Enantioselectivity switch in direct asymmetric aminoxylation catalyzed by binaphthyl-based chiral secondary amines

Article abstract of DOI:10.1055/s-0029-1216635

Binaphthyl-based amino acids (S)-1 and an aminosulfonamide (S)-2 were applied for direct asymmetric aminoxylation with nitrosobenzene. In the presence of either (S)-1 or (S)-2, the aminoxylation of aldehydes proceeded smoothly, and subsequent reduction wi

Full text of DOI:10.1055/s-0029-1216635

SPECIAL TOPIC
1557
Enantioselectivity Switch in Direct Asymmetric Aminoxylation Catalyzed by
Binaphthyl-Based Chiral Secondary Amines
Asymmetric
A
m
a
inoxylatio
i
n
of
A
l
c
dehydes hi Kano, Akihiro Yamamoto, Fumitaka Shirozu, Keiji Maruoka*
Department of Chemistry, Graduate School of Science, Kyoto University, Sakyo, Kyoto 606-8502, Japan
Fax +81(757)534041; E-mail: maruoka@kuchem.kyoto-u.ac.jp
Received 16 January 2009
CO2H
NHTf
NH
Abstract: Binaphthyl-based amino acids (S)-1 and an aminosul-
fonamide (S)-2 were applied for direct asymmetric aminoxylation
with nitrosobenzene. In the presence of either (S)-1 or (S)-2, the
aminoxylation of aldehydes proceeded smoothly, and subsequent
reduction with NaBH4 gave 2-aminoxyl alcohols with good to ex-
NH
cellent enantioselectivities. In each case, binaphthyl-based chiral
amine catalysts (S)-1 and (S)-2, which have the identical axial
chirality, gave opposite enantiomers as the major product. This
method represents a rare example of the direct asymmetric aminox-
ylation by a non-proline type catalyst.
R
(S)-1a:
(S)-1b:
(S)-1c:
(S)-1d:
(S)-1e:
(S)-2
R = H
R = Ph
R = 3,5-Ph2C6H3
R = 3,5-(CF3)2C6H3
R = 3,4,5-F3C6H2
Key words: enamine catalysis, asymmetric aminoxylation, organo-
catalyst
Figure 1
synthesized new binaphthyl-based amino acids (S)-1b–e
Nitroso compounds are frequently utilized as a nitrogen
and/or an oxygen source in organic synthesis,1 and vari- having an aromatic substituent at the 3-position to control
ous catalytic asymmetric reactions, such as aminoxyla- the enamine conformation.
tion,2–6 hydroxyamination,5–8 and the nitroso Diels–Alder
The requisite binaphthyl-based amino acids (S)-1b–e
reaction9 have been developed by exploiting their unique
were synthesized in a six-step sequence from bis-triflate
properties. In this area, highly enantioselective aminoxy-
lation reactions of aldehydes and ketones using ni-
(S)-4,14 which was prepared from (S)-BINOL, as shown in
Scheme 2. Suzuki–Miyaura coupling and carboxylation
of (S)-4 gave the methyl esters (S)-5, which were convert-
ed with NBS into dibromides (S)-6. Treatment of (S)-6
with allylamine afforded the cyclic amines (S)-7. Finally,
Pd(OAc)2-catalyzed deallylation of (S)-7, followed by hy-
drolysis of the resulting methyl esters (S)-8 under basic
conditions provided the binaphthyl-based amino acids
(S)-1b–e.
trosobenzene have been realized by organocatalysts
through the generation of the enamine intermediate.3 To
the best of our knowledge, however, most of the reported
organocatalysts for the aminoxylation reaction are proline
and its derivatives, and structurally different catalysts
have not yet been studied. Accordingly, we have been in-
terested in the development of the direct asymmetric ami-
noxylation of aldehydes with binaphthyl-based chiral
With catalysts (S)-1b–e in hand, the direct asymmetric
secondary amine catalysts (S)-1 and (S)-2 (Figure 1),
aminoxylation of propanal with nitrosobenzene was car-
which are effective catalysts for the direct asymmetric al-
ried out, and the results are summarized in Table 1. Unex-
dol reaction10,11 and Mannich reaction,12 respectively.13
Herein, we wish to report a direct asymmetric aminoxyla-
tion reaction with nitrosobenzene using binaphthyl-based
chiral secondary amine catalysts.
(S)-1
or
(S)-2
O
O
N
We first attempted to use (S)-1a as a catalyst for the direct
asymmetric aminoxylation reaction of an aldehyde. Treat-
ment of propanal with nitrosobenzene in the presence of 5
mol% of (S)-1a in CHCl3 at 0 °C and subsequent reduc-
tion with NaBH4 in CHCl3–EtOH furnished the corre-
sponding 2-aminoxy alcohol in good yield with moderate
enantioselectivity (Table 1, entry 1). Since the enantiose-
lectivity in the present reaction reflects the conformation
of the enamine intermediate (Scheme 1), we designed and
X
X
+
Ph
Ph
N
N
H
Ph
H
N
N
R
O
O
R
R
s-cis-enamine
s-trans-enamine
O
O
O
O
NHPh
NHPh
R
R
SYNTHESIS 2009, No. 9, pp 1557–1563
Advanced online publication: 14.04.2009
x
x
.
x
x
.2
0
0
9
(R)-3
(S)-3
DOI: 10.1055/s-0029-1216635; Art ID: C00209SS
© Georg Thieme Verlag Stuttgart · New York
Scheme 1 Conformation of the enamine intermediate formed

1558
T. Kano et al.
SPECIAL TOPIC
were obtained (entries 2, 3). Switching the solvent to ace-
tonitrile resulted in no improvement (entry 4). In the case
of amide solvents DMF and NMP as well as THF, signif-
icant decreases in yield were observed, although the enan-
tioselectivities were increased to >90% ee (entries 5–7).
Aromatic solvents benzene, toluene, and mesitylene were
found to be effective both in terms of the yield and enan-
tioselectivity (entries 8, 9, and 12). The reaction per-
formed at lower concentration afforded the aminoxylated
product with good enantioselectivity, albeit with moder-
ate yield (entries 11, 13, and 14). Toluene proved to be op-
timal for the present reaction due to its ease of handling
and was selected for further studies.
Table 1 Direct Asymmetric Aminoxylation of Propanal with Ni-
trosobenzene Catalyzed by (S)-1a
O
OH
O
N
(S)-1 (5 mol%)
NaBH4
EtOH
O
+
NHPh
CHCl3, 0 °C, 1 h
Ph
Me
Me
Entry
Catalyst
Yield (%)b
ee (%)c
49
1
2
3
4
5
(S)-1a
(S)-1b
(S)-1c
(S)-1d
(S)-1e
82
99
82
88
87
64
60
62
Table 2 Solvent Effects in Direct Asymmetric Aminoxylation of
Propanal with Nitrosobenzene Catalyzed by (S)-1ea
79
a The reaction of propanal (3 equiv) with nitrosobenzene was carried
out in CHCl3 (2 M) in the presence of catalyst (S)-1 at 0 °C.
b Isolated yield.
O
OH
O
N
(S)-1e (5 mol%)
NaBH4
EtOH
O
+
NHPh
c Determined by HPLC analysis using chiral column (Chiralpak AD-
H, Daicel Chemical Industries, Ltd.).
solvent, 0 °C
Ph
Me
Me
Entry Solvent
Concn (M) Time (h) Yield (%)b ee (%)c
OTf
CO2Me
1
2
CHCl3
2.0
2.0
2.0
1.0
2.0
2.0
2.0
1.0
2.0
1.0
0.5
1.0
0.5
0.2
1
87
86
88
81
<10
30
40
85
86
89
70
94
62
64
79
77
76
77
90
92
90
85
83
86
89
86
91
91
1. ArB(OH)2, Pd(OAc)2, Ph3P
K3PO4, THF
Me
Me
Me
Me
CH2Cl2
ClCH2CH2Cl
MeCN
1
2. Pd(OAc)2, dppp, i-Pr2NEt
DMSO, MeOH, CO
3
1
OTf
Ar
CO2Me
N
4
1
(S)-4
(S)-5
5
DMF
1
CO2Me
6
NMP
2
Br
NBS, AIBN
benzene
allylamine
7
THF
2
MeCN
Br
8
benzene
toluene
toluene
toluene
mesitylene
mesitylene
mesitylene
1
Ar
Ar
9
1
(S)-6
(S)-7
10
11
12
13
14
1
CO2Me
NH
N,N'-dimethyl-
barbituric acid
Pd(OAc)2, Ph3P
1
1 M NaOH
MeOH–THF
(S)-1b–e
1.5
1.5
5
CH2Cl2
Ar
(S)-8
a The reaction of propanal (3 equiv) with nitrosobenzene was carried
out in the solvent mentioned above in the presence of catalyst (S)-1e
at 0 °C.
Scheme 2 Synthesis of binaphthyl-based amino acids (S)-1b–e
b Isolated yield.
pectedly, introduction of an aromatic substituent at the 3-
position of the catalyst resulted in higher R-selectivity in
all cases examined (entries 2–5), and (S)-1e having 3,4,5-
trifluorophenyl group was found to be the best catalyst in
terms of enantioselectivity (entry 5). These results indicat-
ed that the aromatic substituent increased the ratio of the
s-trans-enamine intermediate, and that there may be inter-
action between the aromatic substituent and the olefinic
moiety of the enamine.
c Determined by HPLC analysis using chiral column (Chiralpak AD-
H, Daicel Chemical Industries, Ltd.).
Although amino acid catalysts of type (S)-1 promoted the
aminoxylation of aldehydes smoothly, they were found to
be less effective in terms of enantioselectivity. Due to the
flexibility of the carboxyl group in (S)-1, the C-O bond-
forming reaction is expected to take place not only on the
Re-face of the s-trans-enamine but also on the Si-face of
the s-cis-enamine, thereby affording both (R)-3 and (S)-3
(Scheme 1). As a result, (S)-1 would show moderate enan-
tioselectivity. In this context, we were interested in the
We then examined the effects of solvents on the yield and
enantioselectivity. The results of the reaction using vari-
ous solvents are shown in Table 2. When other halogenat-
ed solvents were used instead of CHCl3, similar results
Synthesis 2009, No. 9, 1557–1563 © Thieme Stuttgart · New York

SPECIAL TOPIC
Asymmetric Aminoxylation of Aldehydes
1559
possibility of developing a highly enantioselective ami- posite (S)-2-aminoxy alcohols in good yield and excellent
noxylation reaction using a binaphthyl-based amino sul- enantioselectivity (entries 5–11). The catalyst loading
fonamide (S)-2, which is known to give a single could be reduced without loss of enantioselectivity, and
stereoisomer predominantly through the s-cis-enamine in- moderate to good yields of the aminoxylation product
termediate in the direct asymmetric aldol reaction11 and were obtained with prolonged reaction time (entries 12–
Mannich reaction.12
14). The reaction at high concentration proceeded in good
yield even at low catalyst loading (0.2 mol%) (entry 15).
We first attempted the direct asymmetric aminoxylation
reaction of propanal catalyzed by (S)-2 under the optimal
conditions for the aminoxylation using (S)-1e (Table 2,
entry 10). As expected, the corresponding 2-aminoxy al-
cohol with the S absolute configuration, which is the op-
posite enantiomer formed in the reaction using (S)-1e, was
obtained in good yield with excellent enantioselectivity
after reduction (Table 3, entry 1). We then examined the
effects of solvents on the yield and enantioselectivity, and
the results of the reaction using various solvents are
shown in Table 3. It was found that solvents did not affect
the enantioselectivity of the present reaction (entries 1–7).
In addition, the enantioselectivity was not affected by the
concentration of the reaction mixture (entries 7–9).
Among the solvents we examined, chloroform was even-
tually chosen as solvent for further investigation.
Table 4 Direct Asymmetric Aminoxylation of Various Aldehydes
with Nitrosobenzene Catalyzed by (S)-1e and (S)-2a
O
OH
O
N
(S)-1e or (S)-2
NaBH4
EtOH
O
+
NHPh
CHCl3, 0 °C
Ph
R
R
Entry Catalyst
(mol%)
R
Time (h) Yield (%)b ee (%)c
1d
2d
3d
4d
5
(S)-1e (5)
(S)-1e (5)
(S)-1e (5)
(S)-1e (5)
(S)-2 (5)
(S)-2 (5)
(S)-2 (5)
(S)-2 (5)
(S)-2 (5)
(S)-2 (5)
(S)-2 (5)
(S)-2 (1)
(S)-2 (0.5)
(S)-2 (0.2)
(S)-2 (0.2)
Me
1
2
89
81
75
69
86
90
92
92
88
92
96
77
70
49
76
86 (R)
88 (R)
59 (R)
86 (R)
98 (S)
97 (S)
98 (S)
97 (S)
97 (S)
97 (S)
98 (S)
98 (S)
98 (S)
98 (S)
98 (S)
Bu
Bn
3
i-Pr
Me
1.5
2
Table 3 Solvent Effects in Direct Asymmetric Aminoxylation of
Propanal with Nitrosobenzene Catalyzed by (S)-2a
6
Et
2
O
OH
7
Bu
2
O
N
(S)-2 (5 mol%)
NaBH4
EtOH
O
+
NHPh
8
allyl
Bn
2
solvent, 0 °C, 2 h
Ph
Me
Me
9
2
Entry
Solvent
toluene
DMF
Concn (M) Yield (%)b ee (%)c
10
CH2OBn
i-Pr
i-Pr
i-Pr
i-Pr
i-Pr
2
1
2
3
4
5
6
7
8
9
1.0
1.0
1.0
1.0
1.0
1.0
1.0
0.5
2.0
78
47
49
67
85
82
86
86
85
98
98
98
98
98
98
98
98
98
11
12
13
14
15e
2
3
THF
8
MeCN
CH2Cl2
ClCH2CH2Cl
CHCl3
CHCl3
CHCl3
8
8
a The reaction of an aldehyde (3 equiv) with nitrosobenzene was car-
ried out in CHCl3 (1 M) in the presence of a catalyst at 0 °C.
b Isolated yield.
c Determined by HPLC analysis using a chiral column (Chiralpak
AD-H, Daicel Chemical Industries, Ltd.).
d Toluene was used as solvent.
e The reaction was carried out at higher concentration (25 M).
a The reaction of propanal (3 equiv) with nitrosobenzene was carried
out in the solvent mentioned above in the presence of catalyst (S)-2 at
0 °C for 2 h.
On the basis of the observed absolute stereochemistry in
this study, plausible transition states are proposed
(Figure 2). The activated and directed nitrosobenzene by
carboxyl group on (S)-1e would approach the Re face of
the s-trans-enamine to give the R-isomer predominantly
(Figure 2, left). On the other hand, nitrosobenzene activat-
ed by the distal acidic proton of the triflamide of (S)-2
could approach only the Si face of the s-cis-enamine, giv-
ing the S-isomer exclusively (Figure 2, right). Additional-
ly, the structure of (S)-2 having the distal acidic proton of
the triflamide group was confirmed by X-ray crystallo-
graphic analysis (Figure 3).
b Isolated yield.
c Determined by HPLC analysis using a chiral column (Chiralpak AD-
H, Daicel Chemical Industries, Ltd.).
Using catalysts (S)-1e and (S)-2, the reaction of other al-
dehydes was then carried out under optimized conditions,
and some selected examples are summarized in Table 4.
With (S)-1e, 2-aminoxy alcohols with the R absolute con-
figuration were obtained with moderate to good enantio-
selectivity in all cases examined (entries 1–4). On the
other hand, the reactions catalyzed by (S)-2 gave the op-
Synthesis 2009, No. 9, 1557–1563 © Thieme Stuttgart · New York

1560
T. Kano et al.
SPECIAL TOPIC
F
F
N
Ph
N
N
F
Ph
X
X
R
O
H
NTf
O
O
N
Ph
O
N
N
H
Ph
H
H
N
N
R
O
O
Figure 2 Transition states of aminoxylation reaction based on cata-
lysts (S)-1e and (S)-2
s-cis-enamine
s-trans-enamine
Figure 4 Transition state models for the aminoxylation of cyclo-
hexanone
In summary, we have shown that the binaphthyl-based
amino acids (S)-1 and aminosulfonamide (S)-2 can be uti-
lized as an organocatalyst in the direct asymmetric ami-
noxylation reaction of both aldehyde and ketone. These
reactions represent a rare example of the highly enantiose-
lective aminoxylation reaction with a non-proline derived
artificial organocatalyst. Further investigations on broad-
ening the synthetic application of this reaction and efforts
toward development of related enantioselective reactions
using these catalysts are in progress in our laboratory.
Figure 3 Single-crystal X-ray crystallographic structure of (S)-
2·HCl salt
IR spectra were recorded on a Shimadzu IRPrestige-21 spectrome-
1
In the aminoxylation of cyclohexanone catalyzed by (S)- ter. H NMR spectra were measured on a Jeol JNM-FX400 (400
1a and (S)-2,3d–l the senses of enantioselection were iden-
tical with those of the reaction using aldehydes
MHz) spectrometer. Chemical shifts were reported in ppm from tet-
ramethylsilane as an internal standard. Data were reported as fol-
lows: chemical shift, integration, multiplicity (s = singlet,
(Schemes 3 and 4). Interestingly, the amino acid catalyst
d = doublet, t = triplet, q = quartet, m = multiplet, br = broad, and
(S)-1a exhibited much higher enantioselectivity than that
observed in the reaction catalyzed by (S)-2 which showed
excellent enantioselectivity in the reaction of aldehydes.
app = apparent), coupling constants (Hz), and assignment. 13C
NMR spectra were recorded on a Jeol JNM-FX400 (100 MHz)
spectrometer with complete proton decoupling. Chemical shifts
These observations can be rationalized by the transition were reported in ppm from the residual solvent as an internal stan-
dard. High-performance liquid chromatography (HPLC) was per-
state models shown in Figure 4. In the reaction of cyclo-
formed on Shimadzu 10A instruments using a Daicel Chiralpak AD
hexanone, the steric repulsion between the phenyl group
and AD-H, 4.6 mm × 25 cm column. The high-resolution mass
of nitrosobenzene and the cyclohexene ring of the s-cis-
enamine intermediate would disfavor this reaction path-
spectra (HRMS) were performed on a Bruker microTOF. Optical
rotations were measured on a Jasco DIP-1000 digital polarimeter.
way. As a result, the ratio of the R-isomer through the s-
trans-enamine intermediate might increase in the reaction
using either (S)-1a or (S)-2. Accordingly, the reaction cat-
alyzed by (S)-2 gave the aminoxylated product with mod-
erate enantioselectivity.
For TLC analysis throughout this work, Merck precoated TLC
plates (silica gel 60 GF254, 0.25 mm) were used. The products were
purified by flash column chromatography on silica gel 60 (Merck
1.09386.9025, 230–400 mesh). Anhyd THF was purchased from
Kanto Chemical. Co. Inc. designated as ‘Dehydrated’. Toluene
was dried over sodium metal. Other solvents were dried over 4 Å
molecular sieves. Aldehydes were distilled and stored under argon
at –17 °C. Other simple chemicals were purchased and used as such.
(S)-1a10 and (S)-212a were synthesized according to the literature
procedures.
O
O
O
N
(S)-1a (5 mol%)
O
+
NHPh
DMF, r.t., 100 min
Ph
63%, 99% ee (R)
Ester (S)-5 (Ar = 3,4,5-F3C6H2)
A mixture of (S)-414 (1.16 g, 2.0 mmol), Pd(OAc)2 (22.5 mg, 0.1
mmol), Ph3P (105 mg, 0.4 mmol), 3,4,5-trifluorophenylboronic acid
(351 mg, 2.0 mmol), and K3PO4·nH2O (1.27 g, 6.0 mmol) in THF
(20 mL) was heated to 65 °C and stirred overnight under argon. The
resulting mixture was poured into aq sat. NH4Cl (20 mL), and fil-
tered to remove the catalyst. After extraction with EtOAc (2 × 50
mL), the organic layers were washed with brine (20 mL), dried
(Na2SO4) and then concentrated. The residue was roughly purified
by flash column chromatography on silica gel (CH2Cl2–
hexane, 1:40 as eluent) to afford a mixture of the mono-coupled
product and the bis-coupled product, which was used in the next
step without further purification. The mixture containing the mono-
Scheme 3 Reaction of cyclohexanone with nitrosobenzene in the
presence of (S)-1a
O
O
O
N
(S)-2 (5 mol%)
O
+
NHPh
CHCl3, r.t., 60 min
Ph
71%, 74% ee (S)
Scheme 4 Reaction of cyclohexanone with nitrosobenzene in the
presence of (S)-2
Synthesis 2009, No. 9, 1557–1563 © Thieme Stuttgart · New York

SPECIAL TOPIC
Asymmetric Aminoxylation of Aldehydes
1561
coupled product, Pd(OAc)2 (121 mg, 0.54 mmol), bis(diphe-
nylphosphino)propane (dppp) (223 mg, 0.54 mmol) and i-Pr2NEt
(1.9 mL, 10.7 mmol) in DMSO (8.0 mL) and MeOH (8.0 mL) was
charged into an autoclave under argon. After pressurizing with CO
(8 atm), the mixture was heated to 80 °C with stirring for 48 h. After
cooling to r.t., the reaction mixture was poured into H2O (20 mL)
and extracted with EtOAc (2 × 50 mL). The combined organic lay-
ers were washed with brine (20 mL), dried (Na2SO4) and then con-
centrated. The residue was purified by flash column
chromatography on silica gel (hexane–EtOAc, 40:1) to give (S)-5
(hexane–EtOAc, 20:1) to give (S)-7 (Ar = 3,4,5-F3C6H2) (136 mg,
0.620 mmol, 86%); [a]D24 +294.6 (c 1.0, CHCl3).
IR (neat): 3055, 3024, 2806, 1721, 1614, 1526, 1442, 1360, 1294,
1240, 1041 cm–1.
1H NMR (400 MHz, CDCl3): d = 8.59 (1 H, s, ArH), 8.01 (1 H, d,
J = 8.0 Hz, ArH), 7.92 (1 H, d, J = 8.7 Hz, ArH), 7.91 (1 H, s, ArH),
7.52–7.45 (4 H, m, ArH), 7.40–7.31 (2 H, m, ArH), 7.28–7.22 (2 H,
m, ArH), 5.85–5.81 (1 H, m, CH=CH2), 5.04 (1 H, app d, J = 10.2
Hz, CH=CHH), 5.02 (1 H, app d, J = 18.1 Hz, CH=CHH), 4.86 (1
H, d, J = 14.0 Hz, ArCHH), 4.00 (3 H, s, CO2CH3), 3.75 (1 H, d,
J = 11.6 Hz, ArCHH), 3.47 (1 H, d, J = 14.0 Hz, ArCHH), 3.28 (1
H, dd, J = 13.4, 5.7 Hz, NCHHCH), 2.81 (1 H, dd, J = 13.4, 7.1 Hz,
NCHHCH), 2.54 (1 H, d, J = 11.6 Hz, ArCHH).
13C NMR (100 MHz, CDCl3): d = 168.5, 150.8 (ddd, JC-F = 250,
9.8, 4.1 Hz), 139.2 (dt, JC-F = 252, 15.2 Hz), 137.0, 137.1–136.8
(m), 136.8, 136.3, 135.9, 132.7, 132.5, 132.2, 131.7, 131.6, 130.9,
129.5, 129.2, 128.9, 128.4, 128.0, 127.5, 127.2, 126.4, 126.3, 126.2,
117.1, 114.0 (dd, JC-F = 16.4, 5.7 Hz), 58.5, 52.4, 51.1, 49.5 (the
signal for an aromatic carbon was not identified due to the overlap
of peaks).
22
(Ar = 3,4,5-F3C6H2) (405 mg, 0.86 mmol, 43%, two steps); [a]D
–71.1 (c 1.0, CHCl3).
IR (neat): 3059, 2951, 1721, 1614, 1527, 1439, 1290, 1265, 1240,
1202, 1148, 1043 cm–1.
1H NMR (400 MHz, CDCl3): d = 8.54 (1 H, s, ArH), 7.97 (1 H, d,
J = 8.2 Hz, ArH), 7.89 (1 H, d, J = 8.0 Hz, ArH), 7.81 (1 H, s, ArH),
7.45 (1 H, app q, ArH), 7.32 (1 H, app t, J = 7.6 Hz, ArH), 7.24 (1
H, app t, ArH), 7.10 (2 H, app dd, ArH), 7.00 (2 H, app dd, ArH),
3.99 (3 H, s, CO2CH3), 2.26 (3 H, s, ArCH3), 1.87 (3 H, s, ArCH3).
13C NMR (100 MHz, CDCl3): d = 168.8, 150.9 (ddd, JC-F = 250,
9.8, 4.1 Hz), 139.1 (dt, JC-F = 252, 15.2 Hz), 138.3, 138.1 (dt, JC-F
=
HRMS (ESI-TOF): m/z calcd for C33H25F3NO2: 524.1832 ([M +
4.9, 7.4 Hz), 137.1, 136.4, 134.1, 133.7, 132.4, 132.0, 131.8, 131.4,
131.2, 129.5, 129.2, 128.6, 128.5, 128.1, 126.9, 126.0 (two peaks
overlap), 125.7, 125.6, 113.8 (dd, JC-F = 14.7, 5.7 Hz), 52.2, 17.98,
17.96.
H]+); found: 524.1828 ([M + H]+).
Amine (S)-8 (Ar = 3,4,5-F3C6H2)
A mixture of (S)-7 (287 mg, 0.55 mmol), N,N¢-dimethylbarbituric
acid (NDMBA) (180 mg, 1.15 mmol), Pd(OAc)2 (6.2 mg, 0.0275
mmol), and Ph3P (29 mg, 0.11 mmol) in CH2Cl2 (3.5 mL) was
stirred at 35 °C for 3 h under argon. After the addition of CH2Cl2 (20
mL), the organic layer was washed with aq sat. NaHCO3 (10 mL),
dried (Na2SO4), and concentrated. The resulting residue was puri-
fied by flash column chromatography on silica gel (CH2Cl2–
MeOH, 100:1) to give (S)-8 (Ar = 3,4,5-F3C6H2) (266 mg, 0.55
mmol, >99%); [a]D23 +312.4 (c 1.0, CHCl3).
HRMS (ESI-TOF): m/z calcd for C30H21F3O2 + Na: 493.1386 ([M +
Na]+); found: 493.1390 ([M + Na]+).
Dibromide (S)-6 (Ar = 3,4,5-F3C6H2)
A mixture of (S)-5 (383 mg, 0.814 mmol), N-bromosuccinimide
(NBS) (320 mg, 1.80 mmol), and 2,2¢-azobis(isobutyronitrile)
(AIBN) (13.5 mg, 10 mol%) in benzene (5 mL) was heated and re-
fluxed for 2 h. After cooling to r.t., the mixture was poured into H2O
(10 mL) and extracted with EtOAc (2 × 20 mL). The combined or-
ganic extracts were dried (Na2SO4) and concentrated. The residue
was purified by flash column chromatography on silica gel (hex-
ane–EtOAc, 50:1–15:1) to give (S)-6 (Ar = 3,4,5-F3C6H2) (483 mg,
0.769 mmol, 94%); [a]D20 –94.9 (c 1.0, CHCl3).
IR (neat): 3055, 3024, 2951, 2841, 1717, 1614, 1528, 1437, 1358,
1294, 1267, 1240, 1209, 1148, 1042 cm–1.
1H NMR (400 MHz, CDCl3): d = 8.56 (1 H, s, ArH), 8.01 (1 H, d,
J = 8.2 Hz, ArH), 7.94 (1 H, d, J = 8.5 Hz, ArH), 7.92 (1 H, s, ArH),
7.53–7.40 (4 H, m, ArH), 7.38–7.32 (2 H, m, ArH), 7.30–7.24 (2 H,
m, ArH), 4.69 (1 H, d, J = 13.5 Hz, ArCHH), 4.02 (3 H, s, CO2CH3),
3.89 (1 H, d, J = 11.4 Hz, ArCHH), 3.30 (1 H, d, J = 13.8 Hz,
ArCHH), 3.19 (1 H, d, J = 11.4 Hz, ArCHH).
13C NMR (100 MHz, CDCl3): d = 168.6, 150.8 (ddd, JC-F = 250,
9.8, 4.1 Hz), 139.3 (dt, JC-F = 252, 15.6 Hz), 137.1, 137.2-137.0
(m), 136.30, 136.28, 133.9, 132.7, 132.4, 132.2, 131.6, 130.9,
130.0, 129.3, 128.4, 128.0, 127.8, 127.4, 127.3, 126.3, 126.2 (two
peaks overlap), 114.0 (d, JC-F = 20.0 Hz), 52.4, 44.5, 44.3 (the sig-
nal for an aromatic carbon was not identified due to the overlap of
peaks).
IR (neat): 3062, 1721, 1614, 1528, 1439, 1362, 1294, 1267, 1242,
1219, 1043 cm–1.
1H NMR (400 MHz, CDCl3): d = 8.70 (1 H, s, ArH), 8.02 (1 H, d,
J = 8.0 Hz, ArH), 7.93 (1 H, d, J = 8.2 Hz, ArH), 7.88 (1 H, s, ArH),
7.56 (2 H, app q, ArH), 7.39 (1 H, app t, ArH), 7.31 (1 H, app t,
ArH), 7.27 (2 H, app dd, ArH), 7.10 (1 H, d, J = 8.5 Hz, ArH), 7.06
(1 H, d, J = 8.5 Hz, ArH), 4.84 (1 H, d, J = 9.9 Hz, ArCHH), 4.63
(1 H, d, J = 9.7 Hz, ArCHH), 4.22 (1 H, d, J = 10.4 Hz, ArCHH),
4.13 (1 H, d, J = 10.6 Hz, ArCHH), 4.06 (3 H, s, CO2CH3).
13C NMR (100 MHz, CDCl3): d = 167.6, 150.8 (ddd, JC-F = 251,
9.8, 4.1 Hz), 139.5 (dt, JC-F = 252, 15.2 Hz), 137.8, 136.5, 136.1 (dt,
HRMS (ESI-TOF): m/z calcd for C30H21F3NO2: 484.1519 ([M +
JC-F = 4.9, 8.2 Hz), 135.9, 133.7, 133.6, 133.0, 132.9, 132.2, 132.1,
H]+); found: 484.1526 ([M + H]+).
132.0, 130.7, 129.2, 128.9, 128.1, 127.83, 127.81, 127.5, 127.4,
126.9, 114.0 (dd, JC-F = 15.6, 6.6 Hz), 52.7, 30.64, 30.60 (the signal
for an aromatic carbon was not identified due to the overlap of
peaks).
Binaphthyl-Based Amino Acid Catalyst (S)-1e; Typical Proce-
dure
A mixture of (S)-8 (243 mg, 0.50 mmol) and aq 1 N NaOH (1.0 mL)
in MeOH (1.5 mL) and THF (1.0 mL) was refluxed for 1 h. After
cooling to r.t., CH2Cl2 (1 mL) was added and the mixture was acid-
ified with aq 1 N HCl. The mixture was then concentrated and the
residue was extracted with CH2Cl2 (2 × 20 mL). The combined or-
ganic layers were washed with brine (10 mL), dried (Na2SO4) and
concentrated. The resulting residue was purified by flash column
chromatography on silica gel (CH2Cl2–MeOH, 10:1) to give (S)-1e
(226 mg, 0.48 mmol, 96%); [a]D22 +161.1 (c 0.5, CHCl3).
HRMS (ESI-TOF): m/z calcd for C30H19Br2F3O2 + Na: 648.9596
([M + Na]+); found: 648.9622 ([M + Na]+).
Allylamine (S)-7 (Ar = 3,4,5-F3C6H2)
To a solution of (S)-6 (454 mg, 0.723 mmol) in MeCN (3.6 mL) was
added allylamine (163 mL, 2.17 mmol) at 50 °C. The mixture was
stirred for 12 h and then poured into H2O (10 mL). After extraction
with EtOAc (2 × 25 mL), the combined organic layers were washed
with brine (10 mL), dried (Na2SO4) and concentrated. The resulting
residue was purified by flash column chromatography on silica gel
IR (neat): 3055, 2739, 2594, 1614, 1526, 1437, 1375, 1242, 1043
cm–1.
Synthesis 2009, No. 9, 1557–1563 © Thieme Stuttgart · New York

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T. Kano et al.
SPECIAL TOPIC
1H NMR (400 MHz, CD3OD): d = 8.53 (1 H, s, ArH), 8.11 (1 H, s,
ArH), 8.08 (2 H, app dd, ArH), 7.60 (2 H, app q, ArH), 7.41–7.34
(4 H, m, ArH), 7.26–7.21 (2 H, m, ArH), 5.29 (1 H, d, J = 13.1 Hz,
ArCHH), 4.39 (1 H, d, J = 13.5 Hz, ArCHH), 3.68 (1 H, d, J = 13.8
Hz, ArCHH), 3.54 (1 H, d, J = 12.6 Hz, ArCHH).
d, J = 12.8 Hz, ArCHH), 4.28 (1 H, d, J = 13.5 Hz, ArCHH), 3.76
(1 H, d, J = 13.8 Hz, ArCHH), 3.51 (1 H, d, J = 12.8 Hz, ArCHH).
13C NMR (100 MHz, CD3OD–CDCl3, 4:1): d = 175.5, 143.3, 138.6,
137.9, 137.3, 137.0, 134.4, 134.3, 132.8 (q, JC-F = 32 Hz), 132.4,
132.0, 131.7, 131.3, 130.1, 129.5, 128.7, 128.31, 128.26, 128.0,
127.8, 127.5, 126.8, 124.4 (q, JC-F = 273 Hz), 122.6, 42.7, 42.4 (the
signals for two aromatic carbons were not identified due to the over-
lap of peaks).
13C NMR (100 MHz, CD3OD–CDCl3, 4:1): d = 174.2, 151.9 (app d,
JC-F = 249 Hz), 140.6 (dt, JC-F = 252, 15.6 Hz), 138.0, 137.9, 137.5,
136.9, 135.1 (app s), 134.4, 134.1, 132.6, 132.5, 132.0, 131.7,
130.2, 129.5, 128.7 (two peaks overlap), 128.3 (two peaks overlap),
128.0, 127.8, 127.3, 126.7, 115.5 (d, JC-F = 18.8 Hz), 42.9, 42.7.
HRMS (ESI-TOF): m/z calcd for C31H20F6NO2: 552.1393 ([M +
H]+); found: 552.1389 ([M + H]+).
HRMS (ESI-TOF): m/z calcd for C29H19F3NO2: 470.1362 ([M +
H]+); found: 470.1367 ([M + H]+).
Direct Asymmetric Aminoxylation Reaction of Aldehydes with
Nitrosobenzene; General Procedure
Amino Acid (S)-1b
To a suspension of (S)-2 (3.3 mg, 0.0075 mmol) in CHCl3 (150 mL)
at 0 °C were added nitrosobenzene (16 mg, 0.15 mmol) and the ap-
propriate aldehyde (0.45 mmol) in this order. After stirring for 2 h
at 0 °C, the reaction mixture was then transferred to a suspension of
NaBH4 (30 mg) in EtOH at 0 °C. After 15 min, the reaction mixture
was treated with sat. aq NaHCO3 (5 mL), extracted with CH2Cl2
(2 × 15 mL) and the combined organic extracts were dried
(Na2SO4). The resulting residue obtained after evaporation of the
solvent was purified by flash column chromatography on silica gel
to give the corresponding 2-aminoxy alcohol. The enantiomeric ex-
cess of 2-aminoxy alcohol was determined by chiral HPLC analy-
sis.3a,b,h Spectral data of 2-aminoxy alcohols were in accordance
with those previously reported.3a,b,h
Amino acid (S)-1b was prepared in a similar manner as described
above using phenylboronic acid instead of 3,4,5-trifluorophenylbo-
ronic acid; [a]D23 +223.6 (c 0.5, CHCl3).
IR (neat): 3053, 2959, 2581, 1557, 1442, 1373, 1043 cm–1.
1H NMR (400 MHz, CD3OD): d = 8.45 (1 H, s, ArH), 8.10–8.05 (3
H, m, ArH), 7.60–7.45 (7 H, m, ArH), 7.36–7.30 (2 H, m, ArH),
7.25 (2 H, app d, ArH), 5.18 (1 H, d, J = 12.8 Hz, ArCHH), 4.45 (1
H, d, J = 13.3 Hz, ArCHH), 3.65 (1 H, d, J = 14.0 Hz, ArCHH),
3.55 (1 H, d, J = 12.6 Hz, ArCHH).
13C NMR (100 MHz, CD3OD–CDCl3, 2:1): d = 175.4, 140.6, 140.5,
137.6, 137.4, 134.3, 134.1, 132.2, 131.5, 131.3, 130.5, 129.9, 129.3,
129.2, 128.6, 128.2, 128.1, 128.0, 127.9, 127.8, 127.6, 127.0, 126.9,
43.0, 42.7 (the signals for two aromatic carbons were not identified
due to the overlap of peaks).
Direct Asymmetric Aminoxylation Reaction of Cyclohexanone
with Nitrosobenzene; 2-(Phenylaminooxy)cyclohexanone; Typ-
ical Procedure
HRMS (ESI-TOF): m/z calcd for C29H22NO2: 416.1645 ([M + H]+);
To a solution of (S)-1a (5.1 mg, 0.015 mmol) and cyclohexanone
(93 mL, 0.90 mmol) in DMF (2.2 mL) at r.t. was added a solution of
nitrosobenzene (32 mg, 0.30 mmol) in DMF (0.4 mL) slowly over
the course of 40 min with a syringe pump. After stirring for 1 h, the
reaction mixture was directly purified by flash column chromatog-
raphy on silica gel to give 2-(phenylaminooxy)cyclohexanone (39
mg, 0.19 mmol, 63%). The enantiomeric excess was determined by
chiral HPLC analysis.3h Spectral data of 2-(phenylaminooxy)cyclo-
hexanone were in accordance with those previously reported.3h
found: 416.1625 ([M + H]+).
Amino Acid (S)-1c
Amino acid (S)-1c was prepared in a similar manner as described
above using 3,5-diphenylphenylboronic acid instead of 3,4,5-tri-
fluorophenylboronic acid; [a]D24 +94.8 (c 0.5, CHCl3).
IR (neat): 3055, 2322, 1620, 1574, 1445, 1373 cm–1.
1H NMR (400 MHz, CD3OD–THF-d8, 4:1): d = 8.42 (1 H, s, ArH),
8.22 (1 H, s, ArH), 8.12–8.05 (2 H, m, ArH), 7.98 (1 H, app s, ArH),
7.80–7.78 (5 H, app d, ArH), 7.61 (1 H, t, J = 8.0 Hz, ArH), 7.57 (1
H, t, J = 7.6 Hz, ArH), 7.48 (4 H, app t, ArH), 7.40–7.28 (7 H, m,
ArH), 5.22 (1 H, d, J = 12.8 Hz, ArCHH), 4.62 (1 H, d, J = 13.3 Hz,
ArCHH), 3.76 (1 H, d, J = 14.0 Hz, ArCHH), 3.56 (1 H, d, J = 12.8
Hz, ArCHH).
13C NMR (100 MHz, CD3OD–CDCl3, 1:2): d = 174.9, 142.6, 140.9,
140.8, 139.7, 137.5, 136.7, 136.3, 133.5, 133.3, 131.5, 131.3, 131.0,
130.5, 129.6, 129.2, 128.6, 128.1, 127.8, 127.7, 127.3, 127.1, 126.9,
126.7, 125.8, 41.7 (the signals were not identified due to the overlap
of peaks).
Crystallographic Data for (S)-2·HCl Salt15
2(C23H18ClF3N2O2S), colorless prisms, 0.14 × 0.03 × 0.01 mm3,
monoclinic, P21, a = 12.6729(15), b = 7.3537(8), c = 13.0053(15)
Å, V = 1068.3(2) Å3, rcalcd = 1.489 gcm–3, Z = 2, 2qmax = 39.9°,
m = 2.947 mm–1. A total of 4878 reflections were measured.
R = 0.0794, and Rw = 0.2236 for 1239 observed reflections with I >
2.0s (I).
Acknowledgment
This work was partially supported by a Grant-in-Aid for Scientific
Research on Priority Areas ‘Advanced Molecular Transformation
of Carbon Resources’ from the Ministry of Education, Culture,
Sports, Science and Technology, Japan. We thank Dr. Motoo Shiro
(Rigaku Co. Ltd.) for X-ray crystallographic expertise.
HRMS (ESI-TOF): m/z calcd for C41H30NO2: 568.2271 ([M + H]+);
found: 568.2252 ([M + H]+).
Amino Acid (S)-1d
Amino acid (S)-1d was prepared in a similar manner as described
above using 3,5-bis(trifluoromethyl)phenylboronic acid instead of
3,4,5-trifluorophenylboronic acid; [a]D24 +207.5 (c 0.5, CHCl3).
References
IR (neat): 3053, 2363, 1616, 1560, 1445, 1373, 1277, 1179, 1132
(1) For reviews, see: (a) Adam, W.; Krebs, O. Chem. Rev. 2003,
103, 4131. (b) Merino, P.; Tejero, T. Angew. Chem. Int. Ed.
2004, 43, 2995. (c) Janey, J. M. Angew. Chem. Int. Ed. 2005,
44, 4292. (d) Yamamoto, H.; Momiyama, N. Chem.
Commun. 2005, 3514. (e) Yamamoto, Y.; Yamamoto, H.
Eur. J. Org. Chem. 2006, 2031. (f) Yamamoto, H.;
cm–1.
1H NMR (400 MHz, CD3OD): d = 8.41 (1 H, s, ArH), 8.22 (2 H, s,
ArH), 8.15 (1 H, s, ArH), 8.12 (1 H, s, ArH), 8.11 (1 H, d, J = 8.7
Hz, ArH), 8.06 (1 H, d, J = 8.5 Hz, ArH), 7.62 (1 H, t, J = 7.5 Hz,
ArH), 7.57 (1 H, t, J = 7.5 Hz, ArH), 7.39–7.32 (2 H, m, Ar-H), 7.28
(1 H, d, J = 8.5 Hz, ArH), 7.27 (1 H, d, J = 8.5 Hz, ArH), 5.18 (1 H,
Kawasaki, M. Bull. Chem. Soc. Jpn. 2007, 80, 595.
Synthesis 2009, No. 9, 1557–1563 © Thieme Stuttgart · New York

SPECIAL TOPIC
Asymmetric Aminoxylation of Aldehydes
1563
(2) Momiyama, N.; Yamamoto, H. J. Am. Chem. Soc. 2003,
125, 6038.
(6) Momiyama, N.; Yamamoto, H. J. Am. Chem. Soc. 2004,
126, 5360.
(3) Representative papers: (a) Zhong, G. Angew. Chem. Int. Ed.
2003, 42, 4247. (b) Brown, S. P.; Brochu, M. P.; Sinz, C. J.;
MacMillan, D. W. C. J. Am. Chem. Soc. 2003, 125, 10808.
(c) Hayashi, Y.; Yamaguchi, J.; Hibino, K.; Shoji, M.
Tetrahedron Lett. 2003, 44, 8293. (d) Bøgevig, A.; Sundén,
H.; Córdova, A. Angew. Chem. Int. Ed. 2004, 43, 1109.
(e) Hayashi, Y.; Yamaguchi, J.; Sumiya, T.; Shoji, M.
Angew. Chem. Int. Ed. 2004, 43, 1112. (f) Yamamoto, Y.;
Momiyama, N.; Yamamoto, H. J. Am. Chem. Soc. 2004,
126, 5962. (g) Momiyama, N.; Torii, H.; Saito, S.;
Yamamoto, H. Proc. Natl. Acad. Sci. U.S.A. 2004, 101,
5374. (h) Hayashi, H.; Yamaguchi, J.; Sumiya, T.; Hibino,
K.; Shoji, M. J. Org. Chem. 2004, 69, 5966. (i) Wang, W.;
Wang, J.; Li, H.; Liao, L. Tetrahedron Lett. 2004, 45, 7235.
(j) Ramachary, D. B.; Barbas, C. F. III Org. Lett. 2005, 7,
1577. (k) Huang, K.; Huang, Z.-Z.; Li, X.-L. J. Org. Chem.
2006, 71, 8320. (l) Font, D.; Bastero, A.; Sayalero, S.;
Jimeno, C.; Pericàs, M. A. Org. Lett. 2007, 9, 1943.
(4) Representative papers on the asymmetric synthesis of
natural products and chiral building blocks via
(7) (a) Guo, H.-M.; Cheng, L.; Cun, L.-F.; Gong, L.-Z.; Mi, A.-
Q.; Jiang, Y.-Z. Chem. Commun. 2006, 429. (b) Kano, T.;
Ueda, M.; Takai, J.; Maruoka, K. J. Am. Chem. Soc. 2006,
128, 6046. (c) Kim, S.-G.; Park, T.-H. Tetrahedron Lett.
2006, 47, 9067. (d) Palomo, C.; Vera, S.; Velilla, I.; Mielgo,
A.; Gómez-Bengoa, E. Angew. Chem. Int. Ed. 2007, 46,
8054.
(8) López-Cantarero, C. J.; Cid, M. B.; Poulsen, T. B.; Bella,
M.; García Ruano, J. L.; Jørgensen, K. A. J. Org. Chem.
2007, 72, 7062.
(9) (a) Yamamoto, Y.; Yamamoto, H. J. Am. Chem. Soc. 2004,
126, 4128. (b) Yamamoto, Y.; Yamamoto, H. Angew. Chem.
Int. Ed. 2005, 44, 7082. (c) Jana, C. K.; Studer, A. Angew.
Chem. Int. Ed. 2007, 46, 6542.
(10) (a) Kano, T.; Takai, J.; Tokuda, O.; Maruoka, K. Angew.
Chem. Int. Ed. 2005, 44, 3055. (b) Kano, T.; Tokuda, O.;
Takai, J.; Maruoka, K. Chem. Asian J. 2006, 1, 210.
(11) Kano, T.; Yamaguchi, Y.; Maruoka, K. Angew. Chem. Int.
Ed. 2007, 46, 1738.
(12) (a) Kano, T.; Yamaguchi, Y.; Tokuda, O.; Maruoka, K.
J. Am. Chem. Soc. 2005, 127, 16408. (b) Kano, T.;
Yamaguchi, Y.; Maruoka, K. Angew. Chem. Int. Ed. 2009,
48, 1838.
(13) (a) Kano, T.; Yamamoto, A.; Mii, H.; Takai, J.; Shirakawa,
S.; Maruoka, K. Chem. Lett. 2008, 37, 250. (b) Kano, T.;
Yamamoto, A.; Maruoka, K. Tetrahedron Lett. 2008, 49,
5369.
organocatalytic aminoxylation: (a) Enders, D.; Lenzen, A.;
Müller, M. Synthesis 2004, 1486. (b) Zhong, G. Chem.
Commun. 2004, 606. (c) Zhong, G.; Yu, Y. Org. Lett. 2004,
6, 1637. (d) Kumarn, S.; Shaw, D. M.; Longbottom, D. A.;
Ley, S. V. Org. Lett. 2005, 7, 4189. (e) Kumarn, S.; Shaw,
D. M.; Longbottom, D. A.; Ley, S. V. Chem. Commun. 2006,
3211. (f) Kotkar, S. P.; Sudalai, A. Tetrahedron: Asymmetry
2006, 17, 1738. (g) Kim, S.-G.; Park, T.-H.; Kim, B. J.
Tetrahedron Lett. 2006, 47, 6369. (h) Kotkar, S. P.; Sudalai,
A. Tetrahedron Lett. 2006, 47, 6813. (i) Talluri, S. K.;
Sudalai, A. Tetrahedron 2007, 63, 9758.
(14) Ooi, T.; Kameda, M.; Maruoka, K. J. Am. Chem. Soc. 2003,
125, 5139.
(15) CCDC-710886 contains the supplementary crystallographic
data of (S)-2·HCl salt for this paper. These data can be
obtained free of charge from The Cambridge
Crystallographic Data Centre via www.ccdc.cam.ac.uk/
data_request/cif.
(5) (a) Momiyama, N.; Yamamoto, H. J. Am. Chem. Soc. 2005,
127, 1080. (b) Momiyama, N.; Yamamoto, Y.; Yamamoto,
H. J. Am. Chem. Soc. 2007, 129, 1190.
Synthesis 2009, No. 9, 1557–1563 © Thieme Stuttgart · New York