are only a few instances where a high diastereoselectivity was
achieved.3c,10,19 We studied the reaction of nitroethane with
aromatic aldehydes. The results are presented in Table 4.
The reaction of 2-naphthaldehyde with nitroethane was
carried out in MeOH, EtOH, and iPrOH (Table 4, entries
1-3). EtOH was again the best solvent in terms of reactivity
and stereoselectivity. In all of the evaluated cases, the ratio of
the obtained anti/syn isomers was not very high (from 2:1 to
4:1). However, the isolated yield and the enantiomeric purity
of the obtained anti and syn diastereoisomers were almost
equally high (up to 96%).
Cu(OAc)2 H2O and Ligand 4c Complexa
3
entry
Ar
solvent time (h) yieldb (%) syn/antic eec (%)
1
2
3
4
5
6
7
8
2-naphthyl
2-naphthyl
2-naphthyl
Phenyl
o-NO2-phenyl EtOH
p-Br-phenyl EtOH
p-MeO-phenyl EtOH
1-naphthyl EtOH
MeOH
EtOH
iPrOH
EtOH
21
24
19
47
19
25
67
47
47
86
89
86
88
95
96
74
22:78
31:69
23:77
19:81
25:75
18:82
20:80
28:72
71/86
80/88
75/82
89/96
74/89
80/94
84/92
81/93
aConditions: reaction was run at -25 °C in the presence of Cu-
(OAc)2 H2O (10 mol %), ligand 4c (10 mol %), Et3N (5 mol %), and
nitroethane (10 equiv). bIsolated yield of the mixture of diastereoi-
somers. cDetermined by chiral HPLC.
3
(found 332.1527; theoretical 332.1525; see the Supporting Infor-
mation for details). Calculations of the geometry of the complex
and energetic parameters were performed at the B3LYP/
6-31þG* highest level,20 using the Gaussian03 program.21 The
optimal geometry is represented in Figure 2. One can see that
(20) Becke, A. D. J. Chem. Phys. 1993, 98, 5648–5652.
(21) Gaussian 03, Revision C.02:Frisch, M. J.;Trucks, G. W.; Schlegel, H. B.;
Scuseria, G. E.; Robb, M. A.; Cheeseman, J. R.; Montgomery, J. A., Jr.; Vreven,
T.; Kudin, K. N.; Burant, J. C.; Millam, J. M.; Iyengar, S. S.; Tomasi, J.; Barone,
V.; Mennucci, B.; Cossi, M.; Scalmani, G.; Rega, N.; Petersson, G. A.; Nakatsuji,
H.; Hada, M.; Ehara, M.; Toyota, K.; Fukuda, R.; Hasegawa, J.; Ishida, M.;
Nakajima, T.; Honda, Y.; Kitao, O.; Nakai, H.; Klene, M.; Li, X.; Knox, J. E.;
Hratchian, H. P.; Cross, J. B.; Bakken, V.; Adamo, C.; Jaramillo, J.; Gomperts,
R.; Stratmann, R. E.; Yazyev, O.; Austin, A. J.; Cammi, R.; Pomelli, C.;
Ochterski, J. W.; Ayala, P. Y.; Morokuma, K.; Voth, G. A.; Salvador, P.;
Dannenberg, J. J.; Zakrzewski, V. G.; Dapprich, S.; Daniels, A. D.; Strain,
M. C.; Farkas, O.; Malick, D. K.; Rabuck, A. D.; Raghavachari, K.; Foresman,
J. B.; Ortiz, J. V.; Cui, Q.; Baboul, A. G.; Clifford, S.; Cioslowski, J.; Stefanov,
B. B.;Liu, G.;Liashenko, A.;Piskorz, P.;Komaromi, I.;Martin, R. L.;Fox, D. J.;
Keith, T.; Al-Laham, M. A.; Peng, C. Y.; Nanayakkara, A.; Challacombe, M.;
Gill, P. M. W.; Johnson, B.; Chen, W.; Wong, M. W.; Gonzalez, C.; Pople, J. A.
Gaussian, Inc., Wallingford, CT, 2004.
To rationalize the stereochemical outcome of the reaction,
first the complex was characterized by ESI HRMS. The main
peak corresponds to a ligand 4c copper monoacetate complex
(19) (a) Nitabaru, T.; Nojiri, A.; Kobayashi, M.; Kumagai, N.; Shibasaki, M.
J. Am. Chem. Soc. 2009, 131, 13860–13869. (b) Arai, T.; Watanabe, M.;
Yanagisawa, A. Org. Lett. 2007, 9, 3595–3597. (c) Sasai, H.; Tokunaga, T.;
Watanabe, S.; Suzuki, T.; Itoh, N.; Shibasaki, M. J. Org. Chem. 1995, 60, 7388–
7389.
J. Org. Chem. Vol. 75, No. 4, 2010 1315

Noole et al.
JOCNote
SCHEME 1. Proposed Catalytic Cycle of the Henry Reaction
FIGURE 2. Calculated conformation of (S,S)-N-iPr-bipiperidine
and Cu(OAc)2 complex in ethanol.
the N-iPr group of the piperidine ring is perpendicular to the
almost planar structure of the tetra-coordinated copper com-
plex. According to the model proposed by Evans,3d in the most
reactive intermediate nitromethane is also in the perpendicular
position and aldehyde is in the same plane with the ligand. In
our case, catalyst 4 in the (S,S) configuration afforded the
product with an R configuration. Thus, nitronate attacked the
si-face of the aldehyde. It is assumed that the nitronate in the
axial position (opposite the iPr group) was fixed with the
hydrogen bonding with the N-H group and the electrophile
in the equatorial position was oriented in the most appropriate
way, leading to the si attack (Scheme 1).
ether and ethyl acetate to yield 81 mg (97%) of product as clear
oil. Enantiomeric purity (96%) was determined by HPLC
analysis (Chiralcel OD-H column, 1 mL/min, 15% iPrOH in
hexane, 230 nm), (R) tR = 9.31 min (minor) and (S) tR = 11.02
min (major); [R]25 = þ12.5 (c = 2.04 in EtOH), absolute
D
In conclusion, we have shown that an easily available
bipiperidine 4c and commercially available Cu(OAc)2 H2O
stereochemistry assigned by comparison of the retention times
in HPLC and optical rotation signs with literature data: 1H
NMR (400 MHz, CDCl3) δ 7.45 - 7.33 (m, 5H), 5.47 (dd, J =
9.6, 3.0 Hz, 1H), 4.61 (dd, J = 13.4, 9.6 Hz, 1H), 4.52 (dd, J =
13.4, 3.0 Hz, 1H), 2.85 (s, 1H); 13C NMR (101 MHz, CDCl3) δ
138.2, 129.2, 129.1, 126.1, 81.4, 71.1.
3
formed a new practical catalytic system that afforded a
highly stereoselective Henry reaction between aromatic al-
dehydes and aliphatic nitro compounds. Henry adducts were
formed in good yields and high enantioselectivities, under
mild conditions.
Acknowledgment. We thank the Estonian Science Foun-
dation (Grant No. 6662), the Ministry of Education and
Research (Grant No. 0142725s06), and the EU European
Regional Development Fund (3.2.0101.08-0017) for finan-
cial support. We are grateful to Lauri Peil, Ph.D., from the
Institute of Technology at the University of Tartu for HRMS
analysis.
Experimental Section
General Procedure for the Asymmetric Henry Reaction. (S)-2-
Nitro-1-phenylethanol (Table 3, Entry 2). A solution of ligand 4c
(0.05 mmol, 10.5 mg, 10 mol %) and Cu(OAc)2 H2O (0.05
3
mmol, 10 mg, 10 mol %) in EtOH (0.9 mL) was stirred for 10 min
at an ambient temperature to generate the catalyst. Benzal-
dehyde (0.5 mmol, 53 mg, 1 equiv) was added, and the reaction
mixture was cooled to -25 °C. Nitromethane (5 mmol, 270 μL,
10 equiv) and a solution of Et3N (0.025 mmol, 3.5 μL, 5 mol %)
in 100 μL of EtOH were added after 5 min of stirring. After the
completion of the reaction, 200 μL of 1 N HCl was added, and
the mixture was concentrated and directly purified by column
chromatography on silica gel, using a mixture of petroleum
Supporting Information Available: Experimental proce-
dures and characterizations, NMR and chiral-phase HPLC
data, computational aspects, and optimized structures for cal-
culated species. This material is available free of charge via the
Internet at http://pubs.acs.org.
1316 J. Org. Chem. Vol. 75, No. 4, 2010