Direct proline catalyzed asymmetric α-aminooxylation of aldehydes

Article abstract of DOI:10.1016/j.tetlet.2003.09.057

The direct catalytic enantioselective α-aminooxylation of aldehydes has been developed using nitrosobenzene as the oxygen source and L-proline as catalyst, affording versatile α-aminooxylated aldehydes in high yield with excellent enantioselectivities.

Full text of DOI:10.1016/j.tetlet.2003.09.057

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 8293–8296
Direct proline catalyzed asymmetric a-aminooxylation
of aldehydes
Yujiro Hayashi,* Junichiro Yamaguchi, Kazuhiro Hibino and Mitsuru Shoji
Department of Industrial Chemistry, Faculty of Engineering, Tokyo University of Science, Kagurazaka, Shinjuku-ku,
Tokyo 162-8601, Japan
Received 27 August 2003; revised 8 September 2003; accepted 8 September 2003
Abstract—The direct catalytic enantioselective a-aminooxylation of aldehydes has been developed using nitrosobenzene as the
oxygen source and
ities.
L
-proline as catalyst, affording versatile a-aminooxylated aldehydes in high yield with excellent enantioselectiv-
© 2003 Elsevier Ltd. All rights reserved.
Optically active a-hydroxyaldehydes are important
intermediates in organic synthesis. Because of this util-
ity, many methods have been developed for their prepa-
ration,1 for instance, transformation from chiral natural
sources such as amino acids,2 sugars,3 and chiral a-
hydroxy acids.4 Diastereoselective reactions such as
nucleophilic addition to chiral glyoxal derivatives,5 or
alkylation of chiral hydrazones,1 are other useful syn-
thetic methods. Asymmetric hydrocyanation,6 and
enzymatic resolution7 have also been employed as a key
step for their synthesis. Most of these preparations,
however, require multiple manipulations and there is no
direct method, nor catalytic asymmetric method for
their synthesis from the corresponding aldehyde.
ered the direct,
L-proline catalyzed, asymmetric
a-aminooxylation of ketones (Scheme 1).13 As an exten-
sion of this methodology to the synthesis of the much
more versatile a-aminooxy- and a-hydroxy-aldehydes,
we have developed the direct catalytic enantioselective
a-aminooxylation of aldehydes using nitrosobenzene as
an oxidant and proline as catalyst, which is reported in
this communication.14
The reaction of propanal and nitrosobenzene was
selected as a model and the effect of solvent was
examined with the results summarized in Table 1. As
the a-aminooxy aldehyde product is rather labile, isola-
tion and characterization was performed after conver-
sion to the corresponding a-aminooxy alcohol by
treatment of the reaction mixture with NaBH4. Though
the a-aminooxylation reaction is readily accomplished
with very high enantioselectivity in most of the solvents
employed, the solvent effect is found to be rather
different from that of the a-aminooxylation of ketones:
While polarized solvents such as DMF, DMSO,
CH3NO2, NMP,15 and CH3CN are all suitable for the
a-aminooxylation of ketones,13 CH3CN is superior in
the reaction of aldehyde, which proceeds at −20°C,
On the other hand, proline8 has been found to be an
excellent asymmetric catalyst of the aldol reaction9 and
Mannich reaction,10 and for a-amination of carbonyl
compounds.11 Recently, Momiyama and Yamamoto
have reported an excellent catalytic asymmetric nitroso-
aldol reaction, in which the tin enolate of a ketone
reacts with nitrosobenzene in the presence of a catalytic
amount of BINAP–AgOTf complex, affording an a-
aminooxy ketone in high enantioselectivity, which is
easily converted into the corresponding a-hydroxy
ketone.12 Inspired by the notion that nitrosobenzene
could act as an electrophilic aminooxylating reagent,
we examined the reaction between a ketone and nitro-
sobenzene in the presence of proline, and have discov-
Keywords: organocatalyst; asymmetric reaction; catalytic reaction;
proline; a-aminooxylation.
* Corresponding author. Fax: +81-3-5261-4631; e-mail: hayashi@
ci.kagu.tus.ac.jp
Scheme 1. Direct asymmetric a-aminooxylation of cyclohexa-
none.
0040-4039/$ - see front matter © 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2003.09.057

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Y. Hayashi et al. / Tetrahedron Letters 44 (2003) 8293–8296
Table 1. Solvent effect of a-aminooxylation of propanala
such as the homo-dimerization of nitrosobenzene,
which proceed at 0°C (vide infra). The self-aldol reac-
tion of propanal is another side reaction, which is
known to proceed at 4°C.18
The catalyst loading can be reduced to 5 mol% without
loss of enantioselectivity, and while still giving a syn-
thetically useful yield (entry 4).
Entry
Solvent
Yield (%)b
ee (%)c
1
2
3
4
5
6
7
THF
NMP
18
34
43
43
49
63
Quant.
99
98
98
98
98
98
98
For the synthesis of a-aminooxy ketones, syringe pump
addition of nitrosobenzene to the ketone in the pres-
ence of proline is a key for obtaining the high yield in
order to suppress both dimerization of nitrosobenzene
and a,a%-di-aminooxylation.13 On the other hand, such
slow addition is not necessary in the reaction of alde-
hydes. That is, because of the higher reactivity of
aldehydes compared to that of ketones, a-aminooxyla-
tion of aldehydes proceeds at a lower temperature
(−20°C) than that of ketones (0°C), and at this lower
temperature dimerization of nitrosobenzene to form
azoxybenzene does not proceed.
CH3NO2
CHCl3
DMF
CH2Cl2
CH3CN
a Reaction conditions: propanal:nitrosobenzene:
reaction time: 24 h, reaction temperature: −20°C.
b Isolated yield of the alcohol (two steps).
c Determined by chiral HPLC.
L
-proline=3:1:0.3,
affording the a-aminooxylated aldehyde quantitatively
in 98% ee.16 In this reaction, no a-hydroxyamino alde-
hyde was formed at all, while a-hydroxyamino ketones
are major products in the reaction of nitrosobenzene
with a variety of alkali metal or tin enolates of
ketones.17
As the best reaction conditions had been established,
the generality of the reaction was examined with the
results summarized in Table 2. Not only propanal, but
also linear chain aldehydes such as n-butanal and n-
pentanal react with nitrosobenzene, affording a-
aminooxy aldehydes in good yield with excellent
enantioselectivity. Branched aldehydes such as 3-
methylbutanal are also suitable substrates, successfully
converted to the a-aminooxylated product in good yield
with excellent enantioselectivity. Aldehydes containing
an aromatic moiety such as 3-phenylpropanal and
phenylacetaldehyde were successfully employed in this
reaction, affording the a-aminooxylated compounds in
moderate yield and excellent enantioselectivity. With
regard to the temperature effect, the same influence on
yield and enantioselectivity as for propanal was
observed with all the aldehydes examined except for
3-methylbutanal: Better yield and the same enantio-
selectivity are obtained when the reaction is carried out
at −20°C compared with that at 0°C.
Next, reaction temperature was investigated with the
results summarized in Table 2 (entries 1 and 2). The
yield decreases to 80%, while the excellent enantioselec-
tivity is maintained when the reaction is conducted at
higher temperature (0°C), because of side reactions
Table 2. Proline-catalyzed direct asymmetric a-aminooxyla-
tion of aldehydesa
Entry
R
Temp. (°C)
Yield (%)b
ee (%)c
1
2
Me
Me
Me
Me
Et
Et
n-Pr
n-Pr
i-Pr
i-Pr
Ph
Ph
CH2Ph
CH2Ph
−20
0
−20
−20
−20
0
−20
0
−20
0
Quant.
80
Quant.
81
87
64
81
71
77
77
98
98
98
98
99
98
95
95
97
97
99
99
99
99
The absolute configuration of the 2-anilinooxypropanal
product was determined as follows: 2-Anilino-
oxypropanol 1 was converted into tert-butyldiphenyl-
silyl (TBDPS) ether 2 by treatment with TBDPSCl and
imidazole. The transformation of the anilinooxy moiety
into an hydroxy group can be successfully carried out
by treatment with a catalytic amount of copper sulfate
under the conditions developed by Yamamoto,12
affording alcohol 3. The absolute stereochemistry of
alcohol 3 was unambiguously determined to be (R),
based on HPLC analysis19 and comparison of the opti-
cal rotation with that of authentic (S)-3 prepared from
(S)-methyl lactate as shown in Scheme 2.
3d
4e
5
6
7
8
9
10
11
12
13
14
−20
0
−20
0
62
44
70
53
a Unless otherwise noted, reactions were conducted with 30% mol of
-proline, 1.0 equiv. of nitrosobenzene, and 3.0 equiv. of aldehyde
L
The following transition state model (Fig. 1), which is
the same as that proposed for the a-aminooxylation of
ketones,13 and similar to that proposed for the aldol
reaction9 and the a-amination of aldehydes11a by List,
explains the absolute stereochemistry of the a-
in CH3CN for 24 h at the temperature indicated.
b Isolated yield of alcohol (two steps).
c Determined by chiral HPLC.
d Reaction was conducted with 10% mol of catalyst.
e Reaction was conducted with 5% mol of catalyst.

Y. Hayashi et al. / Tetrahedron Letters 44 (2003) 8293–8296
8295
Brion, F. J. Am. Chem. Soc. 1980, 102, 7984; (b) Merrer,
Y. Le.; Dureault, A.; Gravier, C.; Languin, D.; Depezay,
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Tadano, K.; Iimura, Y.; Yokoo, H. J. Carbohydrate
Chem. 1986, 5, 1.
4. See, for example: (a) Ito, Y.; Kobayashi, Y.; Kawabata,
T.; Takase, M.; Terashima, S.; Tetrahedron 1989, 45,
5767; (b) Hayashi, Y.; Kanayama, J.; Yamaguchi, J.;
Shoji, M. J. Org. Chem. 2002, 67, 9443.
5. (a) Colombo, L.; Giacomo, M. D. Tetrahedron Lett.
1999, 40, 1977; (b) Review: Eliel, E. L. In Asymmetric
Synthesis 2A; Morrison, J. D., Ed.; Academic Press: New
York, 1983; p 125, and references cited therein.
6. Reviews, see: (a) Kanai, M.; Hamashima, Y.; Takamura,
M.; Shibasaki, M. J. Syn. Org. Chem. 2001, 59, 766; (b)
Mori, A.; Inoue, S. In Comprehensive Asymmetric Cataly-
sis II; Jacobsen, E. N.; Pfaltz, A.; Yamamoto, H., Ed.;
Springer-Verlag: Berlin, 1999; p 983.
Scheme 2. The determination of the absolute configuration of
1.
aminooxylated aldehydes, though two reaction mecha-
nisms have been proposed for the nitroso-aldol reaction
of ketones, one proceeding via a nitrosobenzene-
monomer, the other a nitrosobenzene-dimer.17
7. (a) Pederson, R. L.; Liu, K. K.; Rutan, J. F.; Chen, L.;
Wong, C.-H. J. Org. Chem. 1990, 55, 4897; (b) Effen-
berger, F.; Null, V.; Ziegler, T. Tetrahedron Lett. 1992,
33, 5157 and references cited therein.
8. Reviews, see: (a) List, B. Synlett 2001, 1675; (b) List, B.
Tetrahedron 2002, 58, 5573.
9. Pidathala, C.; Hoang, L.; Vignola, N.; List, B. Angew.
Chem. Int. Ed. 2003, 42, 2785 and references cited therein.
10. (a) List, B.; Pojarliev, P.; Biller, W. T.; Martin, H. J. J.
Am. Chem. Soc. 2002, 124, 827; (b) Cordova, A.; Watan-
abe, S.; Tanaka, F.; Notz, W.; Barbas, C. F., III. J. Am.
Chem. Soc. 2002, 124, 1866; (c) Hayashi, Y.; Tsuboi, W.;
Ashimine, I.; Urushima, T.; Shoji, M.; Sakai, K. Angew.
Chem. Int. Ed. 2003, 42, 3677; (d) Hayashi, Y.; Tsuboi,
W.; Shoji, M.; Suzuki, N. J. Am. Chem. Soc. 2003, 125,
11208, and references cited therein.
11. (a) List, B. J. Am. Chem. Soc. 2002, 124, 5656; (b)
Kumaragurubaran, N.; Juhl, K.: Zhuang, W.; Bøgevig,
A.; Jørgensen, K. A. J. Am. Chem. Soc. 2002, 124, 6254;
(c) Bøgevig, A.; Juhl, K.: Kumaragurubaran, N.;
Zhuang, W.; Jørgensen, K. A. Angew. Chem. Int. Ed.
2002, 41, 1790; (d) Review: see, Duthaler, R. O. Angew.
Chem. Int. Ed. 2003, 42, 975.
Figure 1. The transition state model.
In summary, the direct a-aminooxylation of aldehydes
has been realized in excellent enantioselectivity by using
nitrosobenzene as oxidant and
L-proline as catalyst.
The success of this process lies in the low temperature
used (−20°C), at which side-reactions such as the dimer-
ization of nitrosobenzene and aldol reactions can be
suppressed. Because of the easy conversion of the a-
aminooxy moiety to an a-hydroxy group, the present
method is synthetically useful for the preparation of
a-hydroxy aldehydes, which are versatile chiral interme-
diates in natural product synthesis.20
12. Momiyama, N.; Yamamoto, H. J. Am. Chem. Soc. 2003,
125, 6038.
13. Hayashi, Y.; Yamaguchi, J.; Sumiya, T.; Shoji, M.
submitted.
Acknowledgements
14. During the preparation of this manuscript, an excellent
paper dealing with the same reaction has appeared.
Brown, S. P.; Brochu, M. P.; Sinz, C. J.; MacMillan, D.
W. C. J. Am. Chem. Soc. 2003, 125, 10808.
This work was supported by a Grant-in-Aid for Scien-
tific Research on Priority Areas (A) ‘Exploitation of
Multi-Element Cyclic Molecules’ from the Ministry of
Education, Culture, Sports, Science and Technology,
Japan.
15. N-methyl-pyrrolidinone.
16. Though CHCl3 is reported to be a suitable solvent by
MacMillan et al.14 CH3CN is found to be superior in our
hands.
17. (a) Momiyama, N.; Yamamoto, H. Angew. Chem. Int.
Ed. 2002, 41, 2986; (b) Momiyama, N.; Yamamoto, H.
Org. Lett. 2002, 4, 3579.
References
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Enders, D.; Reinhold, U. Synlett 1994, 792 and references
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1996, 1427 and references cited therein.
18. Northrup, A. B.; MacMillan, D. W. C. J. Am. Chem.
Soc. 2002, 124, 6798.
19. HPLC conditions: Chiral OD-H column, i-PrOH:hexane
1:40, 0.5 mL/min, retention time: 11.5 min (R-isomer)
and 12.7 min (S-isomer). Racemic ( )-3 was prepared
from hydroxyacetone by the two steps: (1) TBDPSCl,
imidazole, (2) NaBH4.
3. See, for example: (a) Corey, E. J.; Marfat, A.; Goto, G.;

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Y. Hayashi et al. / Tetrahedron Letters 44 (2003) 8293–8296
20. Typical experimental procedure is as follows (Table 2,
entry 1): To a CH3CN solution (3 mL) of propanal (108
mL, 1.5 mmol) and nitrosobenzene (53.5 mg, 0.5 mmol)
stirred for 10 minutes at that temperature. After addition
of the phosphate buffer, the organic materials were
extracted with AcOEt three times and the combined
organic phase was dried over Na2SO4. Purification by
column chromatography with silica gel (AcOEt/hexane=
1/10–1/3) afforded aminooxy aldehyde (83.5 mg, 0.5
mmol) quantitatively.
was added L-proline (17.3 mg, 0.15 mmol, 0.3 equiv.) at
−20°C. After stirring the reaction mixture for 24 h at that
temperature, MeOH (1 mL) and NaBH4 (94.5 mg, 2.5
mmol) were added to the reaction mixture, which was