Multi-Step synthesis by using modular flow reactors: The preparation of Yne-Ones and their use in heterocycle synthesis

Article abstract of DOI:10.1002/chem.200902906

"Chemical Equation Presented" Multi-step in flow: The palladium-catalysed acylation of terminal alkynes for the synthesis of yne-ones as well as their further transformation to various heterocycles in a continuous-flow mode is presented. Furthermore, an extension of the simple flow configuration that allows for easy batch splitting and the generation of a heterocyclic library is described (see scheme).

Full text of DOI:10.1002/chem.200902906

COMMUNICATION
DOI: 10.1002/chem.200902906
Multi-Step Synthesis by Using Modular Flow Reactors: The Preparation of
À
Yne Ones and Their Use in Heterocycle Synthesis
Ian R. Baxendale,[a] Søren C. Schou,[b] Jçrg Sedelmeier,[a] and Steven V. Ley*[a]
The development of new and improved chemical process-
ing techniques that conduct both complex and routine chem-
ical transformations in a safe, reproducible and scalable
fashion without recourse to costly route modification or re-
development is very desirable. The introduction of continu-
ous-flow reactor technologies offers the ability to test, opti-
mise and create scalable syntheses rapidly by using a simple
bench-top device.[1] In combination with the concept of im-
mobilised reagents, scavengers and catch-and-release proto-
cols, a powerful tool arises that can perform chemical trans-
formations without the need for traditional workup proce-
dures.[2] Moreover, these devices enable the rapid progres-
sion of a clean product flow stream from one synthetic
transformation to the next in a multi-step sequence. Further-
more, the intrinsic design of the flow equipment allows real-
time, in-line monitoring and accommodates high tempera-
tures and pressures, which permit reactions to be performed
that were previously difficult to carry out in conventional
batch synthesis. The reaction setup also facilitates contain-
ment of hazardous reagents or intermediates and is readily
scalable to provide bulk samples.
extension of the simple flow configuration that allows for
easy batch splitting through a four-way splitter device and
the generation of a heterocyclic library.
For this work we used a commercially available synthesis
platform, the Vapourtec R2+/R4 unit (Figure 1).[6] The Va-
pourtec integrates a twin pumping unit with an independent-
Herein, we report the palladium-catalysed acylation of
[3]
À
terminal alkynes for the synthesis of yne ones and their
further transformation into various heterocycles.[4] The reac-
tions are performed as a continuous-flow procedure by
using a commercially available pumping system and heated
flow coils in combination with a suite of packed Omnifit
glass tubes[5] containing appropriate scavenger materials to
ensure the quality of the final product. We also present an
Figure 1. Vapourtec R2+/R4 flow system.
ly controlled four-channel air-circulated heating module. A
low-pressure input valve is used to route either solvent or
bulk stock solutions directly to the self-regulating HPLC
pumps. Two additional Rheodyne 6-port–2-position switch-
ing valves can be used to introduce reagents or substrates
into the main flow line through individual sample loop ar-
rangements of user-defined variable volumes.
A positive system pressure was maintained by using an in-
line 100 or 250 psi back-pressure regulator. The use of an
appropriate back-pressure regulator allows superheating of
solvents as required. Mixing of the reagent streams is
[a] Dr. I. R. Baxendale, Dr. J. Sedelmeier, Prof. S. V. Ley
ITC, Department of Chemistry
University of Cambridge
Lensfield Road, Cambridge, CB2 1EW (UK)
Fax : (+44)1223-336362
E-mail: svl1000@cam.ac.uk
[b] S. C. Schou
LEO Pharma, Medicinal Chemistry Research
55 Industriparken, 2750 Ballerup (Denmark)
AHCTUNGTREGaNNNU chieved with a simple T-piece and the combined output is
then directed through perfluoroalkoxy (PFA) tubing to the
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.200902906.
Chem. Eur. J. 2010, 16, 89 – 94
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
89

[a]
À
Table 1. Palladium-catalysed acylations for the synthesis of yne ones.
convection flow coil (CFC), which can be precisely heated
to 1508C. Upon exiting the CFC, the flow stream is cooled
rapidly and is then directed to scavenger cartridges that con-
sist of simple Omnifit glass columns packed with appropri-
ate immobilised materials. The final flow line can then be
collected and evaporated to give the purified product.
Entry
R1
R2
3
Yield [%]
A rapid screening of reaction parameters was performed,
which included reaction temperature, residence time (flow
rate), internal pressure, solubility, reagent concentrations
and stoichiometry. Practical conditions were determined
1
4-F-C6H4
4-CN-C6H4
4-CF3-C6H4
3,4-OCH2O-C6H4
3-NO2-C6H4
3-Br-C6H4
3-Br-C6H4
cinnamyl
C6H5
C6H5
C6H5
4-F-C6H4
Me
tBu
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
nBu
C6H5
cyclohexenyl
C6H5
nBu
SiEt3
C6H5
C6H5
C6H5
C6H5
C6H5
3a
3b
3c
3d
3e
3 f
3 f
3g
3h
3i
3j
3k
3l
3m
3n
3o
3p
80
63
94
78
88
79
41
95
70
89
87
49
89
65
72
75
86
2[b]
3
4[b]
5
6
7
8
that involved the introduction of a 1m solution of PdACTHNUTRGNEUNG(OAc)2
(1 mol%) and Hꢁnigꢂs base (1.0 equiv) in dichloromethane
through an injection loop (Scheme 1, stream 1), which was
then mixed through a T-piece with a 1m solution of the acid
chloride (1.2 equiv) and terminal acetylene (1.0 equiv) in di-
chloromethane (Scheme 1, stream 2). The mixture was then
heated to 1008C through a CFC (2ꢃ10 mL) to give a resi-
dence time of 30 min. Upon exiting the CFC, the flow
stream was directed through a series of scavenger columns.
Firstly, a tube packed with a Amberlite polyol resin (IRA-
743) operating at room temperature effectively removed
any excess acid chloride, subsequently the CaCO3 cartridge
deprotonates the ammonium salts and traps the HCl that
was formed during the reaction. The sulfonic acid resin
9
10
11
12
13
14
15
16
17
cyclopropyl
nPr
2,4-OMe-C6H4
[a] Reactions conducted on
30 min at 1008C with Pd(OAc)2 (1 mol%), iPr2NEt (1.0 equiv), acid chlo-
ride (1.2 equiv) and terminal acetylene (1.0 equiv). [b] Small amounts of
DMF were added to improve the solubility of the starting materials.
a 2 mmol scale in dichloromethane for
AHCTUNGTRENNUNG
when aliphatic alkynes were
used as starting materials, the
yield for the corresponding
À
yne one dropped slightly. Sim-
ilarly, not all substrates reacted
smoothly. Esters and anhy-
drides did not undergo the de-
sired coupling reaction with
terminal acetylenes under the
standard reaction conditions,
whereas challenging substrates
containing heterocyclic sub-
stituents, such as furans and
À
Scheme 1. Flow synthesis of yne ones.
À
(QP-SA) scavenges the tertiary amine by protonation. Final-
ly, a thiourea (QP-TU) resin removes any residual palladi-
thiophenes, led to yne ones in high purity (>95% by
1H NMR spectroscopy and LC–MS) and in good yield
(Scheme 2).
À
um contamination to give a pure yne one product stream
(Scheme 1). Evaporation of the solvent by using a Vapour-
tec V10 instrument affords the coupling products in excel-
lent purity and good yield.
The whole system is maintained under positive pressure
by using an in-line 100 psi back-pressure regulator. Typically,
we used IRA-743 (3.0 g), CaCO3 (3.0 g), QP-SA (5.0 g) and
QP-TU (2.0 g) to perform three consecutive experimental
runs on a 2.0 mmol scale to obtain clean reaction products
À
(Scheme 1). After evaporation of the solvent the yne ones
required no additional purification.
Scheme 2. Formation of heterocyclic products.
From the examples depicted in Table 1, it can be noted
that the couplings proceed smoothly for substrates with elec-
tron-donating and -withdrawing substituents. Functionalities
such as halide, nitro and cyanide are all tolerated under the
reaction conditions. Couplings proceeded successfully by
using aromatic as well as aliphatic acid chlorides. However,
In an effort to expand the product diversity of these flow
reactions, an additional pump providing a further hydrazine
input stream (Scheme 3, stream 3) was used to prepare vari-
ous pyrazoles in a single operation. The main stream con-
À
taining the pure yne one was processed as previously de-
90
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Chem. Eur. J. 2010, 16, 89 – 94

Multi-Step Synthesis by Using Modular Flow Reactors
COMMUNICATION
À
Scheme 3. Two-step formation of pyrazoles from yne ones.
scribed. However, the polyol IRA-743 resin needed to be
action with phenyl hydrazine at 1008C for 30 min. When
methyl hydrazine was used at room temperature and when
hydrazine was used at 808C then only one regioisomer was
detected. The regioselectivity follows the literature prece-
dent.[8] The reaction sequence is general and links an impor-
tant coupling reaction to the generation of potentially haz-
ardous and bioactive substrates and intermediates all con-
tained within the flow system.
À
placed after the yne one formation to avoid amide forma-
tion by reaction of the hydrazine with residual acid chloride.
À
After exiting the IRA-743 scavenger column, the yne one
solution passes into a T-piece that enables an in-line sample
analysis. The use of an in-line UV detector can be used as a
trigger for the pump that provides the hydrazine stream,
thereby enabling a reduction in the amount of nucleophile
required. The product was then mixed within a second T-
piece with a solution of hydrazine (5.0 equiv) in ethanol
(Scheme 3). The combined flow stream was then heated to
1008C through a CFC (2ꢃ10 mL) to give a residence time
of 20–30 min. Ammonium salts are formed during the reac-
tion, but since the remaining acetylene did not hinder the
heterocycle formation they both remained in the reaction
mixture and were removed later in the sequence. Upon exit-
ing the CFC, the pyrazole-containing flow stream was di-
rected through a series of scavenger columns as shown in
Scheme 3. Since the use of scavenger resin columns causes
dispersion of the product, the carbonate, QP-SA and QP-
TU columns were located at a late stage of the reaction se-
Although the above two-step sequence for the synthesis
of pyrazoles proceeded smoothly, we wished to extend the
À
sequence still further. We therefore generated the yne one
derivatives as shown in Scheme 1. After exiting the scaveng-
er cartridges, the pure product line was divided into four
equal side streams by using a splitter (Scheme 4). Each of
the side arms was subsequently mixed through a T-piece
with a stock solution of different nucleophiles to generate
À
four different products based on the yne one synthesised in
the first step of the sequence. To obtain equal flow rates for
each of the four channels, we attached commercial capillary
peek tubing[7] (1/16ꢃ0.005) to the exit of each flow reactor
acting as a tuneable back-pressure regulator (16 bar). By
cutting the red tubing to the appropriate length, we equili-
brated the four flow streams under the required reaction
conditions. The relatively high back-pressure employed was
required to maintain the dichloromethane in the liquid
phase at the elevated reaction temperatures, thus avoiding
decomposition of chemicals, which eventually leads to
blockage of the flow reactor. In addition, we avoided cross-
contamination of the nucleophile flow streams by using four
one-way valves each connected to the four-way splitter
À
quence. Therefore, the high concentration of the yne one
stream is maintained and the mixing of which with the hy-
drazine is simplified. However, due to the excess of hydra-
zine used for the heterocycle formation, a larger amount of
QP-SA scavenger resin was necessary (12 g for two experi-
mental runs on a 2.0 mmol scale). Simple evaporation of the
solvent provides pyrazole derivatives in a pure form (>95%
1
by H NMR spectroscopy and LC–MS) with good to excel-
lent regioselectivity and good yield over two steps. De-
creased regioselectivity was observed by conducting the re-
À
device. The combined mixtures of yne one and nucleophile
Chem. Eur. J. 2010, 16, 89 – 94
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www.chemeurj.org
91

S. V. Ley et al.
For the synthesis of pyrimi-
À
dines, the yne one flow stream
was mixed through a T-piece
with a 1m solution of benzami-
dine (5.0 equiv) in a solvent
mixture of acetonitrile/ethanol
(2:1). The reaction mixture
was heated to 1208C through a
CFC (10 mL) to give a resi-
dence time of 20 min.
The formation of pyrazoles
was achieved by mixing the
À
yne one flow line through a T-
piece with a solution of hydra-
zine derivative in ethanol and
the combined stream was then
directed through PFA tubing
to the CFC, which was heated
to various temperatures de-
pending on the hydrazine reac-
tivity. Preparation of N-
methyl-substituted
pyrazoles
proceeded smoothly at room
temperature within 20 min.
À
However, generation of N H-
pyrazoles required gentle heat-
ing at 808C for 30 min, where-
as N-phenyl hydrazine re-
quired 30 min at 1008C to give
high conversion.
Since the 2-alkyn-1-one O-
methyl oximes represent versa-
tile intermediates for the syn-
thesis of isoxazoles, we have
also incorporated these in a
continuous-flow process. Treat-
ment of the oximes with vari-
ous electrophiles (I2, Br2, ICl,
PhSeBr) initiates the cyclisa-
tion to highly substituted isoxa-
zoles. For the synthesis of 2-
alkyn-1-one O-methyl oximes
À
the yne one flow line was
mixed through a T-piece with a
Scheme 4. Four-way split approach for the generation of a heterocyclic library.
solution
of
MeONH2·HCl
were heated independently to 1208C through separate CFC
units (10 mL) to give a residence time of 20–30 min. Upon
exiting the CFC, the flow stream was rapidly cooled, collect-
ed and the solvent was evaporated. To remove the excess of
the nucleophile used, the crude mixtures were dissolved in
Et2O and extracted with aqueous 1n HCl. After evapora-
tion of the solvent, the products were obtained in high
(5.0 equiv) in methanol. The reaction mixture was then
heated to 1208C through a CFC (10 mL) to give a residence
time of 20 min. The condensation product was obtained in
quantitative yield as an E/Z mixture in a ratio of 3:1. Inves-
tigations into the continuous production of isoxazoles
through a multi-component three-step sequence, that is, acy-
lation, oxime formation and subsequent cyclisation, are cur-
rently on going in our laboratories.
1
purity (>95% by H NMR spectroscopy and LC–MS) and
good yield. In this way key intermediates, for example, pyri-
midines, pyrazoles, oximes, guanidines and flavones, have
been synthesised and required only a simple aqueous
workup (Scheme 5).
For the preparation of guanidine derivatives, slightly
À
harsher reaction conditions were required. The yne one
flow line was mixed through a T-piece with a solution of
guanidine hydrochloride (5.0 equiv) in a solvent mixture of
92
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Chem. Eur. J. 2010, 16, 89 – 94

Multi-Step Synthesis by Using Modular Flow Reactors
COMMUNICATION
to the formation of the final
product in high purity. In par-
ticular, we demonstrated the
palladium-catalysed prepara-
À
tion of yne ones and their fur-
ther transformation into vari-
ous heterocycles and 2-alkyn-
1-one O-methyl oximes.
Experimental Section
General description for the synthesis
À
of yne ones in flow (Scheme 1): Two
flow streams were driven by the Va-
pourtec R2+/R4. Stream 1 contained
a
solution of PdACTHUNGRETNNU(G OAc)2 (1 mol%)
and (iPr)2NEt (1.0m, 1.0 equiv,
2 mmol) in CH2Cl2, whilst the termi-
nal acetylene (1.0m, 1.0 equiv,
2 mmol) and the acid chloride (1.0m,
1.2 equiv, 2.4 mmol) in CH2Cl2 were
dispensed from stream 2. These
Scheme 5. Formation of heterocycles by using the four-way split flow setup.
streams were mixed through
a T-
piece before entering the CFC for
30 min at 1008C. The stream was then directed through a series of scav-
enger columns: firstly IRA-743, secondly CaCO3, thirdly QP-SA and fi-
nally QP-TU. Typically, IRA-743 (3.0 g), CaCO3 (3.0 g), QP-SA (5.0 g)
and QP-TU (2.0 g) were used to perform three consecutive experimental
runs on a 2.0 mmol scale to obtain clean reaction products. A 100 psi
back-pressure regulator ensured the system was pressurised before elut-
ing into a reaction flask. Finally, the solvent was concentrated in vacuo to
ethanol/water (1:1) followed by heating through a CFC
maintained at 1308C for 20 min.
Furthermore, we have generated a flavone derivative by
using the four-way split flow setup. Mixing of the flow
À
stream containing yne one 3p with a solution of ICl
(5.0 equiv) in dichloromethane is achieved by using a T-
À
piece. The ICl solution was injected into the yne one line
À
provide the desired yne one derivative.
through an injection loop to avoid contact with the pump
head. The combined reaction line was then directed into a
CFC and the reaction proceeded at room temperature for
20 min. The product stream was collected in an aqueous so-
lution of sodium thiosulfate to quench the excess electro-
phile. Phase separation gave the flavone derivative in excel-
lent purity and good yield.
À
General description for the synthesis of pyrazoles from yne ones in flow
(Scheme 3): The yne one derivatives were prepared as described above
and in Scheme 1. The stream containing the yne one (1.0 equiv, 2 mmol)
À
À
followed the standard pathway and was passed through an IRA-743 scav-
enger column at a total flow rate of 500 mLminÀ1 driven by the Vapourtec
R2+/R4 unit. This stream was mixed with a stream of hydrazine deriva-
tive (5.0 equiv, 10 mmol) in EtOH (1.0m) through a second T-piece
before the combined flow stream was passed through the second CFC
(20–30 min residence time; RT–1008C) and then directed through a
series of scavenger columns as shown in Scheme 1. Finally, a 100 psi
back-pressure regulator was used before eluting into a reaction flask. The
solvent was removed in vacuo to provide the desired product.
From the examples summarised in Scheme 5, it can be
seen that the various transformations investigated proceed
well and the procedure appears to be general. Furthermore,
the process demonstrates the potential for library generation
and rapid optimisation of reaction conditions in a safe, scal-
able and reproducible manner.
À
Further investigations, based on the use of yne ones, into
Acknowledgements
the synthesis of different heterocycles, incorporating the for-
mation of terminal alkynes by using the Bestmann–Ohira re-
agent[9] developed previously in the group, are currently in
progress. This approach offers the ability to produce a col-
lection of heterocycles in a short time and is therefore of in-
terest for pharmaceutical and medicinal applications.
In conclusion, we have presented the application of a
modular flow reactor to achieve multi-component, multi-
step transformations to give products in excellent purity
without the necessity of common column chromatography.
In the case of the four-way split approach, only a simple
aqueous extraction was required to remove the excess nu-
We gratefully acknowledge financial support from The Royal Society (to
I.R.B.), the BP endowment (to S.V.L.), LEO Pharma (to S.C.S.) and the
DAAD (to J.S.).
Keywords: alkynes
supported reagents · yne ones
·
flow chemistry · heterocycles ·
À
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[5] Omnifit columns are commercially available from Kinesis. http://
www.kinesis.co.uk/.
[6] Vapourtec R2+/R4 is commercially available from Vapourtec Ltd,
Place Farm, Ingham, Suffolk, IP31 1NQ, UK. http://www.vapourtec.
co.uk/.
[7] The thin polymer tubing is commercially available from Upchurch
Scientific Inc., Oak Street, Oak Harbor, WA 98277, http://www.
upchurch.com.
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4021.
Received: October 21, 2009
Published online: November 24, 2009
94
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