usage. The lack of an extractive procedure to remove the
LR-derived byproducts is a commonly cited disadvantage
of this reagent. In some cases, the requisite chromatographic
separation of the desired product from the LR byproducts
can be really cumbersome or impossible, which limits the
reagent utility. Herein, we report a possible solution of this
long-standing separation problem by the synthesis and
application of a fluorous LR.
pentasulfide (2) failed to give any fluorous Lawesson’s
reagent, demonstarting the necessity of a longer insulating
element.
To increase the number of the insulating methylene seg-
ment, we have developed a simple method for the construc-
tion of a fluorous anisole derivative 7 with a 5 methylene
spacer (Scheme 1). Thus, the reaction of commercially avail-
Recently, much attention has been focused on fluorous
chemistry as an alternative solution-phase tagging approach
in catalysis and high-throughtput synthesis.4 The highly
hydrophobic perfluoroalkyl tags, in effect, serve as a handle
to allow fluorous molecules to be separated efficiently from
the reaction mixture via fluorous liquid-liquid or solid-
liquid extraction.
Scheme 1. Synthesis of Fluorous Lawesson’s Reagent 8
To avoid the chromatographic purification step after LR
application, we were intrigued with the idea of synthesizing
and utilizing a fluorous version of LR. It was hoped that the
attached perfluorinated tag would simplify the product
isolation via a fluorous reversed-phase solid extraction
technique.5 Moreover, if the thionation reactions proceed
virtually to completion, so that filtration through and washing
of reversed-phase fluorous silica cartidges are all that is
required to separate product, automation of the process would
be relatively easy, which would be an obvious attraction in
combinatorial chemistry.
The LR is generally obtained by the reaction of phosphorus
pentasulfide (2) with anisole at elevated temperature.6
Consistent with this procedure, we envisioned a fluorous
Lawesson’s reagent to arise from a fluorous anisole having
a reactivity toward phosphorus pentasulfide (2) similar to
anisole. In our first probe, we have synthesized a series of
fluorous anisole derivatives 3a-c7 (Figure 1) from the
able cinnamaldehyde derivative 4 with Wittig reagent derived
from [Rf8CH2CH2PPh3]+I- (5) gave the fluorous diene 6,
which was easily hydrogenated to the corresponding fluorous
anisole derivative 7. In fact, this sequence is a vinylogous
extension of the Wittig methodology developed by Gladysz
and co-workers.8 Due to the simplicity of this process, we
could synthesize the fluorous anisole 7 on a 10 g scale.
Finally, the pivotal thermal reaction between 7 and phos-
phorus pentasulfide (2) was attempted in a molar ratio of
10:1. The reaction was maintained at 150 °C for 4 h, during
which time all of the solid starting material dissolved. On
cooling, the fluorous Lawesson’s reagent 8 precipitated and
was washed with hexanes and dried in vacuo. Besides IR
(4) (a) Curran, D. P. In Stimulating Concepts in Chemistry; Stoddard,
F., Reinhoud, D., Shibasaki, M., Eds.; Wiley-VCH: New York, 2000; p
25. (b) Gladysz, J. A.; Curran, D. P. Tetrahedron 2002, 58, 3823 and the
following articles in this special issue entitled “Fluorous Chemistry”. (c)
The Handbook on Fluorous Chemistry; Gladysz, J. A., Horva´th, I. T.,
Curran, D. P., Eds.; Wiley-VCH: New York, 2004.
(5) Curran, D. P.; Hadida, S.; He, M. J. Org. Chem. 1997, 62, 6714.
(6) Thomsen, I.; Clausen, K.; Scheibye, S.; Lawesson, S.-O. Org. Synth.
1984, 62, 158.
Figure 1. Fluorous anisoles 3a-c with three methylene spacers.
(7) For details of the synthesis of the fluorous anisoles 3a-c, see the
Supporting Information.
corresponding aromatic aldehyde using the Wittig reaction
as a key step.8 The built-in three methylene spacer was hoped
to serve as an efficient insulator of the electron-withdrawing
effect of the perfluoroalkyl groups.9 However, it was finally
established that their thermal agitation with phosphorus
(8) Development and application of Wittig methodology in fluorous
chemistry: Rocaboy, C.; Rutherford, D.; Bennett, B. L.; Gladysz, J. A. J.
Phys. Org. Chem. 2000, 596.
(9) Study on the insulation of the electron-withdrawing effect of the
perfluoroalkyl groups: Alvey, L. J.; Meier, R.; Soo´s, T.; Bernatis, P.;
Gladysz, J. A. Eur. J. Inorg. Chem. 2000, 1975.
1094
Org. Lett., Vol. 8, No. 6, 2006