The structure of polymer-supported triphenylphosphine ditriflate: A potentially useful reagent in organic synthesis

Article abstract of DOI:10.1021/jo800447v

(Chemical Equation Presented) The structure of a polymer-supported version of the Hendrickson "POP" reagent, prepared by the reaction of polymer-supported triphenylphosphine oxide 1 with triflic anhydride, is established as an equilibrium mixture of polym

Full text of DOI:10.1021/jo800447v

The Structure of Polymer-Supported
Triphenylphosphine Ditriflate: A Potentially
Useful Reagent in Organic Synthesis
Maria J. Petersson,† Ian D. Jenkins,*,† and
Wendy A. Loughlin‡
Eskitis Institute for Cell and Molecular Therapies, Griffith
UniVersity, Nathan, Brisbane, QLD 4111, Australia, and
School of Biomolecular and Physical Sciences, Griffith
UniVersity, Brisbane, QLD 4111, Australia
i.jenkins@griffith.edu.au
ReceiVed February 26, 2008
FIGURE 1. 31P NMR stack spectra (162 MHz) of the addition of Tf2O
(0-4 equiv) to swollen, polymer-supported Ph3PO beads, 1, in CD2Cl2
at 25 °C (bottom to top): (a) 0, (b) 0.5, (c) 1.0, and (d) 4.0 equiv.
version of this reagent could be readily prepared by reaction of
the corresponding polymer-supported phosphine oxide with
triflic anhydride (Tf2O). This reagent has the advantage over
the Hendrickson reagent that, unlike triphenylphosphine oxide
(Ph3PO), it is easily removed from the reaction product by
simple filtration of the polymer beads. Moreover, it can be
recycled and reused without loss of efficiency. The reagent is
particularly useful in medicinal chemistry for the direct synthesis
of sulfonamides from sulfonic acids and amines,9 and since
2007, the precursor to the reagent, polymer-supported Ph3PO,
has been commercially available. We believe that this reagent
has considerable potential in organic synthesis as a very
powerful but mild dehydrating/activating agent. For example,
it should prove useful as an alternative to the Hendrickson
reagent for the synthesis of heterocycles such as oxazolines,
thiazolines, and imidazolines.10
The structure of a polymer-supported version of the Hen-
drickson “POP” reagent, prepared by the reaction of polymer-
supported triphenylphosphine oxide 1 with triflic anhydride,
is established as an equilibrium mixture of polymer-supported
triphenylphosphine ditriflate 3 (δ 79.4 ppm) and polymer-
supported phosphonium anhydride 4 (δ 73.3 ppm). The 31
P
NMR chemical shift reported previously for 3 is shown to
be incorrect.
The Hendrickson “POP” reagent1,2 (triphenylphosphonium
anhydride trifluoromethanesulfonate, or bis(triphenyl)oxodiphos-
phonium trifluoromethanesulfonate 6) brings about dehydrations
and coupling reactions (such as ester and amide formation), in
a similar manner to the Mitsunobu reaction3–6 through what
appears to be the same intermediate (an alkoxyphosphonium
salt). In previous work,7,8 it was shown that a polymer-supported
On the basis of 31P NMR and other data, the structure of this
polymer-supported reagent was assigned as 3 (where the
majority of phosphoryl groups on the polymer bead were in
the form of the ditriflate). However, characterization of 3 proved
difficult due to its extreme sensitivity to moisture. Here, we
provide evidence that the actual dehydrating reagent consists
of a mixture of polymer-supported triphenylphosphine ditriflate
3 and polymer-supported triphenylphosphonium anhydride
trifluoromethanesulfonate 4.
Addition of freshly distilled Tf2O (0.5 equiv) to an NMR
tube of swollen, dried, polymer-supported Ph3PO 1 in CD2Cl2
under nitrogen resulted in two peaks in the gel-phase 31P NMR
spectrum at δ 52.9 and 73.3 ppm, respectively (Figure 1b).
When 1 was treated with 1.0 equiv of Tf2O, the peak at δ 52.9
ppm was not observed. The original peak at δ 73.3 was still
present, but in addition, a new peak appeared at δ 79.4 ppm
† Eskitis Institute for Cell and Molecular Therapies, Griffith University,
Nathan.
‡ Eskitis Institute and School of Biomolecular and Physical Sciences, Griffith
University.
(1) Hendrickson, J. B. In Encyclopaedia of Reagents for Organic Synthesis;
Paquette, L. A. Ed.; Wiley: New York, 1995; Vol. 8, pp 5404-5407.
(2) (a) Hendrickson, J. B.; Hussoin, M. S. J. Org. Chem. 1987, 52, 4137–
4139. (b) Hendrickson, J. B.; Hussoin, M. S. J. Org. Chem. 1989, 54, 1144-
1149.
(3) Mitsunobu, O. Synthesis 1981, 1–28.
(4) Hughes, D. L. Org. React. 1992, 42, 335–656.
(5) Jenkins, I. D.; Mitsunobu, O. In Encyclopaedia of Reagents for Organic
Synthesis; Paquette, L. A. Ed.; Wiley: New York, 1995; Vol. 8, pp. 5379-
5390.
(9) Caddick, S.; Wilden, J. D.; Judd, D. B. J. Am. Chem. Soc. 2004, 126,
1024–1025.
(6) Hughes, D. L. Org. Prep. Proced. Int. 1996, 28, 127–164.
(7) Elson, K. E.; Jenkins, I. D.; Loughlin, W. A. Tetrahedron Lett. 2004,
45, 2491–2493.
(10) (a) You, S.-L.; Kelly, J. W. J. Org. Chem. 2003, 68, 9506–9509. (b)
You, S.-L.; Kelly, J. W. Org. Lett. 2004, 6, 1681-1683. (c) You, S.-L.; Kelly,
J. W. Tetrahedron Lett. 2005, 46, 2567-2570. (d) You, S.-L.; Kelly, J. W.
Tetrahedron, 2005, 61, 241-249.
(8) Fairfull-Smith (nee´ Elson) , K. E.; Jenkins, I. D.; Loughlin, W. A. Org.
Biomol. Chem. 2004, 2, 1979–1986.
10.1021/jo800447v CCC: $40.75
Published on Web 05/23/2008
2008 American Chemical Society
J. Org. Chem. 2008, 73, 4691–4693 4691

SCHEME 1. Formation of Polymer-Supported Reagent 3 a 4
It should be noted that there may be a contribution to the δ
52.9 ppm peak from the protonated polymer-supported Ph3PO
2, as a result of hydrolysis of some of the Tf2O by adventitious
moisture. Thus, treatment of 1 (δ 26.8 ppm) with 0.5, 1.0, and
2.0 equiv of triflic acid gave signals at δ 42.8 ppm (0.5 equiv),
δ 52.5 ppm (1.0 equiv), and δ 56.0 ppm (2.0 equiv), respec-
tively. Given the precautions taken in these experiments (Figure
1), and their reproducibility, this contribution should be minor.
However, adventitious moisture may explain the previously
reported 31P NMR shift for 3 of δ 53.3 ppm.4 Treatment of the
polymer-supported reagent (3 a 4, generated as before) with
water (2 drops) resulted in immediate replacement of the peaks
at δ 73.3 and 79.4 ppm by a peak at δ 38.2 ppm. This is
consistent with hydrolysis to give a mixture of the starting
material 1 (δ 26.8 ppm) in rapid equilibrium with the protonated
phosphine oxide 2 (δ 52.5 ppm).
To provide further support for these assignments and equi-
libria, Ph3PO (0.5 equiv relative to 1) was added to the polymer-
supported reagent (3 a 4, generated as before). 31P NMR signals
were generated at δ 79.4, 75.6, and 52.9 ppm (relative amounts
ca. 9:12:1). When 1.0 equiv of Ph3PO was used, only the peaks
at δ 75.6 and 52.9 ppm (ca. 5:2) remained. With excess Ph3PO
(4 equiv), a single peak at δ 40.7 ppm was observed.
A small amount of Ph3PO (0.5 equiv) would be expected to
react preferentially with the anhydride 4 to give the mixed
anhydride 5 [reaction with Ph2P(OTf)2 groups in 3 would be
slower as these groups were the ones that failed to form
anhydride linkages previously, as a result of being more hindered
or less accessible, therefore the 31P NMR signal for 3 (δ 79.4
ppm) would remain]. The mixed anhydride 5 can undergo
further reaction with Ph3PO to give the Hendrickson reagent 6
(together with starting material 1), or alternatively, a rapid (null)
exchange reaction to give back 5. This latter process would result
in a time-averaged 31P NMR signal of approximately δ 53 ppm
arising from the Ph3PO (δ 29.1 ppm),12 polymer-supported
Ph3PO 1 (δ 26.8 ppm), and the “outer” phosphorus atom in 5
(ca. δ 75.6 ppm). Conversely, the “inner” phosphorus atom
in 5 (the one attached directly to the polymer backbone)
would not be subject to time-averaging and would therefore
give a 31P NMR signal of approximately δ 75 ppm (any
conversion 5 f 4 would be expected to be slow on the 31P
NMR time scale by analogy with the equilibrium between 3
and 4, while reaction between the two polymer beads 1 and
5 would be expected to be extremely slow). With excess
Ph3PO (4 equiv), there would be negligible 5 present and the
31P NMR signal would be dominated by the exchange between
6 and Ph3PO (i.e., the peak at δ 40.7 ppm).
It should also be noted that formation of the “POP” bond in
4 could be between separate polymer beads, or between
phosphoryl groups on the same polymer bead. As the polymer
loading is quite high (∼3 mmol P/g of polymer, corresponding
to almost 80% of the phenyl groups of the polystyrene backbone
bearing a diphenylphosphoryl moiety), it might be expected that
formation of a POP bond between adjacent phosphoryl groups
on the same polymer bead, possibly to give a [3.3]paracyclo-
phane-like structure 7, would be most likely. The structure 7
would be expected to be more strained than [3.3]paracyclo-
phane13 itself due to the additional substituents on the ring and
(Figure 1c). The spectrum was unchanged after standing for
24 h. The relative intensity of the peak at δ 79.4 ppm increased
as the Tf2O was increased from 1 to 4 equiv (Figure 1d).
In the 0.5 equiv experiment, there is partial formation of the
ditriflate 3. Some of the phosphonium ditriflate [Ph2P(OTf)2]
groups undergo further reaction with neighboring diphenylphos-
phoryl (Ph2PO) groups on the polymer backbone to give
anhydride (P-O-P) 4 (δ 73.3 ppm). However, such anhydride
formation is presumably not possible for all Ph2P(OTf)2 groups
on 3, as not all would have a neighboring Ph2PO group, and
some would be more hindered or less accessible. This would
mean that there should be three phosphorus species present,
Ph2P(OTf)2 and Ph2PO as shown in 3 and P-O-P as shown
in 4. We suggest that all three of these species are in equilibrium
(Scheme 1). In the case of Ph2PO (δ 26.8 ppm) and Ph2P(OTf)2
(δ 79.4 ppm), the equilibrium (represented by 1 a 3) must be
fast (on the 31P NMR time scale) to give a time-averaged peak
at δ 52.9 ppm (very close to the calculated value of δ 53.1),
whereas the equilibrium between 3 and 4 must be slow (on the
31P NMR time scale) so that a separate signal is seen for the
P-O-P species 4. As expected, the gel-phase 31P NMR signal
for 4 (δ 73.3 ppm) is close to that of the solution-phase
Hendrickson reagent 6 (δ 75.6 ppm).11 The fact that the
equilibrium between 1 and 3 is fast whereas that between 3
and 4 is slow (on the 31P NMR time scale) is not surprising as
the former involves a solution phase reagent (Tf2O) interacting
with Ph2PO groups on the polymer, while the latter involves a
gel-phase reaction where the relative movement of the phos-
phoryl groups is restricted by the (insoluble) cross-linked
polymer network.
In the 1.0 equiv experiment (Figure 1c), there is sufficient
Tf2O to react with all of the Ph2PO groups in 1, so that only
the ditriflate (3) and anhydride (P-O-P) species 4 are observed.
With excess Tf2O (4 equiv), the equilibrium shifts in favor of
the ditriflate 3.
(12) Elson, K. E.; Jenkins, I. D.; Loughlin, W. A. Org. Biomol. Chem. 2003,
1, 2958–2965.
(13) See: Longone, D T.; Kusefoglu, S. H.; Gladysz, J. A. J. Org. Chem.
1977, 42, 2787–2788, and references cited therein.
(11) Crich, D.; Dyker, H. Tetrahedron Lett. 1989, 30, 475–476.
4692 J. Org. Chem. Vol. 73, No. 12, 2008

the fact that the POP linkage prefers to be linear.14 However,
examples of cyclic P-O-P compounds (such as 8 and 9) where
the P-O-P linkages cannot be linear are known.15 As the
concentration of phosphoryl groups within the swollen polymer
bead is quite high, much larger rings containing P-O-P
linkages could also be formed between phosphoryl groups in
close proximity. Conversely, the likelihood of P-O-P forma-
tion between polymer beads seems much less likely given that
these are insoluble polymer particles of the order of 0.05 mm
in diameter. On a molecular scale, the polymer beads are huge
and therefore their surface area is quite small.
In conclusion, these experiments provide evidence that the
structure of the polymer-supported version of the Hendrickson
“POP” reagent is an equilibrium mixture of polymer-supported
triphenylphosphine ditriflate 3 (δ 79.4 ppm) and polymer-
supported phosphonium anhydride 4 (δ 73.3 ppm). Or, more
precisely, the polymer beads contain a mixture of Ph2P(OTf)2
and P-O-P groups. The ditriflate becomes the dominant
structure only in the presence of excess Tf2O. The fact that the
structure consists of an equilibrium mixture of two distinct
species does not appear to interfere with its use as a potent
dehydrating agent.7–9
Experimental Section
Polymer-supported Ph3PO, 1, was prepared as described previ-
ously,8 and dried under vacuum at 125 °C for 2 days, using a
Kugelrohr oven.
31P NMR spectra were determined at 162 MHz. In a typical
procedure, the polymer beads were dried under high vacuum for
48 h prior to use. In a 5 mm NMR tube, dry polymer-supported
Ph3PO (75 mg, 0.23 mmol, 3 mmol/g) was allowed to swell in
CD2Cl2 (750 µL) for 0.5 h to generate a gel-phase sample. Tf2O
(39 µL, 0.23 mmol) was added and the slurry mixed for 0.5 h. The
31P NMR spectrum was then recorded at 25 °C.
Finally, it is interesting to note that the only product formed
when Ph3PO is treated with excess Tf2O is the Hendrickson
reagent 6. Triphenylphosphine ditriflate is not observed. Such
a species becomes possible, however, with polymer-supported
Ph3PO, where some of the phosphoryl groups are relatively
inaccessible to attack by a second phosphoryl group, or where
the formation of a POP species involves considerable ring strain.
Acknowledgement. Financial support for this work was
provided by Griffith University, and the Eskitis Institute for Cell
and Molecular Therapies, Griffith University. We thank a referee
for constructive comments and Dr. Ezio Rizzardo of the CSIRO
for useful discussions.
(14) Aaberg, A.; Gramstead, T.; Husebye, S. Acta Chem. Scand. 1980, A34,
717–724.
(15) Elson, K. E.; Jenkins, I. D.; Loughlin, W. A. Aust. J. Chem. 2004, 57,
371–376.
JO800447V
J. Org. Chem. Vol. 73, No. 12, 2008 4693