LETTER
Oxidative Hydrolysis of Ketone SAMP Hydrazones
3133
would then deliver the ketone 34 and diazene 35 as a
byproduct.
Acknowledgment
Support was provided by the National Institutes of Health (Institute
of General Medical Sciences) through grant GM-29028 and the
University of Pennsylvania. We thank Drs. G. Furst, J. Gu, and
R. Kohli (University of Pennsylvania) for assistance in obtaining
NMR spectra and high-resolution mass spectra, respectively.
OMe
O
OH
N
SeO2–H2O2
N
OH
Ph
MeOH, pH 7 buffer
(3:1)
Ph
28
References and Notes
78%
25
(1) Enders, D.; Eichenauer, H. Angew. Chem., Int. Ed. Engl.
1976, 15, 549.
OMe
(2) Job, A.; Janeck, C. F.; Bettray, W.; Peter, R.; Enders, D.
Tetrahedron 2002, 58, 2253; and references therein.
(3) Enders, D.; Wortmann, L.; Peters, R. Acc. Chem. Res. 2000,
33, 157.
(4) Enders, D.; Plant, A. Synlett 1994, 1054.
(5) Said, S. B.; Skarzewski, J.; Mlochowski, J. Synthesis 1989,
223.
O
OH
N
N
OH
SeO2–H2O2
Ph
Ph
MeOH, pH 7 buffer
(3:1)
81%
29
26
(6) Stupp, S. I.; Son, S.; Li, L. S.; Lin, H. C.; Keser, M. J. Am.
OMe
Chem. Soc. 1995, 117, 5212.
(7) Eichenauer, H.; Friedrich, E.; Lutz, W.; Enders, D. Angew.
Chem., Int. Ed. Engl. 1978, 17, 206.
O
OH
N
N
O
OH
SeO2–H2O2
Ph
MeOH, pH 7 buffer
(3:1)
(8) General Procedure for the Synthesis of Hydrazones
A mixture of SAMP (0.04 mmol), ketone (0.04 mmol), and
PTSA (0.004 mmol) was heated at reflux in cyclohexane
(1 mL) overnight. The mixture was then cooled to r.t.,
neutralized with sat. NaHCO3 (3 mL) and the aqueous layer
was extracted with EtOAc (3 × 5 mL). The combined
organic layers were dried over Na2SO4 and concentrated.
The residue was purified by flash chromatography to
provide the desired hydrazone (70–98%).
Ph
O
65%
30
27
Scheme 4 Oxidative hydrolysis of SAMP aldol products to regene-
rate b-hydroxy ketones
O
+
H2O2
SeO2
(9) General Procedure for the Synthesis of Ketones 7–15 and
22–24
HOO Se OH
To a r.t. solution of hydrazone (0.18 mmol) and SeO2 (0.14
mmol) in MeOH (2.3 mL) was added pH 7 phosphate buffer
(0.066 mL) followed by 30% H2O2 (0.066 mL). After
completion of the hydrolysis reaction, sat. NaHCO3 (3 mL)
was added, and the aqueous layers were extracted with
pentane (3 × 3 mL). The combined organic layers were
combined, dried over Na2SO4, and concentrated. The residue
was purified via flash chromatography to provide the
corresponding ketone in 68–96% yield.
O
N
MeO
N+
HOO Se OH
OH
MeO
N
H2O
N
R
R
H2SeO3
31
32
(10) General Procedure for the Synthesis of Alkylated SAMP
Hydrazones 19–21
+
H2O
SeO2
O
To a solution of the corresponding hydrazone (0.26 mmol) in
THF (2 mL) at –78 °C was added t-BuLi (1.6 M in pentane,
0.39 mmol). The mixture was kept at this temperature for 2
h before cooling to –100 °C. (S)-(+)-1-Iodo-2-methylbutane
(0.52 mmol) was then added via syringe, the solution stirred
at –100 °C for 0.5 h, and then at –78 °C for 2 h. The reaction
was quenched with sat. NH4Cl (3 mL). The aqueous layers
were extracted with Et2O (3 × 5 mL), and the combined
organic layers were dried over Na2SO4, concentrated, and
the residue was purified by flash chromatography to furnish
the alkylated hydrazone in 90–96% yield.
N+
R
MeO
N
OH
R
MeO
34
N+
N–
diazene
35
33
Scheme 5 Proposed mechanism for the oxidative hydrolysis of
SAMP hydrazones using peroxyselenous acid
(11) Enders, D.; Bockstiegel, B. Synthesis 1989, 493.
(12) General Procedure for the Synthesis of SAMP Aldol
Products 25–27
In summary, an efficient method to regenerate ketones
from SAMP ketone hydrazones employing SeO2 and
H2O2 under buffered conditions has been developed. Al-
dol hydrazone adducts derived from the SAMP hydrazone
require additional buffer to suppress side reactions. Given
the scope of this protocol, this method holds promise as an
effective and mild alternative to the more conventional
methods to regenerate ketones from SAMP hydrazones.
To a solution of hydrazone (0.18 mmol) in THF (1.2 mL) at
–78 °C was added t-BuLi (1.6 M in pentane, 0.18 mmol).
The mixture was maintained at this temperature for 2 h
before cooling to –100 °C. Benzaldehyde (0.36 mmol) was
then added via syringe, the solution stirred at –100 °C for 0.5
h, and then at –78 °C for 2 h. The reaction was quenched
with sat. NH4Cl (3 mL), the aqueous layer extracted with
Et2O (3 × 5 mL), and the combined organic layers were
Synlett 2009, No. 19, 3131–3134 © Thieme Stuttgart · New York