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Angewandte
Communications
Synthetic Methods
Hot Paper
AVersatile Room-Temperature Route to Di- and Trisubstituted
Allenes Using Flow-Generated Diazo Compounds**
Jian-Siang Poh, Duc N. Tran, Claudio Battilocchio, Joel M. Hawkins, and Steven V. Ley*
Abstract: A copper-catalyzed coupling reaction between flow-
generated unstabilized diazo compounds and terminal alkynes
provides di- and trisubstituted allenes. This extremely mild and
rapid transformation is highly tolerant of several functional
groups.
case of accessing trisubstituted allenes by direct coupling
reactions, these are scarce and proceed with very low
functional-group tolerance.[6a,e,f] We report herein a new
practical method to generate functionalized di- and trisub-
stituted allenes using flow-generated unstabilized diazo com-
pounds at room temperature.
T
he use of machine-based enabling technologies can accel-
Copper(I) is known to be a suitable catalyst for the
coupling between diazo compounds and terminal alkynes. We
anticipated that by generating unstabilized diazo compounds
in flow, we could perform this coupling reaction under much
milder reaction conditions. Following the mechanism de-
scribed by Wang et al.,[6a] the reaction is expected to be
initiated by the formation of the copper acetylide species 5
from the copper(I) catalyst and terminal acetylene 3 in the
presence of a base (Scheme 1). The copper acetylide inter-
erate the chemical discovery process and improve research
efficiency.[1] Likewise, flow chemistry methods can play
a useful role by assisting the adoption of new synthesis
concepts.[2] Nevertheless, any new technology will be dis-
ruptive and eventual incorporation must be done with
considerable care and forethought to ensure full integration
with existing practices.
We, as well as others,[3] have been interested in exploiting
the dynamics of flow reactor systems to generate wider
chemical reactivity windows. For example, the generation of
unstabilized diazo compounds in flow has proven to be an
attractive method, as these reactive intermediates can be
combined directly with a variety of substrates under mild
reaction conditions.[3a,b]
Allenes are interesting functional groups owing to their
orthogonal p bonds. Several natural bioactive molecules, as
well as synthetic materials, possess this particular structural
motif.[4] These building blocks are used for a wide range of
transformations, in particular those producing heterocyclic
architectures, for example, furans and pyrrolidines.[5] Direct
access to allenes is possible by various protocols,[6] however,
harsh reaction conditions are often required. In the particular
Scheme 1. Proposed reaction mechanism of coupling between diazo
compounds and terminal alkynes catalyzed by copper(I).
[*] J.-S. Poh, Dr. D. N. Tran, Dr. C. Battilocchio, Prof. S. V. Ley
Innovative Technology Centre, Department of Chemistry
University of Cambridge
mediate can then be intercepted by the diazo compound 2 to
generate the carbene copper complex 6. A 1,2-carbon
migration followed by a 1,3-copper migration would then
form the vinyl copper species 8. A final protonation of this
intermediate should provide the allene 4 and regenerate the
active copper(I) catalyst species for the next catalytic cycle.
The reaction was initially optimized using (4-chloroben-
zylidene)hydrazine (1a)[7] and propargyl alcohol (3a) as
model substrates (Scheme 2). The hydrazone 1a was oxidized
in flow to generate the diazo compound 2a. This latter
compound was immediately quenched by adding it to
a reaction mixture containing 3a, the catalyst, and the base.
Our initial screening showed the importance of the counter-
ion of the copper complex in determining the reaction
outcome. For instance, the use of [Cu(acac)2], CuF2,
CuOAc, CuCl, and CuTC (copper thiophene-2-carboxylate)
resulted in less than 5% yield of the desired allene product
4a. The main by-products detected resulted from the
Lensfield Road, Cambridge CB2 1EW (UK)
E-mail: svl1000@cam.ac.uk
Dr. J. M. Hawkins
Pfizer Worldwide Research and Development
Eastern Point Road, Groton, CT 06340 (USA)
[**] We are grateful to the Cambridge Home and European Scholarship
Scheme (JSP), Swiss National Science Foundation (DNT), Pfizer
Worldwide Research and Development (CB and JMH), and EPSRC
(SVL, grant numbers EP/K0099494/1 and EP/K039520/1) for
financial support.
Supporting information for this article is available on the WWW
ꢀ 2015 The Authors. Published by Wiley-VCH Verlag GmbH & Co.
KGaA. This is an open access article under the terms of the Creative
Commons Attribution License, which permits use, distribution and
reproduction in any medium, provided the original work is properly
cited.
7920
ꢀ 2015 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2015, 54, 7920 –7923