Tagged phosphine reagents to assist reaction work-up by phase-switched scavenging using a modular flow reactor

Article abstract of DOI:10.1039/b703033a

The use of three orthogonally tagged phosphine reagents to assist chemical work-up via phase-switch scavenging in conjunction with a modular flow reactor is described. These techniques (acidic, basic and Click chemistry) are used to prepare various amides

Full text of DOI:10.1039/b703033a

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www.rsc.org/obc | Organic & Biomolecular Chemistry
Tagged phosphine reagents to assist reaction work-up by phase-switched
scavenging using a modular flow reactor
Christopher D. Smith,a Ian R. Baxendale,a Geoffrey K. Tranmer,a Marcus Baumann,a Stephen C. Smith,b
Russell A. Lewthwaitec and Steven V. Ley*a
Received 28th February 2007, Accepted 19th March 2007
First published as an Advance Article on the web 16th April 2007
DOI: 10.1039/b703033a
The use of three orthogonally tagged phosphine reagents to assist chemical work-up via phase-switch
scavenging in conjunction with a modular flow reactor is described. These techniques (acidic, basic and
Click chemistry) are used to prepare various amides and tri-substituted guanidines from in situ
generated iminophosphoranes.
One of the most time-consuming and work-intensive aspects
of a chemical synthesis is the isolation of the desired product
in high purity. Indeed, the necessity for repeated purification
can be a major productivity limiting factor when conducting
multi-step synthetic sequences. We have held a longstanding
interest in the development1 and use2 of immobilised reagents3
to alleviate these purification bottlenecks. We and others have
also been advocating their integration into flow based processes.4
However, it is recognised that these immobilised systems often
react more slowly than their solution phase counterparts. Elevated
temperatures, particularly utilising focused microwave heating,5
can sometimes compensate for this loss of reactivity; however,
another solution which circumvents the problem involves the de-
velopment of specially designed soluble ‘tagged’ reagents (solution
phase reagents with designed functionality that allows their facile
removal from the reaction medium).6 Recent examples include
the use of bipyridyl or boronic acids which can be selectively
scavenged from the reaction solution.7,8 Alternatively, concepts
such as ‘impurity annihilation’ can be applied by, for example,
metathesis induced polymerisation of unwanted by-products and
waste components.9 In addition, Curran has pioneered the use of
appending polyfluorinated chains to chemically active species to
facilitate a phase-switch of the undesired impurities by fluorous
phase extraction.10
Phosphorus reagents are well recognised as being extremely use-
ful for effecting a variety of chemical transformations,11 but their
by-products, typically phosphine oxides, are notoriously difficult
to completely remove and often require multiple chromatographic
cycles. Here we describe how tagged phosphine reagents can
be used to bring about useful chemical reactions and then be
transformed by orthogonal processes that allow phase-switching
of spent reagents from solution to a scavenging support material
in a modular flow reactor system. In this way products can be
obtained in good yields and high purities without the need for
conventional manual work-up and purification protocols.
Our initial investigations were concerned with the use of
simple acidic or basic tags. For example, phosphine 112 (Fig. 1)
could be removed using macroporous polymer supported toluene
sulfonic acid (MP-TsOH).13 This molecule (1) was of particular
interest because of our earlier success in using bipyridine tagged
species with selective metal chelating phase-switch mediators for
conducting organic synthesis.8
Fig. 1 Tagged phosphine species 1, 2 and 3.
Similarly, an acidic tag such as that present in phosphine 2 could
be trapped using polymer supported carbonate (PS-NaCO3).14
However, the reactive nature of the acidic functionality means
it is incompatible with many desired chemistries. As a result,
modified phosphine 315 was prepared and used as a masked tagged
reagent which required removal of the tert-butyl group before
sequestering onto the solid phase. This deprotection was readily
achieved following Douglas’s16 procedure (treatment with TFA
and trimethylsilane) followed by evaporation of the TFA and
removal of phosphine 2 with the addition of a supported carbonate
base and passage through a short plug of silica. During this
research programme a modified procedure was devised enabling
complete removal of the tert-butyl group via treatment with MP-
TsOH in DCM under microwave heating at 120 ◦C for 30 minutes.
In batch mode this enables a one-pot deprotection and scavenging
protocol to be employed using a mixed acid–base resin bed as a
consequence of the site isolation of the immobilised reagents.17
Thus, the procedure offers immediate advantages for speed of
reaction work-up and reagent handling.
Other masked carboxylic acids were also examined (Fmoc and
SEM ester functionalities)18 but these capping units were generi-
cally less stable and proved to be problematic in the subsequent
chemical transformations. We therefore selected phosphine 3 as
our reagent of choice with the added advantage that it was easy to
prepare in multigram quantities. This tagged reagent 3 as well as
pyridine 1 were then applied to the preparation of various amides
and guanidines using a modular flow reactor.
aInnovative Technology Centre (ACS), Department of Chemistry, Lensfield
Road, Cambridge, UK CB2 1EW. E-mail: svl1000@cam.ac.uk; Fax: +44
(0)1223 336442; Tel: +44 (0)1223 336398
bSyngenta, Jealott’s Hill International Research Centre, Bracknell, Berk-
shire, UK RG42 6EY
cPfizer Global Research and Development, Sandwich, Kent, UK CT13 9NJ
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Scheme 1 Flow approach to amide formation.
Table 1 Amides synthesised in flow
Iminophosphorane reaction with acid chlorides
Our initial experiments involved the evaluation of the tagged
reagents 1 and 3 as phosphine sources in a reaction with benzyl
azide to yield the corresponding iminophosphorane 4. This was
in turn reacted with an acid chloride to furnish an intermediate
imidoyl chloride.19,20 Under the reaction conditions the reactive
imidoyl chloride spontaneously hydrolysed on the microfluidic
chip to give the corresponding amide derivative which was isolated
(Scheme 1).
Amide
Isolated yield (%)a
81
73
The pumping system employed for this chemistry was either a
R
Syrris AFRICAꢀ unit,21 or a pair of standard HPLC pumps.22
The phosphine (0.1 M, 1 equiv.), azide (0.1 M, 1 equiv.) and
DMAP (0.05 equiv.) (which was found to dramatically accelerate
the reaction) were premixed as a solution in MeCN and loaded
into an in-line reagent loop (1–5 mL). A second matching sample
reservoir containing the acid chloride component (0.3 M, 3 equiv.)
was also charged and the two feeds brought together at a flow
rate of 25 lL min−1 on a 250 lL microfluidic chip which was
76
71
◦
heated to 80 C. An excess of the acid chloride was found to be
necessary as the reaction did not proceed to completion with equal
stoichiometry. Two volume equivalents of the reagent loops were
pumped through the reactor to permit the starting materials to
react on the chip and allow sufficient time for scavenging the excess
acid chloride with a prepacked column23 of QuadrapureTM BZA
(QP-BZA),24 a benzylamine resin (3 equiv.). The flow rate was then
increased to 250 lL min−1 to elute the products. This was required
due to a significant retention of the reaction components, however
this was easily compensated for by the increased flow rates. A
back pressure regulator of ∼7 bar (100 psi) was installed in-line
at the exit of the flow stream in order to ensure a uniform flow
profile.
a Based on the phosphine reagent used. Purity >95% by NMR and LC-MS.
Phosphine 3 proved more successful; following unmasking of
the acid tag (steps ii–iv; Scheme 1) the removal of the phosphine
oxide by-product 5 could be selectively achieved using PS-NaCO3
(3 equiv.). A small example series of amides were prepared in good
yields and high purities (Table 1).
In the first experiment using phosphine 1 as the tagged reagent,
an additional column of MP-TsOH (3 equiv.) was placed after
the QP-BZA column. Interestingly it was discovered that both the
pyridine tagged reagent and the resultant amide coupling products
were captured by the immobilised acid. Even when substituting
a weaker carboxylic acid (PS-CO2H)25 into the system and using
repeated washing sequences with different solvents (DCM, MeOH
and MeCN) the amide product could never be isolated free from
the pyridine tagged reagent (1).
Iminophosphorane reaction with isothiocyanates
Following the successful generation of amides in flow (described
above), a more ambitious three component coupling sequence
was investigated. This involved a preliminary reaction between
an isothiocyanate and an aza-Wittig substrate (4) leading to a
reactive carbodiimide intermediate along with a phosphine sulfide
by-product 6.19,26 The carbodiimide could then be intercepted with
various amines to afford tri-substituted guanidines (Scheme 2).
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Scheme 2 Formation of guanidines in flow.
However, the reaction to prepare the intermediate carbodiimide
failed to reach completion when equimolar quantities of the
isothiocyanate and iminophosphorane were employed. The use
of an excess of isothiocyanate required an in-line nucleophilic
scavenging cartridge e.g. QP-BZA to eliminate the excess but this
also resulted in removal of the desired carbodiimide. Employing
excesses of the isothiocyanate and the secondary amine input
resulted in the formation of thiourea by-products which proved
impossible to selectively sequester from the reaction stream.
Ultimately a sub-stoichiometric amount of the isothiocyanate
compared to the iminophosphorane was used to ensure that the
reaction went to completion on the microfluidic reactor chip.
The excess iminophosphorane was subsequently quenched by
passage through an immobilised isocyanate resin yielding an
immobilised carbodiimide and the derivatised phosphine oxide
5 as a contaminant.
The final optimised experimental procedure involved initial
formation of the iminophosphorane 4 through the reaction of
phosphine 3 (0.1 M, 1 equiv.) and an azide (0.1 M, 1 equiv.) in
acetonitrile for 15 minutes prior to its introduction to the reactor.
The aza-Wittig component was then injected along with a stream
of the isothiocyanate (0.075 M, 0.75 equiv.) at equal flow ◦rates of
25 lL min−1 into a 1000 lL microfluidic chip heated to 110 C. The
system was maintained with a constant backpressure (7 bar)
to suppress any solvent boiling, with the elevated temperatures
also helping to preserve the solubility of the substrates and
intermediates. The resulting solution was directly eluted into a
connected glass column containing immobilised isocyanate (PS-
NCO; 6 equiv.),27 heated to 90 ◦C using a Vapourtec R-4 column
heater (Fig. 2).28 The PS-NCO resin reacted with the remaining
iminophosphorane creating the tagged by-product 5 which could
be scavenged in a subsequent step. Twice the combined volume
of the sample loops was metered through the reactor supplying
the required residence times before the flow rate was increased to
250 lL min−1 to elute the product from the column. The solution
was dispensed into a vial containing the volatile amine (5 equiv.),
which reacted with the carbodiimide to form the desired guanidine.
Fig. 2 System set-up.
base. The guanidines (Table 2) were isolated as their free bases in
good yields and excellent purities following passage through a
short plug of silica.
The previously described procedure was also modified to
permit the incorporation of non-volatile amine components.
In this alternative sequence the product output from the PS-
isocyanate column was combined directly with a solution of the
amine (0.5 equiv.). The reaction mixture was treated with QP-
BZA (3 equiv.) to facilitate removal of the excess carbodiimide.
Following filtration of the QP-BZA the solution was subjected to
the same unmasking and scavenging routine as employed above
(Scheme 2), allowing isolation of the desired products in good
yields and excellent purities (Table 3).
Terminal alkyne substituted phosphine as an orthogonal tagging
strategy
The use of an acid (2) or base (1) tagged phosphine reagent is
not always suitable, particularly with substrates sensitive to these
functionalities or possessing similar properties themselves. We
therefore examined a neutral tagging strategy. The attachment
of the terminal alkyne functionalised phosphine such as 729 (or
R
The solution was then evaporated using a Vapourtec V-10ꢀ solvent
evaporator28 to remove the solvent and excess amine. The tagged
reagent was then unmasked using the Douglas procedure (steps ii–
iv; Scheme 2) prior to sequestering with an immobilised carbonate
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Table 2 Guanidines synthesised using phosphine 3
Product
Isolated yield (%)
82
Product
Isolated yield (%)a
74
77
61
85
70
73
79
65
59
81
83
63
65
a Calculated compared to the isothiocyanate used. Purity >95% as measured by LC-MS and NMR.
the phosphine oxide 8) onto an azide capped solid phase is
an especially mild process, requiring only catalytic base and a
copper(I) salt (Schemes 3, 4).
This third tagged reagent 7 was devised to take advantage of
our proceeding communication30 on the preparation of 1,2,3-
triazoles31 commonly referred to as Click chemistry. Phosphine
7 was prepared in 91% isolated yield over two steps (Scheme 3)
utilising a lithium–halogen exchange followed by a PS-NaCO3 in
MeOH induced silyl deprotection.
Two methods were found to be effective for the removal of the
phosphine oxide by-product 8 (Scheme 4). Firstly, treatment with
an immobilised azide (PS-BnN3;32 5 equiv.) and catalytic amounts
of copper(I) iodide (3 mol%) and N,N-diisopropylethylamine
(DIPEA),33 permanently bound the phosphine oxide 8 to the solid
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Table 3 Guanidines made using non-volatile amines and phosphine 3
Table 4 Guanidines synthesised using phosphine 7
Isolated yield (%)a
Product
Isolated yield (%)a
85
Product
84
74
71
a Calculated compared to isothiocyanate used. Purity >95% by NMR and
LC-MS.
a Calculated compared to the amine used. Purity >95% by NMR and
LC-MS.
binding mechanism (release by treatment with AcOH) allows the
phosphine oxide 10 to be recovered. In principle this molecule
could be reduced to the phosphine with or without protection of
the carboxylic acid and used as a tagged reagent itself.
Phosphine 7 was evaluated using a similar procedure as
described above for the formation of the guanidines (Scheme 2).
The oxide or sulfide by-product of phosphine 7 was successfully
scavenged by covalent attachment to the solid phase using the PS-
BnN3 resin (5 equiv.). No additional base catalyst was necessary
in these examples due to the inherent basicity of the guanidine
products (Table 4).
Scheme 3 Formation of terminal alkyne functionalised phosphine 7.
In conclusion, it has been shown that various tagged phos-
phines and their by-products, especially those bearing a masked
carboxylic acid, can be easily removed by phase-switch scavenging
from the reaction stream in a modular flow reactor system. As
an application of these methods a three component coupling of
isothiocyanates, azides and amines delivers guanidines in good
yields and high purities. However, the concepts developed here
have wider-ranging implications for flow chemistry in general. For
example, the generation and in situ use of reactive intermediates,
coupled with the simplification of the purification procedure using
tagged reagents and the on-demand synthesis of compounds
through high levels of automation.
Acknowledgements
We gratefully acknowledge financial support from the Royal
Society Wolfson Fellowship (to IRB and SVL), Insight Faraday
and Syngenta (to CDS), the Natural Sciences and Engineering
Research Council of Canada for a Postdoctoral Fellowship (to
GKT), Erasmus Council for support (to MB), GSK for additional
financial support and the BP Endowment (to SVL).
Scheme 4 Removal of phosphine oxide 8.
phase as 9 (Scheme 4). The flow stream was subsequently passed
through a column containing QP-TU34 to remove any copper
residues. The second capture method involves attaching phos-
phine oxide 8 to a functionalised azide; this method is outlined
in our preceding paper using copper(I)-mediated cycloaddition
reactions.30 In this example, a carboxylic acid functionalised azide
was used and the newly functionalised phosphine oxide by-product
10 was removed using PS-NaCO3 (5 equiv.). This reversible
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http://www.syrris.com/. Examples include: (a) S. Saaby, I. R. Baxen-
dale and S. V. Ley, Org. Biomol. Chem., 2005, 3365–3368; (b) I. R.
Baxendale, C. M. Griffiths-Jones, S. V. Ley and G. K. Tranmer, Chem.–
Eur. J., 2006, 4407–4416; (c) I. R. Baxendale, S. V. Ley, C. D. Smith and
G. K. Tranmer, Chem. Commun., 2006, 4835–4837.
22 (a) I. R. Baxendale, C. M. Griffiths-Jones, S. V. Ley and G. K. Tranmer,
Synlett, 2006, 427–430; (b) M. Baumann, I. R. Baxendale, S. V. Ley,
C. D. Smith and G. K. Tranmer, Org. Lett., 2006, 8, 5231–5234.
23 Commercially available Omnifit glass chromatography columns with
adjustable height end pieces (plunger). The polymer supported reagent
is placed in an appropriately sized OmnifitꢀR column, usually 6.6 mm
bore by 150 mm length or shorter, the plungers are adjusted to relevant
bed heights and the polymer swelled/washed with solvent. Website:
http://www.omnifit.com/.
24 QuadrapureTM BZA (QP-BZA) [668591],
a high loading ben-
zylic amine resin. Commercially available from Sigma-Aldrich
(website: http://www.sigmaaldrich.com) or Reaxa Ltd (website:
http://www.reaxa.com).
25 PS-CO2H EHL [01-64-0111]. Commercially available from Nov-
abiochem. Website: http://www.merckbiosciences.co.uk.
26 D. H. Drewry, S. W. Gerritz and J. A. Linn, Tetrahedron Lett., 1997,
3377–3380.
27 PS-NCO [800496]. Commercially available from Biotage. Website:
http://www.biotage.com.
28 Vapourtec V-10ꢀR rapid solvent evaporator. Commercially available
from Biotage. Website: http://www.biotage.com. R-4ꢀR flow reactor
heater available from Vapourtec Ltd, Place Farm, Ingham, Suffolk,
IP31 1NQ, UK. Website: http://www.vapourtec.co.uk/. We thank
Vapourtec for the kind donation of the unit.
6 (a) D. L. Flynn, J. Z. Crich, R. V. Devraj, S. L. Kockerman, J. J. Parlow,
M. S. South and S. Woodward, J. Am. Chem. Soc., 1997, 119, 4874–
4881; (b) D. P. Curran, Angew. Chem., Int. Ed., 1998, 37, 1174–1196;
(c) J. Yoshida and K. Itami, Chem. Rev., 2002, 102, 3693–3716; (d) P.
Lan, J. A. Porco, Jr., M. S. South and J. J. Parlow, J. Comb. Chem.,
2003, 5, 660–669.
29 N. T. Lucas, M. P. Cifuentes, L. T. Nguyen and M. G. Humphrey,
J. Cluster Sci., 2001, 12, 201–221.
This journal is
The Royal Society of Chemistry 2007
Org. Biomol. Chem., 2007, 5, 1562–1568 | 1567
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30 C. D. Smith, I. R. Baxendale, S. Lanners, J. J. Hayward, S. C.
Smith, S. V. Ley, Org. Biomol. Chem., 2007, previous manuscript
10.1039/b702995k.
31 (a) C. W. Tornøe, C. Christensen and M. Meldal, J. Org. Chem., 2002,
67, 3057–3064; (b) V. V. Rostovtsev, L. G. Green, V. V. Fokin and
K. B. Sharpless, Angew. Chem., Int. Ed., 2002, 41, 2596–2599; (c) H. C.
Kolb and K. B. Sharpless, Drug Discovery Today, 2003, 8, 1128–1137;
(d) W. H. Binder and C. Kluger, Curr. Org. Chem., 2006, 10, 1791–
1815.
32 S. Arseniyadis, A. Wagner and C. Mioskowski, Tetrahedron Lett., 2002,
9717–9719.
33 (a) S. Lo¨ber, P. Rodriguez-Loaiza and P. Gmeiner, Org. Lett., 2003, 5,
1753–1755; (b) J. R. Thomas, X. Liu and P. J. Hergenrother, J. Am.
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34 QuadrapureTM TU (QP-TU)[655422], a thiourea-based scavenger resin
that has good affinity for metal ions. Commercially available from
Sigma-Aldrich (website: http://www.sigmaaldrich.com) or Reaxa Ltd
(website: http://www.reaxa.com).
1568 | Org. Biomol. Chem., 2007, 5, 1562–1568
This journal is
The Royal Society of Chemistry 2007
©