DOI: 10.1002/chem.201101590
Rapid Access to a-Alkoxy and a-Amino Acid Derivatives through Safe
Continuous-Flow Generation of Diazoesters
Hannah E. Bartrum,[a] David C. Blakemore,[b] Christopher J. Moody,*[a] and
Christopher J. Hayes*[a]
Despite the wide synthetic potential of diazo compounds
À
(X H insertion, ylide formation, cyclopropanation, cycload-
dition etc.),[1] concerns over the hazards associated with
their preparation, isolation, and use have hindered their full
exploitation in both academic and industrial laboratories. A
few diazo compounds are commercially available (e.g. ethyl
and butyl diazoacetate, TMS-diazomethane and diazodime-
done),[2] but safe and convenient access to a wider range of
useful functionalized diazo species is still desirable.[3] Diazo
transfer can be used to access a-diazocarbonyls, but this
only partially addresses the safety concerns associated with
the diazo species, as the use of equally hazardous azide-
based diazo-transfer reagents is still required.[4] Ideally, it
would be beneficial if the diazo species could be generated
and consumed in situ so that handling of the hazardous
diazo compound is avoided altogether.
Scheme 1. Proposed flow process for diazoester synthesis. CFC=convec-
tion flow coil reactor, BPR=back-pressure regulator, oct=octanoate.
Recent work by Ley,[5] Jamison,[6] Kappe,[7] and
others[4,8–10] has shown that highly reactive diazo and azido
compounds can be used in lab-scale continuous-flow reac-
tors to achieve a number of very useful synthetic transfor-
mations, and indeed work from our own laboratory has
shown that ethyl diazoacetate can be used in-flow to access
b-keto esters.[11] We therefore wondered if it was possible to
actually generate a-diazocarbonyl compounds under flow
conditions and then use these materials directly in further
synthetic manipulations, thus minimizing exposure to any
potentially hazardous material. In effect, could we develop a
continuous-flow diazo generator and then demonstrate its
use to prepare a range of useful a-alkoxy (3a–i) and a-
starting materials that showed an acceptable safety profile,
that is, the precursor molecules and reagents should be safer
to prepare and handle than the diazocarbonyl compounds
being produced. Of the methods available for the generation
of a-diazocarbonyl compounds, we were particularly attract-
ed to the Bamford–Stevens reaction as it uses readily acces-
sible arylsulfonylhydrazones (e.g., 1a–i) as starting materials,
with the corresponding diazocarbonyls being generated
upon exposure to relatively weak base at moderate reaction
temperatures.[12–14]
Thermal stability studies (DSC and TGA) were conduct-
ed on the tosylhydrazone 1b and its corresponding methyl
diazoester 2b[15,16] in order to determine if a safe window of
operation could be identified for the continuous-flow pro-
cess (see the Supporting Information). The results clearly
show that the rate of initial mass loss from diazoester 2b
peaks at 1258C, which corresponds to a significant exo-
therm. In comparison tosylhydrazone 1b has a rate of mass
loss which peaks at 2218C, indicating that it is substantially
more thermally stable.[15] We therefore concluded that there
would be significant safety benefits in adapting the Bam-
ford–Stevens reaction for use in-flow to produce diazoesters,
which in turn could be utilized immediately in subsequent
transformations without needing to be isolated or purified.
Reassured by these data, a wider range of arylsulfonylhydra-
zones 1a–i was readily prepared from simple and inexpen-
sive starting materials[17–19] (Scheme 2).
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amino acid (4a–i) derivatives through O H and N H inser-
tion (Scheme 1)?
At the outset we were aware that in order to provide an
acceptable solution to the problem, we needed to identify a
way to access the diazo compounds of interest (2a–i) from
[a] Dr. H. E. Bartrum, Prof. Dr. C. J. Moody, Prof. Dr. C. J. Hayes
School of Chemistry, University of Nottingham
University Park, Nottingham, NG7 2RD (UK)
Fax : (+44)115-951-3564
[b] Dr. D. C. Blakemore
Pfizer Global Research and Development
Ramsgate Road, Sandwich, Kent, CT13 9NJ (UK)
Supporting information for this article is available on the WWW
9586
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2011, 17, 9586 – 9589