Metal-free direct asymmetric aminoxylation of aldehydes catalyzed by a binaphthyl-based chiral amine

Article abstract of DOI:10.1002/anie.201002965

And I'm free, metal-free fallin': A metal-free direct asymmetric aminoxylation of aldehydes with the oxoammonium salt 1, generated in situ from TEMPO and benzoyl peroxide (BPO), was found to be catalyzed by a binaphthyl-based secondary amine (S)-2. This m

Full text of DOI:10.1002/anie.201002965

Communications
DOI: 10.1002/anie.201002965
Asymmetric Organocatalysis
Metal-Free Direct Asymmetric Aminoxylation of Aldehydes Catalyzed
by a Binaphthyl-Based Chiral Amine**
Taichi Kano, Haruka Mii, and Keiji Maruoka*
Chiral a-hydroxy carbonyl motifs are prevalent in natural
products and biologically active compounds, and are versatile
building blocks for the synthesis of structurally complex
molecules. It is known that such chiral a-hydroxy carbonyl
compounds are prepared by asymmetric oxygenations of
preformed enolates and enamines, such as epoxidation,[1]
dihydroxylation,[2] and aminoxylation.[3] Over the past several
years, a number of direct asymmetric a-oxygenations of
aldehydes and ketones catalyzed by chiral secondary amines
have been reported.[4–8] In this area, nitroso compounds have
been commonly utilized as an electrophile for asymmetric a-
aminoxylation, and virtually optically pure a-aminoxy car-
bonyl compounds have been prepared. However, the a-
aminoxy aldehydes and the reduced b-aminoxy alcohols
tion requires further improvement of the reaction conditions
and the substrate scope, the resulting aminoxy aldehydes are
attractive chiral building blocks as O-protected a-hydroxy
aldehydes because of their stability. Accordingly, we have
been interested in the possibility of utilizing oxoammonium
salt 1, which could be generated in situ by oxidation from
TEMPO, as a non-metal single-electron oxidant and an
aminoxylating agent in the aminoxylation of aldehydes
(Scheme 1b). Herein, we report a metal-free organocatalytic
asymmetric aminoxylation of aldehydes using TEMPO and
benzoyl peroxide (BPO) with high enantioselectivity and
broad substrate scope.
To oxidize TEMPO into 1, which is known as a catalyst in
TEMPO oxidation,[12] BPO was chosen as an organic oxidant.
In the presence of chiral pyrrolidine catalyst (S)-2,[8a] 3-
produced are highly labile, probably owing to oligomerization
[4]
À
and/or N O bond cleavage.
Recently, Sibi and Hasegawa reported the asymmetric a-
aminoxylation of aldehydes using a stable radical, 2,2,6,6-
tetramethylpiperidine 1-oxyl free radical (TEMPO),[5] which
is considered to progress via a radical coupling pathway
between TEMPO and the enamine radical cation generated
from the enamine intermediate and a metal single electron
oxidant (Scheme 1a).[9–11] Whilst this metal-promoted reac-
phenylpropanal was first treated with TEMPO and BPO in
dichloromethane at 08C. As expected, the reaction proceeded
to give the desired a-aminoxy aldehyde. To determine the
enantioselectivity of the reaction, the product was reduced in
situ with NaBH4 to the corresponding alcohol 6, and the
enantioselectivity was found to be moderate (Table 1,
Table 1: Aminoxylation of 3-phenylpropanal.[a]
Scheme 1. Aminoxylation of aldehydes via enamine intermediates.
a) Previous work by Sibi and Hasegawa,[5] and b) this work. SET=sin-
gle electron transfer.
Entry
Catalyst
Solvent
T [8C]
t [h]
Yield [%][b]
ee [%][c]
1
2
(S)-2
(S)-3
(S)-4
(S)-5
(S)-5
(S)-5
(S)-5
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
THF
0
0
0
3
5
9
62
28
53
33
99
40
47
44 (S)
47 (S)
30 (S)
94 (R)
95 (R)
92 (R)
95 (R)
3[d]
4
0
7
[*] Dr. T. Kano, H. Mii, Prof. K. Maruoka
Department of Chemistry, Graduate School of Science
Kyoto University, Sakyo, Kyoto 606-8502 (Japan)
Fax: (+81)75-753-4041
5[e]
6[e]
7[e]
À10
À10
À10
24
23
23
toluene
E-mail: maruoka@kuchem.kyoto-u.ac.jp
[a] The reaction of 3-phenylpropanal (0.1 mmol), TEMPO (0.11 mmol),
and BPO (0.11 mmol) was carried out in 0.5 mL solvent in the presence
of 0.005 mmol catalyst. [b] Yield of isolated product. [c] The ee value of 6
was determined by HPLC analysis using a chiral column. [d] 10 mol% of
(S)-4. [e] 3-Phenylpropanal (0.1 mmol), TEMPO (0.13 mmol), BPO
(0.06 mmol), and a solvent (0.2 mL). TMS=trimethylsilyl.
[**] This work was supported by a Grant-in-Aid for Scientific Research
from MEXT (Japan). H.M. thanks the Japan Society for the
Promotion of Science for Young Scientists for Research Fellowships.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201002965.
6638
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Angew. Chem. Int. Ed. 2010, 49, 6638 –6641

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Chemie
entry 1). Another pyrrolidine-type catalyst (S)-3[13] gave a
lower yield and similar enantioselectivity (Table 1, entry 2).
In terms of enantioselectivity, no improvement was observed
with the binaphthyl-based amino alcohol catalyst (S)-4[14]
(Table 1, entry 3). We assumed that the poor enantioselectiv-
ity might arise from the sterically less-hindered oxygen atom
of 1. Thus, a binaphthyl-based secondary amine catalyst (S)-5,
containing bulky substituents at the 3,3’-positions, was
synthesized by the introduction of trimethylsilyl groups into
(S)-4. Gratifyingly, using the sterically more-congested cata-
lyst (S)-5, the desired aminoxylation product was obtained in
excellent enantioselectivity albeit with low yield (Table 1,
entry 4).
Encouraged by this promising result, the reaction con-
ditions were then optimized. Under the reaction conditions at
08C, 3-phenylpropanal was found to be oxidized into 3-
phenylpropanoic acid, and the catalyst could also be deacti-
vated via oxidation by 1 and/or BPO. These undesired side-
reactions could be suppressed somewhat by lowering the
reaction temperature and decreasing the amount of BPO;
higher concentration also resulted in an improved yield
(Table 1, entry 5). Switching solvent from dichloromethane to
tetrahydrofuran and toluene did not improve the yield
(Table 1, entries 6 and 7).
purity. In this transformation, the 2,2,6,6-tetramethylpiper-
idinyl group was not oxidized and acted as a protecting group.
The reaction of a-aminoxy aldehyde 7 with PhMgBr in
tetrahydrofuran proceeded smoothly to give the correspond-
ing half-protected 1,2-diol 9 in excellent diastereoselectivity
without loss of optical purity [Eq. (2)]. The observed
diastereoselectivity can be explained by non-chelation
control, which might be attributable to the bulky and non-
protic aminoxyl group of 7 (Figure 1, left), and contrasted
sharply with that observed in the chelate-controlled reactions
between Grignard reagents and a-aminoxy aldehydes gen-
erated in situ from nitroso compounds (Figure 1, right).[16]
This reaction system was then applied to various alde-
hydes (Table 2). Under the optimized conditions, the corre-
sponding a-aminoxylated products were obtained with good
to excellent enantioselectivity in all cases examined.
Table 2: Aminoxylation of various aldehydes.[a]
Entry
R
Yield [%][b] ee [%][c] Entry
R
Yield [%][b] ee [%][c]
1[d]
2
3
Me
Et
Bu
Bn
75
88
77
99
91
92
93
95
5
6
7
allyl
iPr
Cy
89
94
95
95
99
98
Figure 1. Possible transition-state models for diastereoselective nucle-
ophilic addition to a-aminoxy aldehydes.
4
[a] The reaction of an aldehyde (0.1 mmol), TEMPO (0.13 mmol), and
BPO (0.06 mmol) was carried out in CH2Cl2 (0.2 mL) in the presence of
(S)-5 (0.005 mmol). [b] Yield of isolated product. [c] The ee value of the
product was determined by HPLC analysis using a chiral column. [d] The
reaction time was 12 h.
For this aminoxylation reaction, two radical reaction
pathways and an ionic reaction pathway could be suggested:
1) The enamine radical cation 11, which is generated by
oxidation of the enamine intermediate 10 with BPO, reacts
with a TEMPO radical to give the iminium intermediate 12
(Scheme 2, path a). 2) The enamine 10 is oxidized by oxoam-
monium salt 1, which is generated from TEMPO and BPO, to
give the enamine radical cation 11 (path b). 3) Enamine 10
reacts directly with 1 in an ionic (nucleophilic addition)
pathway, giving 12 (path c).
Generation of oxoammonium salt 1 from TEMPO and
BPO was confirmed by an experiment in which treatment of
3-phenylpropanol with TEMPO (1 equiv) and BPO
(0.5 equiv) in dichloromethane led to the formation of 3-
phenylpropanal in 85% yield [Eq. (3)]. In addition, when the
aminoxylation of butanal was performed in the presence of 3-
phenylpropanol, the formation of a-aminoxy butanal 13 was
accompanied by oxidation of 3-phenylpropanol and the
aminoxylation of the resulting 3-phenylpropanal [Eq. (4)].
It should be noted that an a-aminoxyl aldehyde could be
isolated by column chromatography without reduction of the
carbonyl group,[15] and neither decomposition nor racemiza-
tion was observed. For instance, the isolated a-aminoxy
aldehyde 7 (89% yield, 96% ee) was stored in [D]chloroform
1
for 60 hours without any change observed by H NMR and
HPLC analyses (see the Supporting Information). To exam-
ine the synthetic utility of this aminoxylation reaction, an
optically enriched a-aminoxy aldehyde 7 was converted into
its corresponding a-hydroxy acid derivative [Eq. (1)]. Thus,
treatment of the a-aminoxy aldehyde 7 with NaClO2 in the
presence of NaH2PO4 and 2-methyl-2-butene resulted in
clean formation of a-aminoxy acid 8 without loss of optical
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Communications
The absolute configuration of the product in this reaction
catalyzed by (S)-5 was determined to be R by comparison of
the HPLC retention time with the literature data.[5] Based on
the observed stereochemistry, transition-state models can be
proposed, as shown in Figure 2. In either the radial or ionic
pathway, one face of the enamine radical cation or the
enamine intermediate is effectively shielded by the bulky
substituent of (S)-5, and consequently, the reaction of an
aldehyde with TEMPO or 1 catalyzed by (S)-5 provides the R
isomer predominantly.
Scheme 2. Possible reaction pathways.
These observations strongly suggest the generation of
oxoammonium salt 1 under the reaction conditions, and 1
might participate in the present aminoxylation, thus suggest-
ing that the reaction proceeds through path b or path c.[17]
Although the partial generation of the radical intermediate 11
by BPO (path a) is possible, we believe that BPO would
preferentially react with a stoichiometric amount of TEMPO
to generate 1.
Figure 2. Plausible transition-state models.
In summary, we have developed the first metal-free direct
aminoxylation reaction of aldehydes with an oxoammonium
salt 1, catalyzed by the novel binaphthyl-based amine (S)-5.
This method represents a rare example of the catalytic and
highly enantioselective synthesis of bench-stable a-aminoxy
aldehydes. The synthetic utility of the obtained stable a-
aminoxy aldehydes has also been demonstrated by taking
advantage of their characteristic features. We are currently
working to expand the scope of this methodology, as well as to
ascertain mechanistic details of the aminoxylation.
Received: May 17, 2010
Published online: July 29, 2010
Keywords: aldehydes · aminoxylation · asymmetric catalysis ·
.
organocatalysis
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