Asymmetric α-aminoxylations of stoichiometric ketones using 2-nitrosotoluene

Article abstract of DOI:10.1055/s-0029-1217750

Asymmetric aminoxylations of a stoichiometric amount of ketones were accomplished through O-nitrosoaldol reactions of 2-nitrosotoluene catalyzed by a proline-based tetrazole. The advantages of 2-nitrosotoluene and the tetrazole over nitrosobenzene and pro

Full text of DOI:10.1055/s-0029-1217750

LETTER
2685
Asymmetric a-Aminoxylations of Stoichiometric Ketones
Using 2-Nitrosotoluene
Asymmetric
ae
n
tions of Stoi
g
chiometric
K
etone
J
Using 2-
i
Nitroso
a
toluene o, Hisashi Yamamoto*
Department of Chemistry, The University of Chicago, 5735 South Ellis Avenue, Chicago, IL 60637, USA
Fax +1(773)7020805; E-mail: yamamoto@uchicago.edu
Received 19 March 2009
yield and the bisaminoxylation product in 8% yield (entry
1). When the reaction was carried out in a 1:1 mixture of
DMSO and DMF at 0 °C, the monoaminoxylation product
was obtained in 82% yield (entry 3). In DMF at 0 °C, the
monoaminoxylation product was obtained in 81% yield
(entry 4). Further decrease of the temperature to –10 °C
did not increase the yield (entry 5). For comparison, pro-
line was used instead of the tetrazole under otherwise
identical conditions: the yield of the monoaminoxylation
product was 59%, and the yield of the bisaminoxylation
product increased to 12% (entry 6). With proline as the
catalyst, CHCl3 (entry 7) or MeCN was also examined as
the solvent. Very low conversions of 2-nitrosotoluene
were observed in these cases. When 2 equivalents cyclo-
hexanone were reacted with 2-nitrosotoluene, the
monoaminoxylation product was obtained in quantitative
yield, and the formation of the bisaminoxylation product
was sufficiently suppressed (entry 8). Nitrosobenzene
gave lower yield (89%) than 2-nitrosotoluene under the
same conditions (entry 9). When 2 equivalents nitroso-
toluene were used, the bisaminoxylation product became
the major one (entry 10). It is clear from these results that
slow addition of 2-nitrosotoluene, low temperature (0 °C),
and the tetrazole catalyst are essential for good yields of
the monoaminoxylation products.
Abstract: Asymmetric aminoxylations of a stoichiometric amount
of ketones were accomplished through O-nitrosoaldol reactions of
2-nitrosotoluene catalyzed by a proline-based tetrazole. The advan-
tages of 2-nitrosotoluene and the tetrazole over nitrosobenzene and
proline, respectively, were demonstrated.
Key words: aminoxylations, O-nitrosoaldol reactions, a-aminoxy
cyclic ketones, proline-based tetrazole, nitrosotoluene
Chiral a-hydroxy aldehydes and ketones are important in-
termediates in organic synthesis. Catalytic asymmetric
preparation of a-hydroxy carbonyl compounds has been
realized by dihydroxylation and epoxidation of silyl enol
ethers.1–3 BINAP–AgOTf complex catalyzed nucleophilic
addition of tin enolates to nitrosobenzene is the first ex-
ample of asymmetric O-selective nitrosoaldol (O-NA)
reaction, affording a-aminoxy ketones in excellent ee,
which are easily converted to a-hydroxy ketones.4 Silyl
enolates can also be used for the same purpose in the pres-
ence of a chiral phosphite ligand and AgBF4.5 In these
methods, the preformed enolates of carbonyl compounds
are used as substrates for the enantioselective introduction
of an a-oxy group. Direct a-oxidation of a carbonyl com-
pound is obviously more attractive with respect to its ease
of manipulation. Sibi et al. used TEMPO (2 equiv) for the
asymmetric a-aminoxylations of aldehydes through a rad-
ical procedure.6 O-NA reactions of nitrosobenzene cata-
lyzed by proline or proline-based tetrazole also give a-
aminoxylated aldehydes and ketones.7,8 Although these
O-NA reactions give the products in excellent ee, excess
(2–3 equiv) carbonyl substrates are required to secure a
good yield. This drawback restricts the wide application
of these O-NA reactions, especially when the carbonyl
compound is very important. In our recent paper, we not-
ed that 2-nitrosotoluene is superior to nitrosobenzene for
the aminoxylations of carbonyl compounds.9 Herein we
further investigate the advantage of 2-nitrosotoluene in
the aminoxylations of a stoichiometric amount of ketones.
Under optimized conditions, aminoxylations of several
six-membered cyclic ketones were examined (Table 2).10
In all the cases, the monoaminoxylation products were ob-
tained in >75% yield and excellent ee. These yields are
comparable to those obtained using excess ketones and
proline as the catalyst. 4-Piperidone (X = N) was also re-
acted with 2-nitrosotoluene. However, the conversion was
very low. In order to further improve the yields of the
monoaminoxylation
products,
2-isopropylnitroso-
benzene11 was used instead of 2-nitrosotoluene. However,
similar selectivities were observed (entries 1, 3, and 4).
Cyclopentanone or cyclododecanone did not react with 2-
nitrosotoluene. Cycloheptanone gave the aminoxylation
product in <10% yield.
The reaction of cyclohexanone with 2-nitrosotoluene was
conducted under various conditions, and the results are
shown in Table 1. With the tetrazole as the catalyst, the re-
action of one equivalent cyclohexanone in DMSO at room
temperature gave the monoaminoxylation product in 74%
Asymmetric aminoxylations of a stoichiometric amount
of aldehydes using 2-nitrosotoluene or 2-isopropyl-
nitrosobenzene were also investigated (Scheme 1). With
slow addition (3 h) of nitrosotoluene, hydrocinnamalde-
hyde, and isovaleraldehyde gave the aminoxylation prod-
ucts in 53% and 61% yield, respectively. 4-Pentenal and
phenylacetaldehyde gave the products in 38% and 44%
yield, respectively, at –20 °C. In these two cases, the con-
SYNLETT 2009, No. 16, pp 2685–2687
x
x
.x
x
.2
0
0
9
Advanced online publication: 03.09.2009
DOI: 10.1055/s-0029-1217750; Art ID: S03409ST
© Georg Thieme Verlag Stuttgart · New York

2686
P. Jiao, H. Yamamoto
LETTER
NHTol
OH
tetrazole
O
NO
(10 mol%)
NaBH4
+
R
CHO
(1 equiv)
R
DMF, 0 °C
MeOH, 0 °C
R = Bn 53% yield, 98% ee
R = i-Pr 61% yield, 98% ee
Scheme 1 Aminoxylations of aldehydes
Table 1 Optimization of Reaction Conditions
Table 2 Aminoxylations of Cyclic Ketonesa
O
O
O
O
O
O
O
O
NHTol
NHTol
NHTol
tetrazole
NO
tetrazole
NO
A
B
A
(10 mol%)
(10 mol%)
X
O
+
+
solvent, Temp
DMF, 0 °C
X
O
O
O
(1 equiv)
TolHN
TolHN
NHTol
B
(1 equiv)
X
N
N
tetrazole:
N
Entry
Ketone X
Yield (%)b
ee (%)c
N
N
H
H
A
B
Entry Ketone TolNO Solvent
(equiv) (equiv)
Temp Time Yield (%)b
(°C)
1
2
3
4
CH2
81 (81)
86
9 (9)
3
>99
(h)a
CMe2
CHt-Bu
O
>99
A
B
84 (88)
75 (71)
16 (12)
11 (12)
>99d, >99e
>99
1
1
1
1
1
1
1
1
2
2
1
1
1
1
1
1
1
1
1
1
2
DMSO
DMSO–DME
DMSO–DMF
DMF
r.t.
0
5
3
3
3
5
3
3
3
3
6
74
79
82
81
77
59
3
8
2
4
9
3
0
a TolNO added over 3 h.
b A and B isolated as a mixture. Yields calculated from the ratio de-
termined by 1H NMR. Yields in parentheses obtained from 2-isopro-
pylnitrosobenzene.
4
0
9
5
DMF
–10
0
6
c Determined by chiral HPLC.
6c
7c
8
DMF
12
0
d The ee of 2R,4R-isomer.
e The ee of 2R,4S-isomer.
CHCl3
0
DMF
0
98
89
32
2
Acknowledgment
9d
DMF
0
1
Financial support has been provided by the NIH (5R01GM068433-
06), the Camille and Henry Dreyfus Foundation and the University
of Chicago.
10
DMF
0
47
a Addition time of TolNO or PhNO.
b A and B isolated as a mixture. Yields calculated from the ratio de-
termined by 1H NMR.
References and Notes
c The amount of 10 mol% L-proline was used.
d Nitrosobenzene used.
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version of 2-nitrosotoluene was 70%, even after a long
reaction time (24 h).
In summary, we have demonstrated that the combination
of 2-nitrosotoluene and the proline-based tetrazole is ef-
fective for asymmetric aminoxylations of a stoichiometric
amount of cyclic ketones. The addition time of nitrosotol-
uene is greatly reduced in comparison with that for pro-
line-catalyzed procedures. The present procedure avoids
the use of excess ketone substrate, which is difficult to
separate from the aminoxylation product.
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LETTER
Asymmetric a-Aminoxylations of Stoichiometric Ketones Using 2-Nitrosotoluene
2687
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(10) Typical Experimental Procedure
2-Nitrosotoluene (1.0 mmol, 121 mg) in DMF (1 mL) was
added over 3 h via syringe pump to a solution of the tetrazole
catalyst (0.1 mmol, 14 mg) and the cyclic ketone (1.0 mmol)
in DMF (1 mL) cooled to 0 °C. After completion of the
addition, the mixture was stirred at 0 °C for a further 5 h.
Saturated aq NHCl4 was added and the mixture extracted
with AcOEt. The crude product was chromatographed on
silica gel to give a mixture of the mono- and bisamin-
oxylation products.
(11) 2-Isopropylnitrosobenzene was prepared in high purity by
oxidation of 2-isopropylaniline with Oxone in H2O at 0 °C.
Synlett 2009, No. 16, 2685–2687 © Thieme Stuttgart · New York