Metal-free enantioselective hydroxyamination of aldehydes with nitrosocarbonyl compounds catalyzed by an axially chiral amine

Article abstract of DOI:10.1021/ja4099627

The first example of a highly regio- and enantioselective hydroxyamination of aldehydes with in situ generated nitrosocarbonyl compounds from hydroxamic acid derivatives was realized by combined use of TEMPO and BPO as the oxidant in the presence of a binaphthyl-modified amine catalyst.

Full text of DOI:10.1021/ja4099627

Communication
pubs.acs.org/JACS
Metal-Free Enantioselective Hydroxyamination of Aldehydes with
Nitrosocarbonyl Compounds Catalyzed by an Axially Chiral Amine
Taichi Kano, Fumitaka Shirozu, and Keiji Maruoka*
Department of Chemistry, Graduate School of Science, Kyoto University, Sakyo, Kyoto 606-8502, Japan
S
* Supporting Information
socarbonyl compounds to date,6 while a number of catalytic
ABSTRACT: The first example of a highly regio- and
enantioselective hydroxyamination of aldehydes with in
situ generated nitrosocarbonyl compounds from hydroxa-
mic acid derivatives was realized by combined use of
TEMPO and BPO as the oxidant in the presence of a
binaphthyl-modified amine catalyst.
asymmetric transformations using relatively stable and easily
handled nitrosobenzene have been developed.8−10 The
difficulty in developing the catalytic asymmetric reaction of
nitrosocarbonyl compounds can be attributed to their high
reactivity as well as instability. Indeed, the development of the
catalytic asymmetric hydroxyamination with nitrosocarbonyl
compounds still remains challenging. In this context, we have
been interested in the possibility of developing such an
asymmetric transformation, which introduces a nitrogen atom
bearing a readily removable protecting group. Herein, we wish
to report a highly regio- and enantioselective hydroxyamination
of aldehydes with in situ generated nitrosocarbonyl compounds
by using a binaphthyl-modified amine catalyst of type 1.11
itroso compounds are frequently utilized as a nitrogen
N
and/or an oxygen source in synthetic organic chem-
istry.1−3 Among them, nitrosocarbonyl compounds, which can
be generated in situ by oxidation of hydroxamic acid derivatives,
are highly unstable transient species and have long been
employed mainly in hetero-Diels−Alder reactions2 and ene
reactions,3 despite their high synthetic potential (Scheme 1).4,5
Scheme 1. Typical Reactions of Nitrosocarbonyl
Compounds
We chose tert-butyl N-hydroxycarbamate (2a) as a precursor
of the nitrosocarbonyl intermediate because of the synthetic
utility of the N-Boc group. In the presence of the binaphthyl-
modified amine catalyst (S)-1a,12 various oxidants were
screened to generate the nitrosocarbonyl intermediate in the
reaction of 3-phenylpropanal with 2a (Table 1). When standard
oxidants such as PhI(OAc)2 and CuCl−pyridine−air for this
purpose were used, the undesired aminoxylated product 4a was
obtained in low yield (entries 1 and 3).2,3,5 While MnO2 gave
only a small amount of the desired hydroxyamination product
3a,6 the aminoxylation product 4a was still the major product
(entry 4). On the other hand, a combination of 2,2,6,6-
tetramethylpiperidine N-oxyl (TEMPO) and benzoyl peroxide
(BPO), which is known to generate the corresponding
oxoammonium salt,12a gave the desired 3a as a major product
in good yield and enantioselectivity (entry 5).13 Since use of
either TEMPO or BPO afforded neither 3a nor 4a (entries 6
and 7), the oxoammonium salt generated from TEMPO and
BPO would be the actual oxidant of 2a.12a
Very recently, both aminoxylation6 and hydroxyamination7 of
β-ketoesters with in situ generated nitrosocarbonyl compounds
were reported as new entries to the reaction of nitrosocarbonyl
compounds (Scheme 2). The asymmetric aminoxylation is only
one example of the catalytic asymmetric reaction of nitro-
Scheme 2. Addition Reactions to in Situ Generated
Nitrosocarbonyl Compounds
We then optimized the reaction conditions and the catalyst
as shown in Table 2. Among the solvents tested, 1,2-
dichloroethane was found to be the best in terms of the
Received: September 26, 2013
© XXXX American Chemical Society
A
dx.doi.org/10.1021/ja4099627 | J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Communication
a
Table 1. Screening of Oxidant
Table 3. Enantioselective Hydroxyamination of Various
Aldehydes
a
b
c
d
entry
oxidant (equiv)
PhI(OAc)2 (2.0)
yield (%)
3a/4a
ee (%)
b
c
d
entry
R
Pg
yield (%)
3/4
ee (%)
1
2
3
4
5
20
nd
10
26
71
nd
nd
1/>20
−
1/>20
1/2.4
2.5/1
−
−
−
−
−
70
−
−
DMP (2.0)
1
2
3
4
5
6
Me
Bu
Boc
Boc
Boc
Boc
Boc
Boc
Boc
Boc
Boc
Boc
Boc
Cbz
66
80
77
67
56
95
56
75
65
nd
nd
60
>20/1
>20/1
>20/1
>20/1
>20/1
>20/1
>20/1
>20/1
>20/1
−
98
99
98
94
99
99
92
99
99
−
CuCl (0.1), pyridine (0.025), air
MnO2 (2.0)
Bn
TEMPO (2.0), BPO (1.0)
TEMPO (3.0)
allyl
e
6
e
CH2Cy
(CH2)3OBn
CH2CO2Me
i-Pr
7
BPO (2.0)
−
e
a
7
The reaction of 3-phenylpropanal (0.050 mmol) with 2a (0.10
mmol) in CH2Cl2 (1.0 mL) was carried out in the presence of (S)-1a
8
b
(0.005 mmol) and an oxidant. Combined yield of 3a and 4a.
9
Cy
c
d
1
Determined by H NMR analysis. The ee of 3a was determined by
10
11
12
t-Bu
e
HPLC using a chiral column. Using 3.0 equiv of 2a.
Ph
−
>20/1
−
99
Bn
a
Table 2. Screening of Reaction Conditions
a
The reaction of an aldehyde (0.050 mmol) with 2 (0.10 mmol) in
1,2-dichloroethane (1.0 mL) was carried out in the presence of (S)-1d
(0.005 mmol), BPO (0.050 mmol), and TEMPO (0.10 mmol).
b
c
d
1
Isolated yield of 3. Determined by H NMR analysis. The ee of 3
e
was determined by HPLC using a chiral column. Use of 2a (0.15
mmol), BPO (0.075 mmol), and TEMPO (0.15 mmol).
b
c
d
entry
solvent
THF
catalyst
yield (%)
3a/4a
ee (%)
hydroxyamination, and the corresponding product with a Cbz
protecting group was obtained with virtually perfect regio- and
enantioselectivity (entry 12). In all cases, the aminoxylation
1
2
3
4
(S)-1a
(S)-1a
(S)-1a
(S)-1a
(S)-1a
(S)-1b
(S)-1c
(S)-1d
20
25
71
69
70
60
47
77
1/>20
1/>20
2.5/1
1.0/1
3.7/1
1.4/1
>20/1
>20/1
−
−
toluene
CH2Cl2
70
61
75
90
95
98
1
products 4 were not observed by TLC and H NMR analysis.
CHCl3
The obtained hydroxyamination product was a useful
intermediate in organic synthesis and readily converted to the
corresponding 1,2-hydroxyamino alcohol and N-Boc-protected
1,2-amino alcohol, respectively (Scheme 3). When a solution of
e
5
(CH2Cl)2
(CH2Cl)2
(CH2Cl)2
(CH2Cl)2
6
7
8
a
The reaction of 3-phenylpropanal (0.050 mmol) with 2a (0.10
Scheme 3. Transformations of Hydroxyamination Product
mmol) in a solvent (1.0 mL) was carried out in the presence of a
catalyst (0.005 mmol), BPO (0.050 mmol), and TEMPO (0.10
b
c
1
mmol). Combined yield of 3a and 4a. Determined by H NMR
d
analysis. The ee of 3a was determined by HPLC using a chiral
e
column. Aminoxylation product (R)-4a was obtained as a major
enantiomer (47% ee).
regio- and enantioselectivity (entry 5). Replacing TMS groups
in the catalyst (S)-1a with TES groups resulted in an increase in
enantioselectivity (entry 6). When the catalysts having 3,5-
difluorophenyl groups instead of phenyl groups were used, a
significant improvement in both regio- and enantioselectivity
was observed and thus led to the formation of 3a exclusively
(entries 7 and 8).14 Introduction of fluorine groups to phenyl
groups of the catalyst might change the conformation of the
catalyst and increase selectivities.
With the optimized conditions in hand, we examined the
substrate scope, and the results are shown in Table 3. In the
presence of 10 mol % of (S)-1d, 2 equiv of TEMPO, and 1
equiv of BPO, the reactions of various aldehydes with 2a gave
the corresponding hydroxyamination products 3 in moderate to
good yields with excellent regio- and enantioselectivities
(entries 1−9). Unfortunately, the reactions of the sterically
hindered 3,3-dimethylbutanal and phenylacetaldehyde did not
afford the desired product (entries 10 and 11). Benzyl N-
hydroxycarbamate (2b) was also applicable to the present
3a in CH2Cl2 was treated with TFA at room temperature, 1,2-
hydroxyamino alcohol 5 was obtained in good yield with
complete retention of stereochemistry. On the other hand,
reduction of 3a with Pd/C under a hydrogen atmosphere at
room temperature gave the N-Boc-protected 1,2-amino alcohol
6 in good yield without loss of optical purity. The absolute
configurations of 3a and 6 were determined to be S by
comparing the optical rotation of 6 with the literature value.15
We have previously reported that the direct asymmetric
aminoxylation of aldehydes with the in situ generated
oxoammonium salt 8 from TEMPO and BPO was catalyzed
by (S)-1a, giving the aminoxylation product 7 with R
configuration (Scheme 4).12a,16 Interestingly, the present
hydroxyamination did not afford 7 under similar conditions
(Scheme 5), and therefore, the oxidation of 2a with 8 must be
significantly faster than the aminoxylation of aldehydes with 8.
Additionally, when the reaction was performed under identical
conditions for the present hydroxyamination, but in the
B
dx.doi.org/10.1021/ja4099627 | J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Communication
Scheme 4. Previous Aminoxylation Using TEMPO and BPO
Scheme 5. Hydroxyamination vs Aminoxylation
absence of 2a, the aminoxylation product 7 with an R
configuration was obtained as the major enantiomer (Scheme
5). Since the enantiofacial selectivity was inversed depending
on the electrophile used,17 we have then examined another
electrophile to clarify the unique behavior of our catalyst. When
tert-butyl glyoxylate was employed instead of the in situ
generated nitrosocarbonyl compounds in the presence of (S)-
1d, the aldol reaction proceeded to give syn-9 with (2R,3R)
configuration as a major stereoisomer (Scheme 6).
Figure 1. Plausible transition state models.
organic synthesis. Further study is underway to ascertain
mechanistic details of the present hydroxyamination.
ASSOCIATED CONTENT
* Supporting Information
Experimental procedure and spectral data for all new
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
Scheme 6. Aldol Reaction of tert-Butyl Glyoxylate
■
S
AUTHOR INFORMATION
Corresponding Author
maruoka@kuchem.kyoto-u.ac.jp
■
Based on the observed stereochemistry, transition state
models can be proposed, as shown in Figure 1. In the present
hydroxyamination and the aldol reaction, both the in situ
generated nitrosocarbonyl intermediate and tert-butyl glyox-
ylate gain access to the sterically more congested Si face of the
enamine compared to the Re face (TS1 and TS2). Both
electrophiles might approach the Si face with the aid of a CH/π
interaction between the tert-butyl group of the electrophiles and
the aryl substituent of the catalyst18 and/or a hydrogen bonding
between Ar−H of the catalyst aryl substituent and electro-
philes.19 In the aminoxylation with either the in situ generated
nitrosocarbonyl compound (Table 2, entry 5) or 8 (Scheme 5),
on the other hand, the Si face of the enamine intermediate is
effectively shielded by the right-hand bulky substituent of (S)-1
(TS3 and TS4). Consequently, the reaction of an aldehyde
with the nitrosocarbonyl intermediate or 8 catalyzed by (S)-1
provides the R isomers predominantly.
In summary, we have realized a highly regio- and
enantioselective hydroxyamination of aldehydes with hydroxa-
mic acid derivatives by using a combination of TEMPO and
BPO as the oxidant and the binaphthyl-modified amine catalyst.
This method represents the first example of using the in situ
generated nitrosocarbonyl compounds for the catalytic
asymmetric hydroxyamination, which provides a new entry to
the enantioselective introduction of a nitrogen functionality in
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by a Grant-in-Aid for Scientific
Research from MEXT, Japan. F.S. is grateful to the Japan
Society for the Promotion of Science for Young Scientists for a
research fellowship.
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dx.doi.org/10.1021/ja4099627 | J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
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D
dx.doi.org/10.1021/ja4099627 | J. Am. Chem. Soc. XXXX, XXX, XXX−XXX