Synthesis and application of crown ether tagged triarylphosphines

Article abstract of DOI:10.1016/S0040-4039(02)02728-4

Crown ether tagged triarylphosphines 1 and 2 were synthesised and applied in Mitsunobu and Heck reactions, their reactivity being evaluated against triphenylphosphine- and polymer-bound triphenylphosphine. Purification of the reactions was effected by pos

Full text of DOI:10.1016/S0040-4039(02)02728-4

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 1305–1307
Synthesis and application of crown ether tagged
triarylphosphines
Toby Jackson and Anne Routledge*
The Department of Chemistry, University of York, Heslington, York YO10 5DD, UK
Received 5 November 2002; revised 21 November 2002; accepted 29 November 2002
Abstract—Crown ether tagged triarylphosphines 1 and 2 were synthesised and applied in Mitsunobu and Heck reactions, their
reactivity being evaluated against triphenylphosphine- and polymer-bound triphenylphosphine. Purification of the reactions was
effected by post-reaction sequestration onto an ammonium functionalised solid-phase. © 2003 Elsevier Science Ltd. All rights
reserved.
The synthesis of chemical libraries is still a burgeoning
area of research for both industry and academia. Early
library syntheses were generally performed on the solid-
phase1 but recently there has been a paradigm shift
towards solution-phase synthesis.2 This has introduced
new enabling technologies such as scavenger resins,3
fluorous-phase synthesis,4 polymer-supported5 and
tagged reagents.6
Crown-5 tagged triarylphosphine 2 was synthesised
from triphenylphosphine alcohol7 and mesylated
hydroxymethyl 15-crown-5 as shown in Scheme 2.
In this letter we describe our preliminary results
towards a novel approach to tagged reagents exem-
plified by the synthesis and application of crown ether
tagged triarylphosphines 1 and 2. Triarylphosphines
have been synthesised on both soluble7 and insoluble8
polymer supports and with a masked carboxylic acid as
a sequestering tag.9 Here we have used the crown ether
as an inert ‘phase label’ to allow selective solid-phase
sequestration of the reagent and/or byproducts from
reaction mixtures. A recent paper has described affinity
purification using crown ether–ammonium ion interac-
tion to isolate compounds that contained a large crown
ether moiety (dibenzo-32-crown-10).10 This was, in
effect, using the crown ether as the ‘support’ on which
synthesis was undertaken. Similarly the use of
aminomethyl-18-crown-6 as an ionisable phase label
has been reported.11
Scheme 1. Reagents and conditions: (i) DCC, DMAP (cat.),
HOBt, DCM, ambient temperature, 18 h, 94%.
In order to demonstrate the application of these
reagents as triphenylphosphine substitutes, both crown
tagged triarylphosphines 1 and 2 were used in the
Mitsunobu synthesis of 7-benzyloxycoumarin 4 from
7-hydroxycoumarin 3 (Scheme 3). The results were
compared to triphenylphosphine and cross-linked
polystyrene supported triphenylphosphine (Nov-
abiochem 1.10 mmol g−1) (Table 1). In the reaction,
15-crown 5-tagged triarylphosphine 2 proved as effec-
tive as both triphenylphosphine and polymer-supported
triphenylphosphine in converting 3 into 4.
The crown tagged triarylphosphine 1 was synthesised in
excellent yield in a one-step reaction from commercially
available 2-aminomethyl 18-crown-6 and triphenyl-
phosphine carboxylic acid as shown in Scheme 1. 15-
The reaction mixture from the 18-crown-6-tagged tri-
arylphosphine-mediated Mitsunobu reaction was
loaded onto an ammonium trifluoroacetate ArgoPore™
column12 then eluted with dichloromethane. No phos-
phine derived adducts passed through the column as
determined by 31P NMR spectroscopy (Fig. 1). Elution
* Corresponding author. Tel.: +44 (0)1094 434540; fax: +44 (0)1904
432516; e-mail: ar30@york.ac.uk
0040-4039/03/$ - see front matter © 2003 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)02728-4

1306
T. Jackson, A. Routledge / Tetrahedron Letters 44 (2003) 1305–1307
Figure 1. 31P NMR spectrum of dichloromethane eluent from
reaction to form 4.
Figure 2. 31P NMR spectrum of dichloromethane (+2%v/v
triethylamine) elution of ammonium functionalised Argo-
Pore™ column.
Scheme 2. Reagents and conditions: (i) TBDMS-Cl, imidazole,
DCM, 24 h, 98%. (ii) BuLi (2.39
M
in hexane),
chlorodiphenylphosphine, THF −78°C, 0.5 h to 20°C, 24 h,
22%. (iii) TBAF (1 M in THF) (2 equiv.), 20°C, 3 h, 75%. (iv)
MsCl (3 equiv.), Et3N (3 equiv.), DCM, 20°C, 18 h, 55%. (v)
Cs2CO3 (2 equiv.), THF, 20°C, 48 h, 70%.
methyl ester of 3-phenylacrylic acid 6 (Scheme 4) from
iodobenzene 5 and methylacrylate. The results were
compared to those obtained with triphenylphosphine
(Table 2).
Scheme 3. Reagents and conditions: (i) L (2 equiv.), benzyl
alcohol (1.1 equiv.), DEAD (2 equiv.), THF, 0–20°C, 3 h.
Scheme 4. Reagents and conditions: (i) L (0.32 equiv.),
Pd(OAc)2 (0.17 equiv.), NEt3 (2 equiv.), THF reflux, 8 h.
Table 1. Synthesis of 7-benzyloxycoumarin 4
Phosphine L
Percentage conversion of 3 to
4a (%)
Table 2. Synthesis of 3-phenylacrylic acid methylester 6
Triphenylphosphine
Polymer-supported
triphenylphosphine
Tagged triarylphosphine 1
Tagged triarylphosphine 2
91
93
Phosphine L
Percentage conversion of 5 to 6a
(%)
63
\95
Triphenylphosphine
\95
Tagged triphenylphosphine \95
2
Tagged triarylphosphine 2ca=‘‘D’’\\\95
a Percentage conversion determined by HPLC analysis.
a Percentage conversion determined by HPLC analysis.
of the column with dichloromethane doped with 2% v/v
triethylamine released all sequestered tagged phosphine
oxide (Fig. 2). After washing to remove triethylamine,
80% of the expected triarylphosphine oxide was
recovered.
In both cases the reaction showed quantitative conver-
sion of iodobenzene 5 to 3-phenylacrylic acid methyl
ester 6. The reaction mixture was loaded onto an
ammonium trifluoroacetate ArgoPore™ column then
eluted with dichloromethane. As expected no phosphine
derived adducts passed through the column as deter-
mined by 31P NMR spectroscopy (Fig. 3).
Palladium-mediated carbonꢀcarbon bond formations
are extensively used in organic synthesis. In order to
explore the application of crown-tagged triarylphos-
phine 2 in a Heck reaction it was used to synthesise the

T. Jackson, A. Routledge / Tetrahedron Letters 44 (2003) 1305–1307
1307
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In conclusion, we have demonstrated that tagged tri-
arylphosphine reagents can be used in both Mitsunobu
and Heck chemistry with removal of phosphine derived
by-products achieved by elution through ammonium
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Acknowledgements
We thank the EPSRC (T.J.) and the University of York
for funding.