Establishing a flow process to coumarin-8-carbaldehydes as important synthetic scaffolds

Article abstract of DOI:10.1002/chem.201201039

Despite their usefulness as fluorophores and synthetic precursors, efficient and reliable routes to coumarin-8-carbaldehydes are lacking. We describe here a high-yielding continuous flow synthesis that requires no manual intermediate purification or work-up, giving access to multigram quantities of the aldehyde product. Aldehyde on tap: Despite their usefulness as fluorophores and synthetic precursors, efficient and reliable routes to coumarin-8- carbaldehydes are lacking. A high-yielding continuous flow synthesis that requires no manual intermediate purification or work-up is described, giving access to multigram quantities of aldehyde product (see scheme). Copyright

Full text of DOI:10.1002/chem.201201039

FULL PAPER
DOI: 10.1002/chem.201201039
Establishing a Flow Process to Coumarin-8-Carbaldehydes as Important
Synthetic Scaffolds
Jaroslav Zak,[a, c] David Ron,[b] Elena Riva,*[a] Heather P. Harding,[b]
Benedict C. S. Cross,[b] and Ian R. Baxendale[a]
Abstract: Despite their usefulness as fluorophores and synthetic precursors, effi-
cient and reliable routes to coumarin-8-carbaldehydes are lacking. We describe
here a high-yielding continuous flow synthesis that requires no manual intermedi-
ate purification or work-up, giving access to multigram quantities of the aldehyde
product.
Keywords: coumarins
chemistry · heterocycles · micro-
reactors · solid-supported reagents
·
flow
Introduction
the ultraviolet region and exhibiting potent fluorescence
and luminescence.[2] In addition, they possess a wide range
of biological activities and have long been considered attrac-
tive drug scaffolds being used in the treatment of viral infec-
tions,[3] neurodegenerative diseases,[4] oedema,[5] inflamma-
tion, and as hepatoprotective agents and antioxidants.[6]
Indeed, several coumarins derivatives[7] (Figure 1) have al-
ready found pharmaceutical application as vitamin K antag-
onists (Warfarin), anticoagulants (Phenprocoumon), antibi-
otics (Novobiocin) and antispasmodics (Hymecromone).
Furthermore, their utilisation in the fight against cancer is
another prominent area, with both natural and synthetic
coumarins showing promising activity in in vivo rat models
and importantly against malignant human cell lines.[8] Apart
from their medicinal applications, coumarins have also
found use as sunscreen ingredients,[9] microbiological mark-
ers,[10] textile and laser dyes,[11] fluorescent labels[12] and,
more recently, as solar cell sensitisers. As a consequence of
their general functionality many synthetic methods for their
preparation have been reported.[13]
Coumarins are a general structural class of aromatic hetero-
cycle defined by the naturally occurring parent compound
(Figure 1), which was first isolated in 1822 from Tonka
beans (Dipteryx odorata).[1] Molecules possessing the 2H-
chromen-2-one core display a diverse range of interesting
properties—many are highly coloured, absorbing strongly in
However, one particular functional pattern that despite its
simple chemical architecture has proven challenging to
access reliably is the 7-hydroxycoumarin-8-carbaldehyde
(e.g., 5a, Scheme 1).[14] This is an important structure motif
with the juxtaposed formyl and phenoxy groups imparting
enhanced fluorescent characteristics and enabling easy as-
sembly of Schiff base Salen ligands which have found many
applications in diagnostic and detection systems.[15] Histori-
cally, installation of the formyl unit is achieved through
functionalization of the corresponding 7-hydroxycoumarin
using a Gattermann–Koch,[16] Reimer–Tiemann,[17] Vilsmei-
er–Haack[18] or Duff[14] reaction. Unfortunately, these meth-
ods all suffer from poor conversion and often require exten-
sive work-up leading to further loss of yield and resulting in
an overall inefficient process (Table 1). Requiring access to
large quantities of 5a as a biological probe[23] we decided to
evaluate alternative synthesis protocols.
Figure 1. Coumarin and coumarin derivatives of pharmaceutical impor-
tance.
[a] J. Zak, Dr. E. Riva, Dr. I. R. Baxendale
Department of Chemistry
University of Cambridge
Lensfield Road, Cambridge, CB2 1EW (UK)
E-mail: theitc@ch.cam.ac.uk
[b] Prof. D. Ron, Dr. H. P. Harding, Dr. B. C. S. Cross
University of Cambridge Metabolic Research Laboratories
Level 4, Institute of Metabolic Science
Box 289, Addenbrookeꢀs Hospital
Cambridge, CB2 0QQ
[c] J. Zak
Current address: Ludwig Institute for Cancer Research
University of Oxford
Old Road Campus Research Building
Oxford, OX3 7DQ (UK)
We have found that the application of flow processing
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201201039.
technologies[24] offers several advantages for the synthesis of
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streams can be readily facilitated by the incorporation of
fixed bed supported reagent cartridges and in-line scaveng-
ing columns.[26] Such an approach appeared to us to be ideal
for achieving a fast, reliable and readily scalable route to
various coumarin carbaldehydes.
Results and Discussion
Having considered several potential routes we selected two
complementary strategies (Scheme 1) which we believed
would deliver high yields of the desired products and gain
significant efficiencies by adoption of flow processing tech-
nologies. However, in order to first facilitate a direct com-
parison of the routes against the pre-existing literature
methods both proposed sequences were evaluated using
standard batch conditions.
The basic route development and reaction optimisation
was thus conducted on the basic target structure 5a. The
first step of both synthetic pathways is common and involves
the formation of the coumarin core. This was achieved using
a Pechmann condensation reaction.[27] A protocol using tri-
fluoroacetic acid (TFA) as a catalyst was identified being
both high-yielding and a generic method of preparation
from simple readily available starting materials; resorcinols
and acetoacetate derivatives. From this reaction numerous
coumarin derivatives were prepared in good yields and ex-
cellent regioselectivity (Table 2) when heated at 1008C for
1 h under microwave irradiation. Using this protocol, only
one coumarin derivative failed to form with the anticipated
regiocontrol. Thus attempts to prepare the corresponding
2H-chromen-2-one from orcinol and ethyl acetoacetate
(Table 2, entry 7) gave compound 1g[28] instead of the ex-
Scheme 1. Proposed routes to 7-hydroxy-4-methyl-2-oxo-2H-chromene-8-
carbaldehyde (5a).
Table 1. Data of comparative yields for the synthesis of 7-hydroxy-
coumarin structures.
Product
Reaction
Yield [%]
Ref.
Duff reaction[a]
22
[19]
5a
5a
5a
5a
5a
Duff reaction[a]
Duff reaction[a]
Duff reaction[a]
Duff reaction[a]
20
15
15
22
ACHTUNGTNER[NUNG 14d]
[20]
[21]
pected
7-hydroxy-4,5-dimethyl-2H-chromen-2-one;
the
structure of 1g was unambiguously confirmed by X-ray crys-
tallography (see the Supporting Information). This is an in-
teresting result as under many alternative reaction condi-
tions 7-hydroxy-4,5-dimethyl-2H-chromen-2-one is the only
product isolated often in exceptionally high yield.[29] Indeed,
following a similar protocol[30] but using H2SO4 as the acid
catalyst we also isolated the 7-hydroxy coumarin derivative
1g.
Following the Pechmann cyclisation the two pathways di-
verge (Scheme 1). In Route A the installation of the formyl
group is provided for through alkene 4a acting as a latent
carbonyl group revealed by ozonolysis. The proceeding alke-
nylation of the aryl ring occurs by a standard allylation of
the phenol (1a!2) followed by a Claisen rearrangement
and metal catalysed isomerisation to yield the necessary
conjugated alkene 4a. Alternatively Route B involved an
aminoalkylation of the coumarin followed by N-oxidation
and a regioselective Polonovski reaction leading to an inter-
mediate benzylic iminium species. Direct iminium hydrolysis
would then furnish the corresponding aldehyde 5a. Each
transformation of both sequences was high yielding and fur-
nishes adequately clean material for further processing with-
out the need for extensive purification.
AHCTUNGTERG[NNUN 14b]
Duff reaction[a]
60
54
84
[22]
Vilsmeier reaction[b]
Vilsmeier reaction[b]
ACHTUNGTNER[NUNG 18a]
AHCTUNGTERG[NNUN 18b]
Reaction conditions: [a] 1) hexamethylene tetramine, glacial acetic acid,
60–808C, 2) HCl. [b] N-methylformanilide, POC13, dichloroethane, 70–
758C.
complex natural products and their derivatives.[25] Of partic-
ular value is the possibility of carrying out two or more se-
quential reactions with no or minimal intermediate workup
and purification between transformations. Indeed, the con-
tinuous processing and downstream clean-up of reaction
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Flow Process to Coumarin-8-Carbaldehydes
FULL PAPER
Table 2. Synthesized coumarin-carbaldehydes and their synthetic intermediates.
Entry
Starting
material
Starting
material
Pechmann
reaction product
Mannich
reaction product
N-Oxidation
reaction product
Polonovski
reaction product
1
1a (quantitative yield)
6a (86%)
6b (70%)
6c (74%)
6d (77%)
7a (31%)
7b (57%)
7c (53%)
7d (71%)
7e (36%)
5a (44%)
5b (41%)
5c (52%)
5d (79%)
5e (67%)
2
3
4
5
1b (92%)
1c (quantitative yield)
1d (quantitative yield)
1e (97%)
1 f (96%)
1g (72%)
6e (99%)
6
7
No reaction
No reaction
Route A batch conditions: The allylation step proceeded
smoothly in essentially quantitative yield using K2CO3 in
acetone under mild conditions (608C, 1 h), aqueous extrac-
tion to remove inorganic salts was the only work-up necessa-
ry. The subsequent [3,3]-sigmatropic rearrangement was
found to require elevated temperatures (2008C) and gener-
ated a mixture of two isomers (3a/3b 9:2) albeit these could
be readily separated by column chromatography (note that
the two isomers can also be carried through the subsequent
steps without separation and the minor isomer easily re-
moved by crystallisation at the stage of the aldehyde forma-
tion 5a). Isomerisation of alkene 3a to yield the vinyl
system 4a was promoted using Felkinꢀs iridium catalyst
[(1,5-cyclooctadiene)-bis(methyldiphenylphosphine)iridi-
um(I) hexafluorophosphate].[31] This gave complete conver-
sion in 24 h using 5 mol% of the catalyst in THF with only
the trans configured alkene being detected by 1H NMR anal-
ysis of the crude product. As a simple purification step the
reaction mixture was filtered through a short plug of silica
and then the resulting THF solution directly subjected to
the ozonolysis conditions. Treatment with ozone gave
a rapid and clean conversion to the corresponding aldehyde
5a in 20 min as determined by TLC analysis. The intermedi-
ate ozonide was subsequently cleaved by treatment with
a polymer-supported triphenylphosphine equivalent (PS-
PPh2, 3 equiv) giving the desired product in 91% isolated
yield after filtration and solvent removal. Although this pro-
cedure worked very efficiently we also decided to investi-
gate an alternative method. It has been widely reported that
vinyl systems, as present in compound 4a, can be oxidatively
fragmented using a combination of osmium tetraoxide and
periodate. To facilitate expedient work-up we selected to
use a microencapsulated osmium source (OsEnCat[32]). In
a THF/water mixture using 4 mol% of the OsEnCat and
a molar excess of NaIO4 at ambient temperature the sub-
strate 4a was efficiently converted to the corresponding al-
dehyde 5a over a period of 4 h. Following work-up and pu-
rification an isolated yield of 78% of 5a was obtained. We
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E. Riva et al.
were particularly pleased by these results as both of these
cleavage methods offered potential for scaling and transfer-
ral to flow.
sis of several different 7-hydroxy-carbaldehydes (Table 1)
demonstrating the routeꢀs general applicability. Regrettably
though the low isolated yields and highly capricious nature
of these later two reactions even with only minor changes in
the rates of reagent addition, purity of the intermediate or
length of reaction incubation was a significant issue in
batch. However, we considered this sequence to be ideally
suited to automated flow processing where fine tuning of re-
actant mixing, thermal regulation and reaction residence
time can be easily achieved.[36] Our main goal was therefore
to develop a simple, reliable and directly scalable continu-
ous flow method for the synthesis of 7-hydroxy-4-methyl-2-
oxo-2H-chromene-8-carbaldehyde (5a). Our ideal vision
was the assembly of an integrated “one-stream” synthesis of
the target molecule where reagents would be added sequen-
tially to the downstream flow path progressing the synthesis
without recourse to offline work-up or intermediate isola-
tion.
Route B batch conditions: Having successfully demonstrated
the feasibility of the first proposed sequence we next evalu-
ated the second pathway - Route B.
The aminoalkylation was achieved via a Mannich reac-
tion, characterised by excellent regioselectivity and high
yields under relatively mild conditions.[33] The scope of this
reaction was further investigated using several additional
coumarin derivatives; furnishing amines 6b–e (Table 2),
which were also prepared in good yields using microwave
heating (1008C for 1 h). Next, the N-oxidation was conduct-
ed using m-CPBA. The reaction was found to proceed rapid-
ly at 08C and proved universally applicable to all the amines
previously prepared. In addition the reaction was also easily
scaled to >20 mmol and was amenable to facile purification
by solid-phase scavenging using QP-DMA resin (N,N-di-
methylbenzylamine polystyrene). A crystal structure for N-
oxide (7c) was obtained, showing the expected planar geom-
etry of the coumarin rings and the puckered pyrrolidine
(Figure 2).
Flow based approach to Route B: Starting with the general
sequence as outlined in Route B (Scheme 1) the individual
reaction steps were transferred to flow separately and then
combined into a single integrated synthetic pathway.
Route B in flow: The Pechmann condensation was readily
converted occurring in quantitative yield by flowing an
acetic acid solution of resorcinol and ethyl acetoacetate
through a CFC (Continuous Flow Coil) reactor maintained
at 1258C (1 h residence time). We surveyed a range of co-
catalysts for the condensation but quickly found that
4 mol% of HCl (37%) was extremely efficient. In light of
this result, we studied the potential for performing all the
subsequent reactions in AcOH thereby avoiding any solvent
switching operations.
The Mannich reaction could also be successfully per-
formed in AcOH under flow conditions. The desired prod-
uct was obtained in 97% yield in 1 h at a temperature of
1208C using paraformaldehyde and pyrrolidine (1.5 equiv).
In the batch mode we performed the N-oxidation reaction
using m-CPBA but, since this reaction required the use of
CH2Cl2 as solvent, we decided to test the reaction in AcOH
using H2O2 as the oxidant. Pleasingly, good conversion to
the N-oxide product 7a (90% yield) was achieved when
flowing the amine and the H2O2 through a preheated CFC
coil held at 1008C with a residence time of 1 h although
a large excess of peroxide (11 equiv) was necessary. Consid-
ering the likely identity of H2O2 in AcOH is invariably that
of peracetic acid we attempted to carry out the same reac-
tion directly using a solution of peracetic acid. We were able
to achieve a halving in the number of equivalents of oxidant
required (6 equiv of peracetic acid, 1 h) and a modest reduc-
tion in the reaction temperature to 808C. It was also encour-
aging to discover that the N-oxidation of both purified
amine 6a and a crude solution obtained directly from the
Mannich reaction gave excellent and comparable conversion
to 7a, enabling the possibility of telescoping the pathway.
Figure 2. X-ray structure of N-oxide 7c showing an intramolecular hydro-
gen bond.
The final stage in the sequence was the Polonovski reac-
tion[34] leading to the benzylic iminium cation, which was im-
mediately hydrolysed using dilute aqueous hydrochloric acid
(1m). The Polonovski reaction required very careful control
to achieve the desired regioselectivity. It was found that the
formation of the benzylic iminium was favoured by the use
of trifluoroacetic anhydride (TFAA, Potier–Polonovski con-
ditions[35]) and the absence of heating as opposed to the
more classical conditions using acetic anhydride at elevated
temperatures.
Unfortunately, the final two steps of the sequence (N-oxi-
dation and Polonovski reaction) proceeded in only modest
overall conversion, 31 and 44% respectively. However, we
were still able to successfully apply the route to the synthe-
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Flow Process to Coumarin-8-Carbaldehydes
FULL PAPER
Next, we appraised the potential for conducting the Polo-
novski reaction in AcOH as the solvent, however we ob-
served no product formation under a wide range of reaction
conditions. Even when using pure isolated N-oxide 7a we
were unable to promote the desired elimination in the pres-
ence of AcOH quantitatively recovering the starting materi-
al. Alternatively a good conversion of the crude N-oxide 7a
to the desired aldehyde 5a could be achieved after AcOH
solvent exchange. The flow sequence could be reinitiated by
re-dissolving the crude product in CH2Cl2 and passing the
solution through a column containing QP-DMA in order to
sequester any peroxides and residual acid. The output
stream was then mixed with a second stream of TFAA also
in CH2Cl2. The optimal conditions for this reaction were
found to be 2 equivalents of the TFAA at ambient tempera-
ture, and a residence time of 1 h. The reactor output was
then collected into a flask containing an appropriate volume
of dilute aqueous HCl (1m) solution to hydrolyse the inter-
mediate and induce precipitation of the final product. The
solid product was readily filtered affording coumarin-8-carb-
aldehyde 5a as a pale yellow powder (68% isolated yield).
On the basis of these results, we combined the steps as
shown in Scheme 2 to create an abridged flow system.
directly coupled with a further input channel containing the
premixed Mannich components (Scheme 2). The stream of
the amine adduct (6a) from these two linked steps was inte-
grated with the N-oxidation reaction performed as previous-
ly described using peracetic acid at 808C. The resulting N-
oxide (7a) was collected as a batch and the AcOH solvent
was removed under reduced pressure. The N-oxide was then
re-dissolved in CH2Cl2 to process it through the final elimi-
nation step. Again, removal of acidic impurities including
peracetic acid was readily achieved using a column of QP-
DMA. The elimination step was best conducted with a two-
fold excess of TFAA which gave quantitative conversion to
the iminium species. Hydrolysis with aqueous HCl in batch
gave the desired aldehyde 5a which precipitated and permit-
ted isolation by simple filtration.
By conducting the reaction in this linked fashion a much
improved and reproducible overall yield of 59% was realiz-
ed. Furthermore the only intermediate handling operation
required of the user is a simple solvent-switch procedure
from AcOH to CH2Cl2. However, our originally stated
desire was to achieve a fully telescoped flow synthesis avoid-
ing any user handling operations. We therefore elected to in-
vestigate the potential of performing all the reaction steps in
an alternative solvent system.
Integrated flow sequence - Route B: For the unified flow
process the output of the Pechmann condensation (1a) was
The Polonovski elimination had proven the most solvent
sensitive step but had been shown to work very efficiently in
CH2Cl2. However, we knew from earlier trials that the Pech-
mann condensation required a protic solvent. Consequently
we screened a series of binary solvent mixtures based upon
CH2Cl2 and an alcohol. We eventually arrived at a 2:1 blend
of CH2Cl2/EtOH. Using identical time and temperature pa-
rameters as previous, a 91% conversion was achieved for
the Pechmann reaction albeit this necessitated an increase
in the number of equivalents of ethyl acetoacetate from 1.05
to 3 and the addition of a larger quantity of the HCl 37%
(0.3 equiv) catalyst (Scheme 3). The need for an excess of
ethyl acetoacetate was ascribed to the rapid hydrolysis and
subsequent decarboxylation of the b-dicarbonyl which oc-
curred under these modified solvent conditions. Fortunately
the liberated acetone had no noticeable effect on the subse-
quent reactions (no incorporation into the Mannich reaction
was observed). The following Mannich reaction was con-
ducted using the previously optimized conditions delivering
a similar result (93% conversion). The N-oxidation reaction
also progressed well in 82% in the presence of m-CPBA as
the oxidant at 08C and with a 1 h residence time (CFC reac-
tor submerged in an ice-bath). The reaction stream contain-
ing the newly generated N-oxide was then passed through
a scavenging column containing QP-DMA before being
combined with a stream of TFAA in CH2Cl2 which facilitat-
ed the Polonovski reaction yielding the desired aldehyde 5a
in 47% overall yield (>95% purity by LC-MS and NMR
spectroscopic analysis). The entire multistep sequence was
therefore performed without the need for purification,
work-up or solvent switching (excluding a simple filtration),
thereby providing access to this valuable product in one
flow sequence.
Scheme 2. Flow synthesis of 4a using AcOH as main solvent.
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Scheme 4. Automated loading procedure for Supleco cartridges. Only 5
of the 10 columns used are shown for clarity.
a threshold based voltage trip switch which triggered upon
detection of a threshold level of the eluting coumarin 1a. A
second HPLC pump (NMP solvent delivery) enabled se-
quential column washing of the newly loaded column there-
by eluting any nonbound starting material 1a which could
be recycled (Scheme 4). The entire loading procedure could
be run using Gilson Unipoint control software.[24g,m,25k]
Scheme 3. Telescoped flow synthesis of 4a using CH2Cl2 as main solvent.
Integrated flow sequence - Route A: We next turned our at-
tention to the conversion of the original Claisen batch con-
ditions (Route A, Scheme 1) into a flow based procedure.
We elected to enlist the pre-made 7-hydroxycoumarin 1a
(2.1 mol) as our starting point as isolation of this material
was readily achieved at scale from our previous acetic acid
flow procedure by direct induced precipitation by dilution
of the output stream with water. The subsequent sequence
was extremely tolerant of moisture meaning only a filtration
of the solid product was required before progressing the
substrate. This was felt to be a more pragmatic approach
rather that requiring the removal of the acetic acid solvent
before the base catalysed allylation. The first step of the se-
quence was therefore the allylation of the phenolic group
with allyl bromide which occurred in NMP (N-methyl-2-pyr-
rolidone) in the presence of an immobilised carbonate base
(Biotage MP-Carbonate, Part No. 800314, 3.2 mmolgꢀ1). To
conduct this reaction a bulk solution of the 7-hydroxycou-
marin 1a in NMP was loaded into a series of Supleco car-
tridges (40 mm i.d. 75 mm depth, 62 g resin; insert
Scheme 4) containing the carbonate resin. A relatively high
concentration and flow rate could be used for this rapid and
efficient ion exchange process. To aid loading two dual auto-
mated 10 position valves (VICI 20271) were used to ex-
change between individual columns as the resin became sa-
turated by the substrate (see supplementary information for
the valve configuration). Breakthrough was monitored for
by an in-line UV/Vis detector (Gilson 156 @254 nm) using
A modified set-up was then used for the subsequent O-al-
lylation reaction and Claisen rearrangement process
(Scheme 5). The primary input feed was switched to a solu-
tion of allyl bromide in NMP (0.93m). A single 10 port valve
assembly was used to direct the flow stream through the
first phenoxide loaded column. Upon O-allylation the cou-
marin material 2 was released and passed through a scaveng-
ing step (QP-BZA) to sequester any unreacted allyl bro-
mide. Real-time monitoring of the reaction stream using
a UV/Vis device enabled automatic succession to a new
phenoxide cartridge (columns A–E) when the signal intensi-
ty received by the detector fell below a pre-prescribed ab-
sorption threshold (also triggering exchange of the latter
scavenger column. Labelled 1–5 in Scheme 5). This allowed
an automatic and essentially seamless transition between
the different reactor cartridges. The reaction flow stream
containing 5 was next relayed into a stainless steel CFC
(20 mL) which was heated at 2358C promoting the Claisen
sigmatropic rearrangement. Interestingly, an improved ratio
between the two possible products was obtained compared
to the batch conditions (22:3 compared to 9:2). At this stage
the Claisen products 3a/b were captured onto a second ion
exchange resin, supported tetraalkylammonium hydroxide
(Ambersep 900 hydroxide form, 1.86 mmolgꢀ1 packed into
Biotage chromatography columns, 108 g per column). This
approach simplified the isolation of the coumarin products
3a/b from the high boiling point NMP solvent as well as en-
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Flow Process to Coumarin-8-Carbaldehydes
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As explained for the Batch Route A, it was possible to
separate the isomers 3a/3b by chromatography column
(ratio 3a/3b 11:1.5). However, due to the large scale flow
route, it was more convenient carrying the two isomers
through the subsequent steps without separation then easily
remove the minor isomer by crystallisation at the end of the
process.
Taking a portion of the neutralised 3a/3b flow stream
(from Scheme 5), after treatment with QP-DMA, we investi-
gated the isomerisation of the double bonds and the subse-
quent oxidative cleavage steps.
We had previously shown in another project[37] that an im-
mobilised version of Felkinꢀs iridium catalyst (Scheme 6)
Scheme 6. Isomerisation of 3a/b and 8a/b using an immobilized iridium
catalyst.
could be prepared and it could function as an effective
double bond isomerisation catalyst which we felt would also
work well in flow. Indeed, this was found to be the case. By
flowing a solution of 3a/b or 8a/b through a column contain-
ing the solid supported catalyst (5 mm i.d.ꢂ100 mm) held at
608C the corresponding conjugated alkenes 4a/b and
9a/b could be generated quantitatively (Scheme 7). A flow
rate of 125 mLminꢀ1 was found to effect complete conver-
sion in a calculated residence time of about 47 min.
Scheme 5. Claisen flow synthesis of 3a/b or analogues 8a/b. In each case
only 5 of the 10 columns used are shown for clarity.
abling their separation from any residual non-rearranged in-
termediate 2 (2.5–4%). Following washing of the column
with THF the release from the resin could be affected elut-
ing with a 1.5% (v/v) solution of TFA in THF. Further pas-
sage of this solution through two consecutive columns con-
taining QP-DMA (3.8 mmolgꢀ1, Biotage chromatography
column, 160 g) could be used to remove excess TFA or the
material could be isolated directly by solvent evaporation.
Alternatively, we also demonstrated that a second alkylation
step (formation of 8a/b) could be performed as part of the
release step (using MeI in THF solution instead of TFA)
adding additional diversity to the sequence. Using this ap-
proach we were able to process 2.1 mol of material corre-
sponding to over 344.7 g of isolated intermediate 3a/b in
76% overall yield.
Scheme 7. Oxidative cleavage of the vinyl substrates 4a/b using OsEnCat
catalyst.
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For the oxidative cleavage of the double bond we first
evaluated a flow protocol based on the OsEnCat and NaIO4
procedure previously used in batch. A mixed bed of the
OsEnCat and a polymer-supported periodate variant was
prepared and the solution of the isomerised substrate
tion was continuously pumped from the chamber as it con-
densed through a packed bed cartridge containing an excess
of the polymer-supported thiourea inducing reductive cleav-
age of the ozonide. This gave the corresponding aldehydes
5a/10 in quantitative conversion and 92% isolated yield
(95% for 11a/11b from 9a/9b). Using the crude reaction so-
lution containing a mixture 4a/b, the desired aldehyde was
isolated pure via recrystallisation from EtOAc in 73% yield.
Using this method we were able to process 37 g of 5a in
4.5 h.
In total this four step sequence involving allylation, Clais-
en rearrangement, isomerisation and ozonolysis could be
used to deliver the desired product 5a in 51% overall yield
after crystallisation. The limiting step of the route was the
iridium catalysed isomerisation although this could conceiv-
ably be performed using parallel reactor cartridges thereby
increasing the throughput.
flowed through the cartridge in
a
recycling set-up
(Scheme 7).[38] Unfortunately, it was discovered that the use
of only periodate was ineffective at turning over the osmium
catalyst giving only low conversion to the desired aldehyde
(18% conversion). However, the addition of a stoichiometric
amount of N-methylmorpholine N-oxide (NMO) as co-oxi-
dant permitted the reaction to progress to completion. The
resulting amine from the reduced NMO could be effectively
scavenged using a column of QP-SA (a sulfonic acid resin).
This enabled the target compound to be isolated in 89%
yield following solvent evaporation.
However, one major difficulty associated with this proce-
dure was that direct scale-up of the sequence was found not
to be possible. The recycling requirement necessary due to
the prolonged reaction time of the oxidation created signifi-
cant complications due to non-linear expansion of the pro-
cessing times. For this reason we decided that although ef-
fective for small scale operation this method would not be
ideal for processing larger quantities of material. We there-
fore decided to test the potential scalability of the alterna-
tive ozonolysis in flow.
Conclusion
We have developed two complementary flow syntheses for
the delivery of 7-hydroxy-4-methyl-2-oxo-2H-chromene-8-
carbaldehyde 5a via key N-oxide or Claisen derived inter-
mediates. In the first synthetic route we established a four
step telescoped sequence to the target molecule which
avoided the need for purification excluding a single filtra-
tion. The protocol could also be readily applied to the syn-
thesis of various analogues and was shown to be easily
scaled. An alternative Claisen based sequence proved very
efficient allowing a four step process to the desired molecule
from previously prepared 7-hydroxycoumarin (1a). The
route was highly automated using in-line monitoring to con-
trol reagent delivery and enable ꢃcatch-and-releaseꢀ purifica-
tion yielding the product in high yield and purity. This work
clearly represents a further demonstration of the advantages
of flow processing in the assembly of synthetically challeng-
ing molecules.
Having some previous experience performing ozonolysis
reactions in flow[39] we quickly established a simple set-up to
perform the transformation using QP-TU as a solid ozonide
quenching agent.[40] The flow setup (Scheme 8) used
Acknowledgements
We would like to gratefully thank the Royal Society (IRB) for financial
support and Dr J. E. Davies for crystal structure determination and the
EPSRC for a financial contribution toward the purchase of the X-ray dif-
fractometer.
Scheme 8. Oxidative cleavage of the vinyl substrates 4a/b and 9a/b via
ozonolysis.
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FULL PAPER
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Received: March 27, 2012
Revised: May 22, 2012
Published online: && &&, 0000
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These are not the final page numbers!

Flow Process to Coumarin-8-Carbaldehydes
FULL PAPER
Aldehyde on tap: Despite their useful-
ness as fluorophores and synthetic pre-
cursors, efficient and reliable routes to
coumarin-8-carbaldehydes are lacking.
A high-yielding continuous flow syn-
thesis that requires no manual inter-
mediate purification or work-up is de-
scribed, giving access to multigram
quantities of aldehyde product (see
scheme).
Flow Chemistry
J. Zak, D. Ron, E. Riva,*
H. P. Harding, B. C. S. Cross,
I. R. Baxendale ............... &&&& — &&&&
Establishing a Flow Process to
Coumarin-8-Carbaldehydes as Impor-
tant Synthetic Scaffolds
Chem. Eur. J. 2012, 00, 0 – 0
ꢁ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
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These are not the final page numbers!