One-pot sequential alcohol oxidation and asymmetric α-oxyamination in aqueous media using recyclable resin-supported peptide catalyst

Article abstract of DOI:10.1039/c0cc02301a

An efficient tandem reaction system was developed, in which primary alcohols were used for the oxidation to the corresponding aldehydes followed by an asymmetric α-oxyamination with a resin-supported peptide catalyst.

Full text of DOI:10.1039/c0cc02301a

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One-pot sequential alcohol oxidation and asymmetric a-oxyamination in
aqueous media using recyclable resin-supported peptide catalystw
Kengo Akagawa, Takuma Fujiwara, Seiji Sakamoto and Kazuaki Kudo*
Received 1st July 2010, Accepted 7th September 2010
DOI: 10.1039/c0cc02301a
An efficient tandem reaction system was developed, in which
primary alcohols were used for the oxidation to the corresponding
aldehydes followed by an asymmetric a-oxyamination with a
resin-supported peptide catalyst.
in an organic solvent at low temperature.6,7 The enantio-
selectivity becomes somewhat lower when the reaction is
performed at room temperature. In this regard, we have found
that the stereoselectivity of this reaction could be improved by
using a peptide catalyst.8 Resin-supported peptide 1 (Fig. 1)9
promoted the reaction specifically in aqueous media, and
worked as a highly enantioselective catalyst at room tempera-
ture. We envisaged that this reaction could be extended to the
one-pot sequential reaction starting from primary alcohols in
which a copper salt works both for oxidation of alcohols and
for a-oxyamination of aldehydes. Furthermore, it was also
expected that the use of a copper salt for a-oxyamination
could provide less detrimental conditions for the catalyst
because of the lower redox potential of Cu2+/Cu+ compared
Recent remarkable advancements in organocatalytic reactions
have led to the development of various synthetic methods.1
One of the features of organocatalysis is its applicability to
sequential reactions. In addition to a number of domino reac-
tions performed by a single organocatalyst, tandem reactions
utilizing multiple catalysts have been receiving increasing
attention.2 Although the compatibility of each catalyst in
one flask should be considered in tandem reactions, they have
great potential for efficient synthesis of target compounds
without isolating/purifying intermediates. So far, tandem reac-
tions employing two kinds of organocatalysts3 and those
combining a metal catalyst and an organocatalyst2a,3d,4 have
been reported.
with Fe3+/Fe2+ 10
.
Initially, the asymmetric a-oxyamination of aldehyde 2 with
TEMPO was tested using copper(I) chloride under an oxygen
atmosphere (Scheme 1). We employed peptide 1 as a catalyst
because it showed good enantioselectivity in the asymmetric
a-oxyamination of aldehydes with iron(II) chloride under
aerobic conditions.8 The reaction proceeded smoothly in
THF–H2O (1 : 2) to give the oxyaminated product with good
enantioselectivity (47% yield, 94% ee). When the reaction was
performed in THF, the yield and selectivity were lowered
(12% yield, 73% ee), indicating that the aqueous solvent
system is essential for an efficient and enantioselective
reaction.
On the other hand, many organocatalytic reactions, especially
amine-catalyzed ones, use aldehydes as substrates. Some
aldehydes are chemically unstable and aldehydes are often
commercially less available than the corresponding primary
alcohols. Therefore, tandem catalytic reactions starting from
the oxidation of a primary alcohol to an aldehyde are syntheti-
cally important. In spite of their expected usefulness, there has
been no report on such tandem reactions. For tandem reac-
tions that include enantioselective transformation of an
aldehyde, mild reaction conditions for the first oxidation step
are required. Oxidation using a catalytic amount of TEMPO
and a copper salt under O2 is a good candidate from amongst
the other oxidizing methods.5 However, to achieve an enantio-
selective tandem reaction catalyzed by the TEMPO/Cu system
and a chiral amine, there are some obstacles: (1) the oxidation
of an alcohol by TEMPO and a copper salt is commonly
performed at or above room temperature, whereas many
chiral-amine-catalyzed reactions need a lowered temperature
for good enantioselectivity; (2) in the presence of an amine
catalyst, TEMPO becomes reactive toward an aldehyde
(vide infra); and (3) the over-oxidation of an aldehyde to a
carboxylic acid causes a decrease in yield, therefore the rate of
an amine-catalyzed reaction should be high.
Next, the conversion of alcohol 4 to aldehyde 2 was
examined (Table 1). When the same conditions as those in
the above asymmetric a-oxyamination were employed, the
oxidation of the alcohol did not proceed at all in THF–H2O
(1 : 2) (entry 1). With the addition of 2,20-bipyridine, which is a
known additive for the Cu/TEMPO-catalyzed oxidation of
alcohols under aqueous conditions,11 the generation of the
aldehyde could be observed with a moderate reaction rate
(entry 2). In contrast, the oxidation of alcohol 4 occurred
Fig. 1 Resin-supported peptide catalyst.
Recently, Sibi et al. developed asymmetric a-oxyamination of
aldehydes with TEMPO catalyzed by a chiral imidazolidinone
Institute of Industrial Science, University of Tokyo, 4-6-1 Komaba,
Meguro-ku, Tokyo, 153-8505, Japan.
E-mail: kkudo@iis.u-tokyo.ac.jp; Fax: +81-3-5452-6359;
Tel: +81-3-5452-6357
w Electronic supplementary information (ESI) available: NMR,
HPLC, MS data and additional experimental results. See DOI:
10.1039/c0cc02301a
Scheme 1 a-Oxyamination using peptide catalyst.
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8040 Chem. Commun., 2010, 46, 8040–8042
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Table 1 Oxidation of alcohol in the presence of TEMPO and Cu(I)
Entry
Solvent
Additive
Time/h
4 : 2 : 5 : 6
1
2
3
4
5
THF–H2O = 1/2
THF–H2O = 1/2
DMF
DMF
DMF–H2O = 1/2
None
2,20-Bipyridine (0.3 equiv)
None
2,20-Bipyridine (0.3 equiv)
2,20-Bipyridine (0.3 equiv)
2
6
2
2
6
100 : 0 : 0 : 0
57 : 23 : 20 : 0
43 : 43 : 0 : 14
1 : 8 : 83 : 8
39 : 22 : 39 : 0
smoothly without/with 2,20-bipyridine in DMF (entries 3 and 4),
a common solvent for oxidation by the Cu/TEMPO system. In
these cases, however, the formation of a-oxyaminated
aldehyde 6 was observed. Such addition of TEMPO at the
a-position of the resulting aldehydes was reported when an
excess amount of TEMPO was used for the oxidation
of primary alcohols in organic solvent.12 This uncatalyzed
addition of TEMPO is undesirable, because it decreases
enantioselectivity in the chiral-amine-catalyzed oxyamination.
The suppression of the background oxyamination in aqueous
solvent (entries 2 and 5) implies the importance of conducting
the sequential reaction under aqueous conditions. A large
amount of carboxylic acid 5 was also generated in the presence
of 2,20-bipyridine. Because the degree of formation of 5 was
somewhat lowered in THF–H2O (1 : 2), we decided to use this
solvent system for the sequential reaction.13
Table 2 One-pot tandem reaction including oxidation of primary
alcohols and asymmetric a-oxyamination
Entry
1
R
Yield (%)
66
ee (%)a
93
a
2
3
4
5
6
7
8
(1st reuse of peptide)
(2nd reuse of peptide)
(3rd reuse of peptide)
(4th reuse of peptide)
(5th reuse of peptide)
(6th reuse of peptide)
(7th reuse of peptide)
60
70
75
73
73
71
71
92
91
92
92
91
92
91
The one-pot tandem oxidation of alcohols to the chiral
oxyaminated products was performed in THF–H2O (1 : 2)
using TEMPO, the copper salt, and peptide catalyst 1
(Table 2).z The two-step oxidation of alcohol 4a without
isolating the aldehyde proceeded successfully in a good enantio-
selective manner (entry 1). With an imidazolidinone catalyst,
this one-pot reaction could not be performed efficiently
under the present reaction conditions.14 The sequential reac-
tion system could be applied to other aromatic alcohols
(entries 9 to 12) and an aliphatic alcohol (entry 13), affording
the products in good yield and enantioselectivity. When
2-phenylethanol was used as a substrate, the oxyaminated
product was obtained in good yield, but was nearly racemic
(entry 14). This might be because the highly enolizable
character of the reaction intermediate phenylacetaldehyde
caused the uncatalyzed rapid addition of TEMPO. In general,
heterogeneous catalysts are advantageous from the viewpoint
of reusability.15 Peptide catalyst 1 was recovered after the
reaction by filtration, and was subjected to repeated use. Even
after being reused seven times, the sequentially oxidized
product was obtained without substantial loss in both yield
and enantioselectivity (entries 2 to 8).16 Such high tolerance
for the recycling use of the peptide catalyst could be attained
presumably because of the mild reaction conditions using the
copper salt as a reagent.17,18
9
b
c
76
70
90
87
10
11
d
e
85
76
91b
86
12
13
f
74
85
92b
4c
14
g
a
Determined by chiral HPLC analysis using Chiralcel OD-H, unless
b
otherwise noted. Determined by chiral HPLC analysis using Chiralpak
c
IA. Determined by chiral HPLC analysis using Chiralcel OJ.
demonstrates that the combination of peptide catalysis under
aqueous conditions with another catalytic system has potential
for developing new reactions. Currently, other one-pot sequential
reactions starting from primary alcohols are under investigation
in our laboratory.
In conclusion, the one-pot sequential oxidation of alcohols
to a-oxyaminated aldehydes was realized using the resin-
supported peptide catalyst 1. In particular, the aqueous media
was important for high enantioinduction by inhibiting the
uncatalyzed addition of TEMPO to an aldehyde. This study
Notes and references
z Typical procedure (Table 2): To a mixture of alcohol 4 (0.1 mmol),
TEMPO (0.4 mmol), 2,20-bipyridine (0.03 mmol), and peptide catalyst
1 9c (150 mg, 0.02 mmol of the terminal prolyl group) in 0.33 mL of
THF and 0.67 mL of distilled water, copper(I) chloride (0.03 mmol)
c
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was added. The mixture was stirred under oxygen atmosphere at room
temperature for 36 h, then the catalyst was filtered off and washed with
chloroform. To the filtrate solution, 10% citric acid aqueous solution
was added, and extracted with chloroform. The organic layer was
dried over anhydrous magnesium sulfate. The solvent was evaporated
under reduced pressure, and excess TEMPO was removed by sublima-
tion using a vacuum pump. The residue was dissolved in 1 mL of THF,
and sodium borohydride (0.5 mmol) was added. The mixture was
stirred for 1 h, then saturated ammonium chloride aqueous solution
was added. The resulting solution was extracted with chloroform, and
the organic layer was dried over anhydrous magnesium sulfate. After
the removal of the solvent under reduced pressure, the crude product
was purified using preparative TLC (hexane–ethyl acetate = 2 : 1) to
afford oxyaminated product 3. The absolute configurations of the
major products were determined according to the literature.6 In the
examination of recycling peptide catalyst 1, the collected catalyst by
filtration after the reaction was washed with DMF and dichloro-
methane, and dried in vacuo before the next use. Copper(I) chloride
and 2,20-bipyridine were added in each cycle.
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14 When (5R)-(+)-2,2,3-trimethyl-5-benzyl-4-imidazolidinone mono-
hydrochloride (Aldrich 663069) was used instead of peptide
catalyst 1, 3a was obtained in 28% yield and 66% ee.
15 For a review, see M. Gruttadauria, F. Giacalone and R. Noto,
Chem. Soc. Rev., 2008, 37, 1666.
16 The resin catalyst was filtered off and washed after each cycle of the
reuse. Gravimetric analysis of the dried resin indicated that 0 to
80% of copper–bipyridine complex remained inside the resin. The
fairly broad range in the amount of the residual copper complex
might be due to the difference in washing conditions. In the reuse
of the peptide catalyst, the copper salt and bipyridine were added in
order to ensure the reproducibility regardless of the way of washing.
17 For example, when cerium(IV) ammonium nitrate, a much stronger
oxidizing agent than a copper salt, was employed for the asymmetric
a-oxyamination of an aldehyde, recycling peptide catalyst 1 drastically
decreased yield and enantioselectivity. In case of 2a, the reaction gave
the product with 71% yield and 89% ee in the first reuse of 1, but with
14% yield and 58% ee in the second reuse.
18 During the revision of this manuscript, Maruoka et al. reported the
elegant asymmetric a-oxyamination using TEMPO and benzoyl
peroxide: T. Kano, H. Mii and K. Maruoka, Angew. Chem., Int.
Ed., 2010, 49, 6638, DOI: 10.1002/anie.201002965. This paper also
includes the one-pot reaction from an alcohol. However, it is not a
tandem-type method, but an orthogonal one in which reagents are
added sequentially.
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8042 Chem. Commun., 2010, 46, 8040–8042
This journal is The Royal Society of Chemistry 2010