DOI: 10.1002/chem.201500118
Communication
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Recyclable Supported Reagents
Alkyl Halide-Free Heteroatom Alkylation and Epoxidation
Facilitated by a Recyclable Polymer-Supported Oxidant
for the In-Flow Preparation of Diazo Compounds
Simon M. Nicolle, Christopher J. Hayes, and Christopher J. Moody*[a]
carbenes can react with aldehydes to produce epoxide prod-
ucts in a process that is similar to the Darzens reaction.[3,4]
Given that the metal carbenes are short-lived and do not per-
sist in reaction mixtures after work-up, they are excellent alter-
natives to alkyl halides for performing alkylation reactions and
for generating epoxides. However, the use of potentially haz-
ardous diazo compounds as precursors to metal carbenes pres-
ents a significant barrier to the wide adoption of this chemis-
try. In order to address this problem, we, and others, have
shown that diazo compounds can be generated safely under
continuous flow chemistry conditions,[5] thus limiting the expo-
sure and hence hazards previously associated with these reac-
tive compounds. In our previous work we have shown that in-
flow base treatment of sulfonyl hydrazones gives ready access
to diazo compounds, and we have shown that these can be
used directly in a variety of synthetically useful transforma-
tions.[6,7] Although this represented a significant improvement
of existing methods for in-flow generation of diazo com-
pounds such as the use nitrosamine precursors,[8–10] or sulfonyl
azides,[11] the production of stoichiometric quantities of 4-tol-
uenesulfinate as waste results in overall poor atom economy,
and further work was required to address this shortcoming.
We now show that highly electrophilic but transient-metal
carbenes, can be generated in situ from simple ketone precur-
sors via the oxidation of hydrazones to diazo compounds
using a new, recyclable, solid-supported oxidant in-flow, and
we show that these can be used directly for heteroatom alkyla-
Abstract: Highly reactive metal carbenes, generated from
simple ketones via diazo compounds, including diazo-
amides and -phosphonates, using a recyclable reagent in-
flow, are transient but versatile electrophiles for hetero-
atom alkylation reactions and for epoxide formation. The
method produces no organic waste, with the only by-
products being water, KI and nitrogen, without the at-
tendant hazards of isolation of intermediate diazo com-
pounds.
The search for new bioactive small molecules remains central
to modern drug discovery programmes, and in an analysis of
the reactions used for the preparation of drug candidates,[1]
heteroatom alkylation was the largest single class, accounting
for ~20% of the reactions used. Traditionally, N-, O- and S-alky-
lations are carried out using alkyl halides as electrophiles in
SN2 reactions, although the possibility of residual alkylating
agent being carried through to the final API is a serious con-
cern. In addition to alkyl halides, epoxides represent another
class of electrophiles that are used to generate lead-like struc-
tures, but access to these intermediates most commonly in-
volves the use of highly reactive peroxide-based oxidants. Al-
though “peroxide-free” methods for epoxide synthesis (e.g.,
Darzens condensation, halohydrin cyclization) exist, they also
require the use of alkyl halide re-
agents, and thus their use for
API generation is met with the
same
concerns
highlighted
above for heteroatom alkylation
reactions.
It is well known that metal
carbenes are highly electrophilic,
and that these species can per-
form heteroatom alkylation via
XÀH insertion reactions.[2] Fur-
thermore, it is known that metal
Scheme 1. From ketones to heteroatom alkylation and epoxide formation in-flow.
tion and epoxide formation, whilst producing only water (from
hydrazone formation), potassium iodide (from hydrazone oxi-
dation) and dinitrogen (from metal carbene formation) as stoi-
chiometric waste products (Scheme 1).
[a] S. M. Nicolle, Prof. Dr. C. J. Hayes, Prof. Dr. C. J. Moody
School of Chemistry
University of Nottingham
University Park, Nottingham NG7 2RD (UK)
A simple recyclable oxidant that can be immobilized on
a readily available solid support is an essential requirement for
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem. 201500118.
Chem. Eur. J. 2015, 21, 1 – 5
1
ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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