Enantioselective Henry reactions under dual Lewis acid/amine catalysis using chiral amino alcohol ligands

Article abstract of DOI:10.1002/anie.200463075

(Chemical Equation Presented) A simple assembly of commercially available materials, namely, zinc triflate (Zn-(OTf)₂), a tertiary amine base (iPr₂EtN), and reusable (+)-N-methylephedrine, effectively activates the Henry reaction bet

Full text of DOI:10.1002/anie.200463075

Angewandte
Chemie
Henry Reaction
Enantioselective Henry Reactions under Dual
Lewis Acid/Amine Catalysis Using Chiral Amino
Alcohol Ligands**
Claudio Palomo,* Mikel Oiarbide, and Antonio Laso
There is increasing interest in developing catalytic asymmet-
ric C C bond-forming processes.[1] In this endeavor the Henry
À
reaction[2] is prominent because of the versatile chemistry of
the nitro group.[3] Remarkably, however, while this reaction is
closely related to the aldol addition reaction, it has been much
less developed than the latter and only a few examples of
efficient catalytic enantioselective Henry reactions are known
to date.[4] The most outstanding examples include the use of
metal-based bifunctional chiral catalysts, as reported by the
groups of Shibasaki,[5] Trost,[6] and Evans,[7] which rely on
concurrent activation of the aldehyde and the nitroalkane.[8,9]
This concurrent activation in Henry reactions has also been
[*] Prof. Dr. C. Palomo, Prof. Dr. M. Oiarbide, A. Laso
Departamento de Quꢀmica Orgꢁnica I
Facultad de Quꢀmica
Universidad del Paꢀs Vasco
Apdo. 1072, 20080 San Sebastiꢁn (Spain)
Fax: (+34)943-015-270
E-mail: qoppanic@sc.ehu.es
[**] This work was financially supported by the University of the Basque
Country and the Ministerio de Educaciꢂn y Ciencia (MEC, Spain). A
predoctoral grant to A.L. from the MEC is acknowledged.
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
Angew. Chem. Int. Ed. 2005, 44, 3881 –3884
DOI: 10.1002/anie.200463075
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3881

Communications
realized by the combined use of discrete Lewis acids and
reaction was maintained although a decrease in enantiose-
lectivity was observed, whereas the reactions of the two
aldehydes in the presence of the related amino alcohol ligands
6, 7, and 9 were sluggish.
In subsequent experiments, it was found that substoichio-
metric quantities of the promoter system sufficed for the
reaction between nitromethane (2) and 1a (Table 2).[17] The
Brønsted bases as structurally independent entities.[10] While
this approach allows the straightforward scrutiny of a wide
range of Lewis acids and Brønsted bases during the optimi-
zation of the catalyst system, it is apparently troublesome
because of the chemical incompatibility of Lewis acids and
Brønsted bases[11] and the occurrence of a nonselective, base-
initiated Henry side reaction.[12] Herein, we report that highly
enantioselective direct Henry reactions can be triggered by a
combination of a simple ZnII salt, an amine base, and a chiral
amino alcohol ligand.
Table 2: Effect of the quantities of metal triflate, amine base, and amino
alcohol ligand on the reaction between hydrocinnamaldehyde (1a,
R=PhCH2CH2) and nitromethane (2).[a]
On the basis of precedents in the literature, the combi-
nation of a metal triflate salt, a tertiary amine base, and a
chiral amino alcohol ligand was initially selected.[13,14] Accord-
ingly, the Henry reaction of nitromethane 2 with hydro-
cinnamaldehyde 1a and benzaldehyde 1i (see Table 3), as
representative aliphatic and aromatic aldehydes, respectively,
was examined in the presence of stoichiometric quantities of
Zn(OTf)2, diisopropylethylamine, and a series of commer-
cially available chiral amino alcohol ligands[15,16] (4–10;
Scheme 1). As the data collected in Table 1 show, (+)-N-
methylephedrine ((+)-NME; 4) was prominent in providing
both nitroaldol products 3a and 3i in good yields and, most
importantly, with 90% and 70% ee, respectively. When 5, 8,
or 10 were employed as the ligand, the efficiency of the
Entry
Zn(OTf)2
[%][b]
iPr2EtN
(+)-NME
Conv.
[%][c]
ee
[%][b]
[%][b]
[%][d]
1
2
3
4
5
6
7
8
30
30
30
30
30
20
10
0
30
30
20
0
30
45
45
45
75
45
45
135
>99
90
48
80
90
50
ꢀ14
ꢀ12
0
88
64
20
10
0
>99
>99
70
84
70
0
[a] Reactions conducted on a 1-mmol scale (1) in nitromethane (1 mL)
for 15–16 h at À208C. [b] Percentage values refer to the mole percentage
(%mol) of the catalyst constituents with respect to the aldehyde.
[c] Percentage conversion of the reaction. [d] Determined by HPLC.
threshold loading for satisfactory results was set at 30 mol%
of metal salt, relative to the aldehyde, with lower loadings
usually accompanied by a diminished selectivity (entries 6
and 7).[18] The optimum result (90% yield, 90% ee) was
obtained by using Zn(OTf)2, iPr2EtN, and (+)-NME (4) in a
percentage mole ratio of 30:30:45 (entry 2). Lowering the
loading of (+)-NME to 30 mol% slightly diminished the
selectivity (entry 1), whereas increasing the ligand loading
above 45 mol% did not improve the result. The quantity of
iPr2EtN was crucial too. Lower loading or absence of iPr2EtN
(entries 3 and 4) led to diminished yields and ee values.
Interestingly, the absence of iPr2EtN could be partially
compensated by increasing the quantity of the ligand
(Table 2, entry 5) which is consistent with the amino alcohol
ligand playing the double role of chiral inductor and base.
Also, while a stoichiometric quantity of (+)-NME (4) alone
promoted the reaction (entry 8), the product was obtained as
a racemic mixture. Amongst the solvents examined, namely
methylene chloride, toluene, diethyl ether, and tetrahydro-
furan, all worked similarly well and lead to high enantiose-
lectivities except for THF.
A representative selection of aldehydes 1 were evaluated
under the optimized conditions and the results obtained are
summarized in Table 3. The enantioselectivities obtained
were above 90% for essentially all the aliphatic aldehydes
explored and even for the branched or sterically hindered
aldehydes, which gave values of up to 98% ee. Aromatic
aldehydes were also tolerated with equal chemical efficiency
although the enantioselectivities were comparatively moder-
ate. Typically, the reactions were carried out at À208C, but
lower temperatures (À408C, or even À608C under stoichio-
Scheme 1. Henry reaction of nitromethane (2) and an aldehyde 1
promoted by zinc triflate, iPr2EtN, and a chiral amino alcohol ligand
(4–10).
Table 1: Effect of the structure of the amino alcohol ligand on the
efficiency of the Henry reaction between nitromethane (2) and either
hydrocinnamaldehyde (1a) or benzaldehyde (1i) under stoichiometric
conditions.[a]
Product 3a (R=PhCH2CH2)
Product 3i (R=Ph)
Ligand
Conv. [%][b]
ee [%][c]
Conv. [%][b]
ee [%][c]
4
5
6
>99
>99
0
90
40
–
>99
>99
20
70
20
8
7
8
9
37
>99
35
24
0
0
60
85
0
40
0
–
10
>99
8
90
20
[a] Reactions conducted on a 1-mmol scale (1) using nitromethane as
solvent (1 mL). 1:1:1:1.5 molar ratio of aldehyde/Zn(OTf)2/iPr2EtN/(+)-
NME. [b] Determined by 1H NMR spectroscopy (500 MHz) after 15–16 h
reaction at À208C. [c] Determined by HPLC. See Supporting Information
for further details.
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Table 3: Scope of the aldehyde 1 for the Henry reaction with nitro-
methane under substoichiometric conditions of Zn(OTf)2/iPr2EtN/(+)-
NME.[a]
Aldehyde
T [8C]
t [h]
Yield [%][b]
ee [%][c]
1a
À20
16
90
90
À20
16
20
16
16
16
15
17
16
20
83
81
92
75
75
68
78
72
74
92
94
92
90
92
97
98
90
94
1b
1c
1d
À40[d]
À20
À20
À30
À20
1e
À40[d]
À20
Figure 1. Proposed reaction pathway and transition state (I) for the
catalytic Henry reaction. L*=(+)-NME (4).
1 f
1g
1h
À40[d]
À20
16
71
96
À20
16
16
87
82
74
87
À60[d]
1i
1j
À60[d]
À60[d]
45
45
82 (91)
68 (80)
92
89
1k
À60[d]
60
77
84
[a] Reactions conducted on the 1-mmol scale (1) in dry nitromethane
(1 mL) using Zn(OTf)2 (30 mol%), iPr2EtN (30 mol%), and (+)-NME
(45 mol%), otherwise stated. [b] Isolated yields after chromatography.
The numbers in parentheses refer to the percentage conversion. If not
specified, conversions are >99%. [c] Determined by HPLC. [d] Using a
1:1 (v/v) mixture of nitromethane and CH2Cl2 as solvent, and a ratio of
1:1:1:1.5 of aldehyde/Zn(OTf)2/iPr2EtN/ligand.
Figure 2. Positive nonlinear effect for the Henry reaction of nitrome-
thane and hydrocinnamaldehyde under substoichiometric conditions.
metric conditions) could also be used effectively to enhance
the enantioselectivity. Enals, however, constitute a limitation
of the present Henry reaction as they were either recovered
unconverted or led to a complex mixture of unidentifiable
products. Of practical relevance, the source of chirality, (+)-
NME (4), could be easily recovered in near-quantitative yield
after the reaction by simple aqueous acid/base workup and
reused (see Experimental Section).
factors of the observed nonlinearity. Studies directed to
clarify these mechanistic aspects as well as the extension of
this Lewis acid–Brønsted base dual-activation strategy to
other reactions is currently underway.
While the present Henry reaction[19] is simple in execution
and uses readily available reagents, the elucidation of its
mechanism is appealing. The sense of the asymmetric
induction imparted may be correctly predicted by transition
model I (Figure 1), which is in accord with previously
reported steric and electronic considerations.[7] However,
the nonlinear effect observed for the substoichiometric
reaction suggests a higher order molecularity of the catalyti-
cally active species. In this respect, the data collected in
Figure 2 for the Henry reaction of nitromethane (2) with
hydrocinnamaldehyde (1a) seem to fit well with Kaganꢀs two-
ligand model.[20] However, control experiments indicate that
there is not an appreciable variation of the nonlinear
magnitude measured at different values of catalyst loading,
while the enantiomeric composition of the product remains
essentially constant regardless of the level of conversion of
the reaction.[21] Accordingly, it also appears that both the
reservoir effect and the possible interaction of the catalytic
species with the forming nitroaldol may be discarded as
Experimental Section
In a typical procedure, diisopropylethylamine (1.04 mL, 6 mmol) was
added to a suspension of Zn(OTf)2 (2.18 g, 6 mmol) in CH3NO2 (2;
15 mL), and the slurry was stirred for 1 h at 258C. (1S,2R)-(+)-N-
Methylephedrine (4; 1.61 g, 9 mmol) was then added, and the
resulting yellow mixture was stirred for an additional 2 h at room
temperature. After cooling the mixture to À208C a solution of
trimethylacetaldehyde (1g; 2.17 mL, 20 mmol) in 2 (5 mL) was added
by syringe, and the mixture was stirred at the same temperature for
17 h. The reaction was quenched with a saturated aqueous solution of
NH4Cl (20 mL), the mixture was extracted with Et2O (3 ꢁ 20 mL), and
the combined organic layer was washed with HCl (12n; 2 ꢁ 10 mL)
and saturated NH4Cl (1 ꢁ 10 mL). The organic layer was dried with
MgSO4 and filtered, and the solvent was removed by evaporation.
The crude product was purified by column chromatography to give
(R)-3,3-dimethyl-1-nitrobutan-2-ol (3g) as the major product (2.3 g,
83% yield, 96% ee; Chiralcel OD, 98:2 hexane/iPrOH,
0.8 mLminÀ1). R major tr = 16.5 min, S minor tr = 19 min; [a]2D5
=
À37.2 (c = 1, CH2Cl2).[22] To recover the chiral ligand from the
aqueous phase, a solution of NaOH (20% w/v) was added dropwise to
the aqueous phase, cooled in an ice bath, until pH 10. The mixture was
extracted with CH2Cl2 (3 ꢁ 10 mL), and the organic layer was dried
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over MgSO4 and filtered, and the solvent was evaporated to afford
chemically and optically pure (1S,2R)-N-methylephedrine (2.8 g,
97% recovered).
[14] For amino-alcohol–ZnII complexes in enantioselective carbonyl
alkylations, see: a) K. Soai, S. Niwa, S. Chem. Rev. 1992, 92, 833 –
856; b) L. Pu, H.-B. Yu, Chem. Rev. 2001, 101, 757 – 824; and in
carbonyl alkynylations, see: c) E. M. Carreira, Acc. Chem. Res.
2000, 33, 373 – 381; d) L. Pu, Tetrahedron 2003, 59, 9873 – 9886;
e) P. G. Cozzi, R. Hilgraf, N. Zimmermann, Eur. J. Org. Chem.
2004, 4095 – 4105.
Received: December 27, 2004
Revised: February 2, 2005
Published online: May 13, 2005
[15] Other reports of Henry reactions using ZnII–amino-alcohol
complexes have met with essentially complete failure. See: a) G.
Klein, S. Pandiaraju, O. Reiser, O. Tetrahedron Lett. 2002, 43,
7503 – 7506; b) Y.-W. Zhong, P. Tian, G.-Q. Lin, Tetrahedron:
Asymmetry 2004, 15, 771 – 776; and with ZnII complexes with
chiral thioaza ligands, see: c) J. Gao, A. E. Martell, Org. Biomol.
Chem. 2003, 1, 2801 – 2806. Also, see Ref. [10c].
[16] Ligand 10 was prepared by the reductive methylation of indanol.
See: S. Yao, J.-C. Meng, G. Siuzdak, M. G. Finn, J. Org. Chem.
2003, 68, 2540 – 2546. The remaining ligands were purchased
from Aldrich.
[17] Other combinations of metal salts and Brønsted bases were also
examined, with either inferior results or complete failure of the
reaction observed. See Supporting Information for more details.
[18] Remarkably, the reaction between nitromethane (2) and piv-
alaldehyde (1d) under a low catalyst loading of Zn(OTf)2/
iPr2EtN/(+)-NME (10:10:15 mol% each) led to product 3d in
75% yield and in 90% ee.
[19] Under the optimized conditions for nitromethane, the reaction
between nitroethane and benzaldehyde gave a mixture of anti-
and syn-nitroaldols in a 65:35 ratio.
Keywords: amines · amino alcohols · asymmetric catalysis ·
.
Henry reaction · Lewis acids
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Downey, J. Am. Chem. Soc. 2003, 125, 12692 – 12693.
[8] For enantioselective fluoride-mediated Henry reactions that
used silyl nitronates as preactivated forms of nitroalkanes, see:
a) T. Risgaard, K. V. Gothelf, K. A. Jørgensen, Org. Biomol.
Chem. 2003, 1, 153 – 156; b) T. Ooi, K. Doda, K. Maruoka, J. Am.
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[20] a) C. Girard, H. B. Kagan, Angew. Chem. 1998, 110, 3088 – 3127;
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Adv. Synth. Catal. 2001, 343, 227 – 233.
[21] Similar results have also been observed in reactions with
butyraldehyde and heptanal. See Supporting Information for
details.
[22] By using (1R,2S)-(À)-N-methylephedrine as the ligand under
otherwise identical reaction conditions, the corresponding (S)-
nitroaldol was obtained (80% yield, 96% ee). [a]2D5 = + 36.8 (c =
1, CH2Cl2) ([a]D25 = + 29.39 (c = 3.39, CH2Cl2), 93% ee).[7]
[9] For reviews on the concept of dual acid/base catalysis, see: a) M.
Shibasaki, N. Yoshikawa, Chem. Rev. 2002, 102, 2187 – 2209;
b) M. Shibasaki, M. Kanai, K. Funabashi Chem. Commun. 2002,
1989 – 1999; c) G. J. Rowlands, Tetrahedron 2001, 57, 1865 –
1882; d) J.-A. Ma, D. Cahard, Angew. Chem. 2004, 116, 4666 –
4683; Angew. Chem. Int. Ed. 2004, 43, 4566 – 4583.
[10] For reactions employing bis(oxazoline)-based CuII complexes
and triethylamine, see: a) C. Christensen, K. Juhl, K. A.
Jørgensen, Chem. Commun. 2001, 2222 – 2223; b) C. Christen-
sen, K. Juhl, R. G. Hazell, K. A. Jørgensen, J. Org. Chem. 2002,
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Tetrahedron: Asymmetry 2004, 15, 3433 – 3441; For reactions
employing chiral imine based CoII complexes and diisopropyle-
thylamine, see: d) Y. Kogami, T. Nakajima, T. Ashizawa, S.
Kezuka, T. Ikeno, T. Yamada, Chem. Lett. 2004, 614 – 615; e) Y.
Kogami, T. Nakajima, T. Ikeno, T. Yamada, Synthesis 2004,
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[11] For a solution to this problem within the context of the double
catalytic activation strategy, see: S. Kanemasa, K. Itoh, Eur. J.
Org. Chem. 2004, 4741 – 4753.
[12] Base-catalyzed, nonselective Henry reactions are long known.
For the incidence of such a process in the efficiency of
asymmetric catalysis, see Ref. [10b].
[13] For the enolization of carbonyl compounds using metal triflates
in combination with tertiary amines, see: a) D. A. Evans, J. S.
Tedrow, J. T. Shaw, C. W. Downey, J. Am. Chem. Soc. 2002, 124,
392 – 393; b) D. A. Evans, C. W. Downey, J. L. Hubbs, J. Am.
Chem. Soc. 2003, 125, 8706 – 8707; c) C. J. Cowden, I. Paterson,
Org. React. 1997, 51, 1 – 200; d) Modern Aldol Reactions (Ed.: R.
Mahrwald), Wiley-VCH, Weinheim, 2004.
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