Development of a simple system for the oxidation of electron-rich diazo compounds to ketones

Article abstract of DOI:10.1016/j.tetlet.2016.01.020

Mild heating of diazo compounds in DMSO furnishes ketone products in moderate to excellent yields. The reaction is particularly effective on electron-rich substrates and exhibits high chemoselectivity, allowing for the use of diazo compounds containing additional oxidation-prone functional groups. This straightforward protocol offers an alternate route to synthetically useful α-ketoesters from readily available aryl diazoacetates.

Full text of DOI:10.1016/j.tetlet.2016.01.020

Accepted Manuscript
Development of a simple system for the oxidation of electron-rich diazo com-
pounds to ketones
Nicholas R. O’Connor, Peter Bolgar, Brian M. Stoltz
PII:
S0040-4039(16)30020-X
DOI:
http://dx.doi.org/10.1016/j.tetlet.2016.01.020
TETL 47184
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
7 December 2015
5 January 2016
6 January 2016
Please cite this article as: O’Connor, N.R., Bolgar, P., Stoltz, B.M., Development of a simple system for the oxidation
of electron-rich diazo compounds to ketones, Tetrahedron Letters (2016), doi: http://dx.doi.org/10.1016/j.tetlet.
2016.01.020
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Development of a simple system for the
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Nicholas R. O’Connor, Peter Bolgar, and Brian M. Stoltz

1
Tetrahedron Letters
Development of a simple system for the oxidation of electron-rich diazo compounds
to ketones
Nicholas R. O’Connor, Peter Bolgar, and Brian M. Stoltz*
The Warren and Katharine Schlinger Laboratory for Chemistry and Chemical Engineering, Division of Chemistry and Chemical Engineering, California
Institute of Technology, 1200 E. California Boulevard, MC 101-20, Pasadena, CA 91125, USA
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
Mild heating of diazo compounds in DMSO furnishes ketone byproducts in moderate to
excellent yields. The reaction is particularly effective on elctron-rich substrates and exhibits
high chemoselectivity, allowing for the use of diazo compounds containing additional oxidation-
prone functional groups. This straightforward protocol offers an alternate route to synthetically
useful α-ketoesters from readily available aryl diazoacetates.
Available online
Keywords:
Oxidation
2009 Elsevier Ltd. All rights reserved.
Diazo compounds
Ketones
Dimethyl sulfoxide
Chemoselective transformation
α-Ketoesters and their derivatives are useful synthetic building
blocks,1 and a number of methods for their synthesis have been
reported.2 The oxidation of diazoacetates offers a convenient
route to α-ketoesters,3 as the starting materials are readily
accessed by treatment of acetic acid derivatives with p-
acetamidobenzenesulfonyl azide and DBU (see the Supporting
Information for details).4 Various methods for this oxidation
have been reported, although many require the use of expensive
transition metal catalysts or harsh oxidants.
with pyridine-N-oxide alone resulted in a moderate yield of α-
ketoester 4 (Table 1, entry 1).
Recently, Wang and coworkers disclosed an efficient
synthesis of aryl α-ketoesters from α-aryl esters by one-pot diazo
transfer/oxidation using DMDO generated in situ.3e This protocol
offers a novel route to α-ketoesters using simple and inexpensive
reagents (acetone, Oxone, and sodium bicarbonate) at room
temperature. The major disadvantage is the strong oxidizing
ability of DMDO, which prevents the use this method with
substrates containing other easily oxidizable functional groups.5
In this communication, we describe our studies on an alternative
system that uses a far milder oxidant for the transformation of
diazoacetates to ketones.6
Scheme 1. Observation of an unexpected oxidation event during an
attempt at pyridine 2-functionalization.
We suspected that mild conditions for the oxidation of an aryl
diazoacetate to the α-ketoester might be synthetically useful.
During optimization studies, we found that lowering the
temperature to 50 °C increased the yield of 4 to 84% (Table 1,
entry 2). A survey of other oxygen-transfer reagents showed that
the use a more electron-rich pyridine-N-oxide did not result in an
increase in yield (entry 3). Triphenylphosphine oxide was
capable of carrying out the desired oxidation, albeit in low yield
(entry 4), while trimethylamine-N-oxide and N,N-dimethyl-4-
nitrosoaniline were not (entries 5 and 6). The use of benchtop
DMSO as both solvent and oxidant provided the oxidation
product in approximately 70% yield, although we observed
varying amounts of the water O–H insertion product with
different batches of benchtop DMSO (entry 7). This undesired
reactivity was suppressed by the use of anhydrous DMSO (entry
In the course of investigations into the synthesis of
functionalized pyridines by C–H activation routes, we subjected
pyridine-N-oxide (1) and aryl diazoacetate 2 to conditions
developed by Chang and coworkers for the synthesis of 2-
arylpyridine-N-oxides, hoping to observe coupling to furnish
diarylmethane 3 (Scheme 1).7 While 3 was not detected, we
unexpectedly found the major product of the reaction to be α-
ketoester 4. Control experiments revealed the palladium and
other additives to be unnecessary, and treatment of diazoacetate 2

2
Tetrahedron
Figure 1. Substrate scope of the oxidation of diazo compounds.
8). We found it optimal to use anhydrous DMSO at 75 °C,
which furnished the α-ketoester 4 in an excellent 91% yield.
The substrate scope of the reaction is shown in Figure 1. An
electron-rich aryl ring was generally found to be necessary, with
4-methoxyphenyl (4–7), 3,4-dimethoxyphenyl (8), and 4-
methylphenyl (9) substituents furnishing the α-ketoester products
in excellent yields. Unfortunately, compounds with less electron-
rich aryl rings afforded the products in lower yields, and
acceptor-acceptor diazos were completely unreactive.13 Notably,
substrates containing functional groups susceptible to oxidation,
including an olefin (5), an adamantyl group (6),14 a pyridyl ring
(7), a thioether (10), and a thiophene ring (11) were all smoothly
converted to the α-ketoesters with no overoxidation observed.
An oxindole scaffold was compatible with the reaction, allowing
for the formation of N-methylisatin (12) in moderate yield.
Finally, an electron-withdrawing group on the diazo carbon was
found to be unnecessary, as diphenyldiazomethane was converted
to benzophenone (13) in moderate yield.
Table 1. Optimization of the oxidation of aryl diazoacetate 2.
Subjection of styrenyl diazoacetate 14 to the reaction
conditions resulted in smooth isomerization of the starting
material to pyrazole 15 in quantitative yield (Scheme 2).15 An
alkyl-subtituted diazo compound (16) also did not undergo the
desired oxidation, but rather was converted to the enoate (17) as a
mixture of olefin isomers via a 1,2-hydrogen shift.16
Scheme 2. Alternative reactivity of styrenyl and alkyl diazoacetates.
A representative procedure is as follows: To an oven-dried 1-
dram vial equipped with a magnetic stir bar were added methyl 2-
diazo-2-(4-methoxyphenyl)acetate (2, 82 mg, 0.40 mmol) and
anhydrous DMSO (0.5 mL). The vial was sealed with a Teflon-
lined plastic cap and placed in a metal heating block at 75 °C.
Upon completion (as determined by TLC analysis and a color
change from deep orange to pale yellow, approx. 2 hours), the
reaction mixture was allowed to cool to room temperature.
Olfactory analysis of the crude mixture suggests dimethyl sulfide
is a byproduct. The mixture was loaded directly onto a silica gel
column, eluting with 20% ethyl acetate in hexanes to obtain 71
mg of methyl 2-(4-methoxyphenyl)-2-oxoacetate (4, 91% yield).
Sporadic examples of the oxidation of diazo compounds using
DMSO have been published, although many of these examples
provide only low or undisclosed yields of the observed oxidation
products.8–12 Furthermore, no reports of this reactivity offer
investigations into the reaction scope and limitations.
In summary, we have identified optimized conditions for a
highly chemoselective and extremely simple method for the
oxidation of diazo compounds to ketones. A study of the
reaction scope reveals a range of aryl diazoacetates to be
compatible with the reaction, even those containing other easily
oxidizable functional groups. Given the ready availability of aryl
diazoacetates, we envision this oxidation will find utility as an
alternative route to synthetically useful α-ketoesters, particularly
when the desired compounds contain other functional groups
sensitive to oxidation.

3
Acknowledgments
The authors wish to thank the NSF (CHE-1265591), Amgen, and
Caltech for financial support. P. B. is grateful to St Catharine’s
College (University of Cambridge) and the Haller US Travel
Fund for their support of an undergraduate summer research
exchange program. Dr. David VanderVelde (NMR), Dr. Mona
Shahgholi (HRMS), and Shoshana Bachman (ATR-IR) are
thanked for assistance with characterization.
Supplementary Material
Supplementary data associated with this article can be found, in
the online version, at ___
References and notes
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