A mild, efficient method for the oxidation of α-diazo-β-hydroxyesters to α-diazo-β-ketoesters

Article abstract of DOI:10.1016/j.tetlet.2008.03.011

A wide variety of α-diazo-β-ketoesters can be prepared in good overall yields via a two-step sequence involving addition of ethyl lithiodiazoacetate to aliphatic, aromatic, and conjugated aldehydes followed by mild oxidation with the Dess-Martin periodina

Full text of DOI:10.1016/j.tetlet.2008.03.011

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Tetrahedron Letters 49 (2008) 3162–3164
A mild, efficient method for the oxidation of
a-diazo-b-hydroxyesters to a-diazo-b-ketoesters
Puhui Li, Max M. Majireck, Ilia Korboukh, Steven M. Weinreb *
Department of Chemistry, The Pennsylvania State University, University Park, PA 16802, USA
Received 12 February 2008; accepted 4 March 2008
Available online 8 March 2008
Abstract
A wide variety of a-diazo-b-ketoesters can be prepared in good overall yields via a two-step sequence involving addition of ethyl
lithiodiazoacetate to aliphatic, aromatic, and conjugated aldehydes followed by mild oxidation with the Dess–Martin periodinane.
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords: Ethyl diazoacetate; Dess–Martin periodinane; Oxidation
diazo
In the course of some natural product syntheses cur-
rently ongoing in these labs, we needed to convert an alde-
hyde 1 into an a-diazo-b-ketoester 4 and two reasonable
sequences seemed possible (Scheme 1). The most common
methodology for this transformation would involve first
homologating 1 to the corresponding b-ketoester 2,
followed by a Regitz diazo transfer step to produce 4.1
Alternatively, a potentially more attractive route would
be to initially add ethyl lithiodiazoacetate to aldehyde 1
to produce an a-diazo-b-hydroxyester 3, which would be
oxidized to the desired diazo compound 4. Although the
addition of metallated ethyl diazoacetate to aldehydes is
well precedented,2 examples of the oxidation of adducts 3
to the corresponding ketones 4 are rare. In the few extant
cases, the b-hydroxy-a-diazoesters 3 are derived only from
aromatic or conjugated aldehydes. Moreover, the only
reagents which have been used for alcohol oxidation in
these few examples are limited to manganese dioxide,3
IBX,4 or barium permanganate.5
O
transfer
CO Et
2
R
2
O
RCHO
CO Et
2
R
DMP
Li
CH Cl
N
1
2
2
2
OH
N
CO Et
2
rt
2
CO Et
2
4
R
o
THF, -78
C
N
2
3
Scheme 1.
methodology further, particularly with regard to the oxida-
tion process. Since there was good literature precedent that
a-diazo-b-ketoesters are stable toward Dess–Martin peri-
odinane (DMP),6 we chose to investigate this reagent for
oxidation of substrates like 3.
As listed in Table 1, several a-diazo-b-hydroxyesters 3
were prepared from a variety of aliphatic, aromatic, and
unsaturated aldehydes and ethyl lithiodiazoacetate in
THF using the experimental procedure of Padwa et al.2b
It was found that exposure of these compounds to Dess–
Martin periodinane in methylene chloride at room temper-
ature indeed led to the formation of the corresponding
a-diazo-b-ketoesters 4. An interesting observation was that
addition of excess pyridine (ꢀ12 equiv) to the oxidation
Since we were particularly interested in effecting this
sequence starting with aliphatic aldehydes, and also
required a mild oxidant for the second step which is com-
patible with sensitive functionality, we have explored this
*
Corresponding author. Tel.: +1 814 863 0189; fax: +1 814 865 3292.
E-mail address: smw@chem.psu.edu (S. M. Weinreb).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.03.011

P. Li et al. / Tetrahedron Letters 49 (2008) 3162–3164
3163
Table 1
Preparation of representative a-diazo-b-ketoesters
Entry
Aldehyde substrate
a-Diazo-b-hydroxyester 3
a-Diazo-b-ketoester 4
O
H
OH
O
O
O
88%a
a
OEt
OEt
N
N
O
2
2
85%
OH
O
O
O
H
OEt
62%
b
c
64%a
OEt
N
2
N
2
OH
O
O
H
O
O
78%a
OEt
OEt
N
2
N
2
80%
OH
O
O
H
O
O
OEt
d
OEt 98%
N
2
N
2
O N
2
O N
O N
2
2
60%
OH
O
O
O
O
O
OEt
e
f
78%
H
H
OEt
N
2
N
2
2
96%
OH
O
O
O
OEt
OEt
92%
N
N
2
N
N
N
Cl
Cl
Cl
97%
COCF
N
3
H
H
COCF
N
COCF
N
3
3
Me
H
H
H
OH
N
O
Me
Me
O
O
O
g
78%
OEt
OEt
H
MeO
H
2
MeO
N
2
MeO
78%
Cl
Cl
Cl
OH
O
O
O
h
94%a
O
H
CbzHN
OEt
42%
CbzHN
OEt
CbzHN
N2
N2
a
ꢀ12 equiv pyridine added to reaction mixture.
reaction resulted in higher product yields in a few cases.
This improvement may be due to the pyridine minimizing
decomposition of the diazo compounds by adventitious
acid.7 A number of examples of this oxidation are listed
in the table along with the isolated yields of diazoketones
4. Thus, Dess–Martin periodinane appears to be a general,
superior oxidant for conversion of all types of a-diazo-b-
hydroxyesters to a-diazo-b-ketoesters and thereby expands
the scope of this two-step procedure for synthesizing the
latter class of compounds.
General procedure for oxidation of a-diazo-b-hydroxy-
esters 3 to a-diazo-b-ketoesters 4: To a solution of alcohol
3 (0.51 mmol) in CH2Cl2 (7.5 mL) was added DMP
(0.76 mmol). The heterogeneous mixture was stirred at rt
until the complete consumption of the starting material
was observed by TLC (ꢀ1–3 h). The reaction mixture
was diluted with a 1:1 mixture of NaHCO3(aq) and
Na2S2O3(aq). The organic layer was separated and the aque-
ous layer was extracted with CH2Cl2. The combined
organic layers were dried with Na2SO4 and the solvent

3164
P. Li et al. / Tetrahedron Letters 49 (2008) 3162–3164
2. See inter alia: (a) Moody, C. J.; Taylor, R. J. Tetrahedron Lett. 1987,
28, 5351; (b) Padwa, A.; Kulkarni, Y. S.; Zhang, Z. J. Org. Chem.
1990, 55, 4144; (c) Moody, C. J.; Morfitt, C. N. Synthesis 1998, 1039;
(d) Hasegawa, K.; Arai, S.; Nishida, A. Tetrahedron 2006, 62, 1390; (e)
Varala, R.; Engula, R.; Nuvula, S.; Adapa, S. R. Tetrahedron Lett.
2006, 47, 877; (f) Kantam, M. L.; Chakrapani, L.; Ramani, T.
Tetrahedron Lett. 2007, 48, 6121.
3. Deng, G.; Xu, B.; Wang, J. Tetrahedron 2005, 61, 10811.
4. (a) Bagley, M. C.; Hind, S. L.; Moody, C. J. Tetrahedron Lett. 2000,
41, 6897; (b) Davies, J. R.; Kane, P. D.; Moody, C. J.; Slawin, A. M. Z.
J. Org. Chem. 2005, 70, 5840; (c) Davies, J. R.; Kane, P. D.; Moody, C.
J. J. Org. Chem. 2005, 70, 7305.
was removed in vacuo. The resulting crude residue was
purified by flash column chromatography on silica gel
using a mixture of ethyl acetate and hexanes. Isolated
yields of products 4 are shown in Table 1.
Acknowledgment
We are grateful to the National Institutes of Health
(CA-034303) for the financial support of this research.
5. (a) Moody, C. J.; Taylor, R. J. Tetrahedron 1990, 46, 6525; (b) Padwa,
A.; Dean, D. C.; Osterhout, M. H.; Precedo, L.; Semones, M. A. J.
Org. Chem. 1994, 59, 5347.
References and notes
6. Hodgson, D. M.; Bailey, J. M.; Villalonga-Barber, C.; Drew, M. G. B.;
Harrison, T. J. Chem. Soc., Perkin Trans. 1 2000, 3432.
7. Pyridine has been used previously as an additive in Dess–Martin
oxidations: Dess, D. B.; Martin, J. C. J. Org. Chem. 1983, 48, 4156.
1. For reviews and lead references see: (a) Regitz, M. Angew. Chem., Int.
Ed. 1967, 6, 733; (b) Kurti, L.; Czako, B. Strategic Applications
of Named Reactions in Organic Synthesis; Elsevier: London, 2005; p
376.