Flow chemistry as a discovery tool to access sp2-sp3 cross-coupling reactions via diazo compounds

Article abstract of DOI:10.1039/c4sc03072a

The work takes advantage of an important feature of flow chemistry, whereby the generation of a transient species (or reactive intermediate) can be followed by a transfer step into another chemical environment, before the intermediate is reacted with a coupling partner. This concept is successfully applied to achieve a room temperature sp²-sp³ cross coupling of boronic acids with diazo compounds, these latter species being generated from hydrazones under flow conditions using MnO₂ as the oxidant.

Full text of DOI:10.1039/c4sc03072a

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Flow chemistry as a discovery tool to access sp2–
sp3 cross-coupling reactions via diazo compounds†
Cite this: DOI: 10.1039/c4sc03072a
Duc N. Tran,a Claudio Battilocchio,a Shing-Bong Lou,a Joel M. Hawkinsb
a
*
and Steven V. Ley
The work takes advantage of an important feature of flow chemistry, whereby the generation of a
transient species (or reactive intermediate) can be followed by a transfer step into another chemical
environment, before the intermediate is reacted with a coupling partner. This concept is successfully
Received 7th October 2014
Accepted 7th November 2014
applied to achieve
a
room temperature sp2–sp3 cross coupling of boronic acids with diazo
DOI: 10.1039/c4sc03072a
compounds, these latter species being generated from hydrazones under flow conditions using MnO2
www.rsc.org/chemicalscience
as the oxidant.
under continuous ow reactions,10 we believed that we could
devise a system capable of delivering reactive unstable diazo
Introduction
compounds on demand. Also, with the aim of better exploiting
the potential of the ow chemistry,11,12 we anticipated that these
ow-generated transient species could be rapidly transferred
into another chemical environment, in order to react the
aforementioned species with a suitable partner, hence avoiding
interference by spent reagents (Scheme 1). This generation/
translocation/reaction sequence should immediately provide
access to new chemical space for the discovery of new reactions
for these reactive intermediates.
Chemical processes dene our modern world in terms of
providing society’s functional materials.1 Many of these
processes involve complex reaction pathways and proceed via
transient reactive intermediates. The lifetime of these reactive
species can vary enormously and their selectivity can oen be
difficult to exploit. Their high level of reactivity, when gener-
ated in batch mode, can be problematic because of incom-
patibilities with their chemical environment or functional
groups, or because of associated exothermic properties. A case
in point relates to diazo compounds which are valuable reac-
tive intermediates.2 For example, isolated stabilised diazo
compounds, bearing one or more electron withdrawing
groups, have been extensively investigated in a wide range of
applications such as dipolar cycloadditions,3 carbonyl
homologation4 and cyclopropanation.5 However, their unsta-
bilised alkyl and aryl diazo counterparts are much more
difficult to harness.2,6 Their chemical preparation is limited
due to the oen tedious, corrosive or toxic synthesis proto-
cols.6a,7 In situ generation of diazo compounds therefore
represents an interesting opportunity for synthesis,8 although
any new procedure must be compatible with both the gener-
ation of the diazo compound and with its subsequent
chemical transformation.
Metal free sp2–sp3 cross-coupling reactions have recently
become a new focus of the chemical community.13 In 2009,
Barluenga et al. reported an efficient coupling between tosyl-
hydrazones and boronic acids.13a Further studies with saturated
heterocyclic sulfonylhydrazones by Nakagawa,13c Kirschning,13e
and ourselves,13f demonstrated a wider scope for the reaction
(Scheme 2). Recently, Wang and co-workers reported an effi-
cient synthesis of a-aryl esters and nitriles via a diazotization
method for the generation of stabilised diazo compounds.13g
However, the relatively harsh reaction conditions (up to 110 ꢀC),
large amount of inorganic additives (bases, NaNO2, NH4Cl) and
low atom economy represent potential drawbacks of these
transformations. We envisaged that we could access new reac-
tivities of unstabilised diazo compounds, in particular their
coupling with boronic acids at room temperature.
Manganese dioxide (MnO2) has been used previously in
batch mode to generate diazo compounds from hydrazones,
although with low efficiency and with very specic substrates.9
Following on from the advantages that accrue when using MnO2
aInnovative Technology Centre, Department of Chemistry University of Cambridge,
Lenseld Road, Cambridge, CB2 1EW, UK. E-mail: svl1000@cam.ac.uk
bPzer Worldwide Research and Development, Eastern Point Road, Groton, CT 06340,
USA
† Electronic supplementary information (ESI) available. See DOI:
10.1039/c4sc03072a
Scheme 1 Flowing scheme for the generation, translocation and
reaction of the diazo species.
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Under the optimised conditions, a 0.1 M solution of hydra-
zone 1 was passed through a conditioned MnO2 column (0.86 g,
activated MnO2) at 0.5 mL minꢁ1 with 2 equiv. of Hunig’s base
¨
in CH2Cl2. In-line IR data (collected using an in-line infrared
spectrometer) suggested that a typical load of activated MnO2
(10 mmol) could cleanly generate 2 mmol of diazo compound
over 40 minutes. The generation of diazo compound, which
proved to be highly practical as the whole process was carried
out at room temperature, was followed by an esterication step
of the transient species produced.
To explore the general application of this process, different
hydrazone derivatives were examined (Table 1). The generated
diazo compound was quenched with different carboxylic acids
(3a–3c) and one phenol substrate (3d). The reaction was
compatible with both electron poor and electron rich aromatic
hydrazones. Electron poor aryl diazo compound gave in general
better yields as they are more stabilised. Investigation of the
reactivity of a vinylic diazo compound revealed the formation of
two regioisomers (3j and 3j0) aer reaction with excess AcOH.
However, when geranyl hydrazone was processed via our
protocol only one isomer was obtained, though only in
moderate yield (3k). On the other hand, diphenyl ketone
hydrazone gave ester 3i in excellent yield.
Scheme 2 Selected metal-free sp2–sp3 cross-coupling reactions.
Results and discussion
Generation of diazo compound
Initial investigations focused on 4-bromophenyl hydrazone (1a)
as model substrate for the generation of the diazo compound
2a. To evaluate the generation of the transient diazo species, the
material processed was quenched with acetic acid to yield the
corresponding acetic acid ester 3a (Scheme 3).6 Amorphous
MnO2 packed into the ow cartridge gave very poor conversion
to 2a with mainly starting material being recovered. By contrast,
a column packed with activated MnO2 gave full conversion to
various products but with aldehyde 4a being the main product
observed. This result was also consistent with batch studies
where aldehyde or azine by-products were generally observed at
ca. 30% yield, even under carefully controlled reaction con-
ditions.9b,c,f However, conditioning of the packed column with a
small amount of sacricial hydrazone14 effectively reduced the
formation of aldehyde and increased the production of diazo
compound 2a as determined via the formation of ester 3a.
Coupling reaction with boronic acids
Diazo compounds are commonly proposed as intermediates for
several useful transformations, in particular carbon–carbon
sp2–sp3 coupling between tosylhydrazone and boronic acids.13
High temperature and an inorganic base are typically required
as the generation of the diazo compound is reported to be the
limiting step of these reactions. We speculated that with our
new protocol the chemical reactivity of diazo compounds could
be studied separately without interference from the generation
step. Pleasingly, aer its generation, the stream of the diazo
compound 2a reacted quickly at room temperature with boronic
acid 7a in the rst attempt, giving the coupled product 8a in very
good yield (Scheme 4). This extremely mild and fast reaction
conditions demonstrated the high chemical reactivity of diazo
compounds and highlighted the advantages of the ow protocol
for these reactive intermediates where the equivalent batch
mode reaction was found to be unsuccessful.
¨
Furthermore, addition of a base (Hunig’s base, 2 equiv.) to the
feedstock solution provided a reliable system with greatly
reduced amounts of by-products generated.15
Different coupling combinations were investigated using the
ow procedure for the generation of clean diazo compounds
(Table 2). With much milder reaction conditions compared to
the original Barluenga coupling, the electronic properties
exerted a strong inuence on the reaction time. For electron
rich or neutral boronic acids the transformation was complete
within 1 hour (compounds 8a–c). By contrast, electron poor aryl
boronic acids required longer reaction time or harsher reaction
conditions (8d–e). Similar trends were observed with other
diazo compounds. Electron poor (more stabilised) diazo
compounds required, in general, longer reaction times when
reacted with the same boronic acid (8j vs. 8b). Interestingly,
vinyl diazo compounds are also compatible with this protocol
giving the desired products in good yields (8n–q). Notably, in
these cases a mixture of products was obtained resulting from a
Scheme 3 Flow generation and quenching of 1-bromo-4-(diazo-
methyl)benzene.
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Table 1 Titration of generated diazo compound to the corresponding
method for geranylation, where the normal Friedel–Cras
alkylation fails. Additionally, we were able to access sp2–sp3
coupling transformations for aryl–alkyl diazomethane deriva-
tives in quite good yield (8m).
estersa
Since the boronic acids are oen the more functionalised of
the two starting materials, the ow-generated diazo partner was
used in excess to fully convert the boronic acid 7b to the desired
coupling product (Scheme 5). Pleasingly, the diaryl compound
8f was obtained in 96% isolated yield using only a slight excess
of diazo compound (1.5 equiv.). In this case, the excess diazo
was subsequently quenched via an acidic aqueous work-up
protocol. The main by-products detected were both the corre-
sponding azine and alcohol.
The strong dependence of the reaction kinetics on the elec-
tronic properties of both starting materials reveals some insight
about the reaction mechanism. It is generally assumed that
aer nucleophilic attack of the diazo compound to the boronic
acid, a rst ate complex 9 is formed. This intermediate rapidly
undergoes a 1,2-carbon migration forming the boronic species
Table 2 Coupling products prepared by reaction of diazo compounds
with boronic acidsa
a
b
Isolated yield over 3 steps based on aldehyde precursor. Combined
yield (r.s. ¼ 1 : 1).
Scheme 4 Flow generation, translocation and reaction of 2a with 7a.
1,3-borotropic rearrangement and the regioselectivity of the
products mixtures was strongly inuenced by the electronic
properties of the two aromatic rings, ranging from 2 : 1 (8n) to
15 : 1 (8q). Different functionalities are tolerated such as halo-
gens, nitro groups and ethers. Heterocycles such as pyridine
(8e) are also compatible with this protocol. The highly reactive
geranyl diazo gave the geranylated product (8l) in good yield,
based on the titration of the corresponding diazo compound.
This process is remarkable as it provides a complementary
a
Isolated yield based on titration of diazo compound with acetic acid.
b
Microwave 100 ꢀC in 15 min. c Combined yields.
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are linked to the harsh conditions employed to generate the
reactive intermediate.13 We started by investigating the kinetics
involved in the sequence of events. Initial NMR studies focused
on a model reaction between diazo compound 2b and boronic
acid 7b and the analysis showed a two-step mechanism (Scheme
6), where the rst step happens at a much faster rate than the
second one. Using the data collected over a large series of
dynamic experiments, we were able to dene that the reaction is
rst order with respect to the diazo compound.
Remarkably, using our mild ow protocol we were also able
for the rst time to intercept the secondary boronic intermediate 10,
proving the presence of this intermediate prior to proto-
deboronation. Indeed, we envisaged that the generation of a
relatively stable boronic intermediate 10 would reduce the rate
of proto-deboronation and this new reactive intermediate could
be intercepted via an alternative reaction pathway. This idea
was realised with the use of acetophenone hydrazone (1b) as
starting material, which was passed through the oxidant-
column, packed with activated MnO2, to form the correspond-
ing diazo compound (as detected by in-line IR); the transient
diazo species was translocated to react with boronic acid 7a and
then further reacted with a solution of hydrogen peroxide. The
analysis of the material revealed the prevalence of alcohol 11
(68%) within the mixture, corroborating the presence of a
boronic species 10c as an intermediate.
Scheme 5 Boronic acid 7b used as limiting reagent.
10 which isomerises to the most stable isomer prior to a proto-
deboronation to give the coupling product 8 (Scheme 6).
Although this mechanism is assumed to describe the actual
chemical combinations of the intermediates involved, no report
has either identied the kinetics of this kind of transformation
or the nature of the species involved. The reasons behind this
To increase the efficiency of the new protocol, the regener-
ation and re-use of MnO2 column was briey investigated. The
spent manganese oxide could be oxidised by passage of a
Scheme 7 Flow regeneration of MnO2 reagent using TBHP.
Scheme 6 Mechanistic studies of coupling reaction between diazo Fig. 1 IR data for the four regeneration cycles of oxidation for a single
compound and boronic acid.
MnO2 load (0.86 g).
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solution of tert-butyl hydroperoxide (TBHP, 1 M in CH2Cl2)
(Scheme 7). Interestingly, the regenerated column produced
diazo compound without the need for a pre-conditioning phase.
The heterogeneous oxidant was recycled over three different
cycles with just a slight decrease in reactivity aer each recycle
as detected by in-line IR (Fig. 1).
Moreover, in a preliminary attempt with tube-in-tube tech-
nology,16 oxygen gas also proved to be a useful re-oxidant for a
low cost regeneration of MnO2 but with lower efficiency.17
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Conclusion
In summary, we have reported a practical ow generation of
unstable diazo compounds as reactive intermediate using the
cheap, recyclable and non-toxic oxidant, MnO2. The diazo ow
stream can be accurately titrated or followed by in-line IR. Using
our protocol, we were able to deliver sp2–sp3 coupling reactions
of the freshly generated diazo species with boronic acids, under
extremely mild and simple reaction conditions providing alky-
lated products in good to excellent yield. The mechanistic
studies demonstrated for the rst time the presence of a specic
boronic intermediate. These results demonstrate that ow
generation/translocation/reaction of transient species opens up
opportunities for the exploitation and study of new chemical
reactivities. Further studies in this area are underway in our
laboratories.
Acknowledgements
We are grateful to the Swiss National Science Foundation
(DNT), Pzer Worldwide Research and Development (CB and
JMH), and the EPSRC (SVL, grant no. EP/K0099494/1). We also
thank the EPSRC (core capability grant no. EP/K039520/1) for
improvements to analytical facilities.
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