Tetraarylphosphonium salts as solubility-control groups: Phosphonium-supported triphenylphosphine and azodicarboxylate reagents

Article abstract of DOI:10.1002/anie.200503599

(Chemical Equation Presented) Predictable solubilities! Reagents supported on a tetraarylphosphonium group have solubilities that can be predicted. The reagents and their by-products can be readily removed, recovered, and recycled after reaction by a precipitation/filtration sequence initiated by the addition of a low-polarity solvent, such as diethyl ether. Furthermore, the supported reagents are robust and exhibit reactivities similar to their parent compounds.

Full text of DOI:10.1002/anie.200503599

Angewandte
Chemie
Supported Catalysts
DOI: 10.1002/anie.200503599
Tetraarylphosphonium Salts as Solubility-Control
Groups: Phosphonium-Supported
Triphenylphosphine and Azodicarboxylate
Reagents**
Jean-Christophe Poupon, Alessandro A. Boezio, and
AndrØ B. Charette*
Tremendous effort has been invested over the last few
decades to develop novel supports to facilitate organic
synthesis. These supports have been used not only to carry
[
1]
out multistep syntheses, but also to bind catalysts, reagents,
[*] J.-C. Poupon, A. A. Boezio, Prof. A. B. Charette
DØpartement de Chimie
UniversitØ de MontrØal, P.O. Box 6128
Station Downtown, MontrØal, QuØbec H3C3J7 (Canada)
Fax: (+1)514-343-5900
E-mail: andre.charette@umontreal.ca
[
**] This work was supported by Valorisation-Recherche QuØbec (VRQ),
Valorisation-Recherche s.e.c. (Univalor), and the UniversitØ de
MontrØal. A.A.B. is grateful to the NSERC (PGF B) and FCAR (B2)
for postgraduate fellowships.
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
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Communications
and scavengers to facilitate either the purification process of a
product or the recovery of a potentially expensive or toxic
dissolved in CH Cl , and the amount of Et O required to
2 2 2
achieve
a quantitative precipitation was evaluated by
[
2]
31
catalyst or reagent.
A landmark achievement by Merrifield used function-
P NMR spectroscopic analysis with triphenylphosphine as
the internal standard (Figure 1). Two general trends were
[
3]
[
4]
alized cross-linked, insoluble polymers as a solid support.
This solid-phase technology revolutionized peptide and
polynucleotide synthesis and was soon used to develop
[
5]
solid-supported reagents and catalysts. As an attempt to
restore classical homogeneous organic-chemistry conditions,
the replacement of insoluble resins by a soluble polymer
[
6]
support became a popular modification. The non-cross-
linked support is typically soluble in some solvents and
insoluble in others. Among the soluble polymers, polyethy-
[
7]
lene glycols (PEGs) and non-cross-linked polystyrene
[
8]
(
NCLP) have been by far the most widely used for the
recovery and recycling of reagents or catalysts. A recent
approach using solid supports derived from ring-opening
[
9]
metathesis polymerization (ROMP) has been reported.
Silica-bound scavengers or reagents have also been exten-
[
10]
sively used recently. The rigid and nonswelling backbone of
the silica eliminates the issue of solvent compatibility.
Complementary approaches have involved linking a catalyst
[
11]
or reagent on a dendrimeric structure or encapsulating it
Figure 1. Relative solubility ofarylphosphonium salts in Et O/CH Cl .
2
2
2
(
homogenous or heterogeneous) in some porous species
Ph
3
PMe; a) Ph
4
PX, X=Br; b) Ph
4
PX, X=ClO
4
; c) Ph
4
PX, X=PF ;
6
[
12]
d) Ph PX, X=Br; e) Ph PX, X=ClO , X=PF (insoluble); f) 3; g) 5.
4 4 4 6
framework.
Another area of interest is the ionic liquids that consist of
pyridinium, imidazolium, ammonium, or phosphonium
[
13]
salts. The structural variations of the salts allow modulation
of their melting points. The most popular ionic liquid is
[
observed: the amount of diethyl ether required to obtain a
quantitative precipitation of the arylphosphonium salts is
counterion dependent (Br> ClO > PF ), and the amount of
+
ꢀ
BMIM] [X] (BMIM = 1-n-butyl-3-methylimidazolium, X =
4
6
OTf, BF , PF , SbF ; Tf = triflate). As ionic liquids are highly
diethyl ether required is generally less for tetraarylphospho-
nium salts than for triarylalkylphosphonium salts for the same
counterion.
Another unique property of tetraarylphosphonium salts is
that they have little propensity to trap organic compounds
upon precipitation under these conditions. This behavior is an
important property that supports for reagents and catalysts
should ideally possess. For example, when diethyl ether was
4
6
6
polar and non-coordinating solvents, they readily dissolve
transition-metal complexes without changing their properties.
An additional versatile alternative is to use the fluorous
[
14]
phase. Reagents and catalysts can be labeled with a certain
number of fluorine atoms to increase their solubilities in the
fluorous phase. Perfluoro protecting groups have been
developed, thus allowing a substrate to be temporarily
tagged for its purification on a fluorous reverse-phase
column or to be soluble in the fluorous phase. Finally,
reagents that carry basic or acidic moieties (free or
added to a solution containing Ph PBr and sudan red 7B
4
(Figure 2A), quantitative precipitation of an easily filtered
[
15]
[16]
masked),
polyaromatic tags,
or stilbene tags (precipi-
[
17]
ton) have also been used. The main advantage of those
approaches is the use of low-molecular-weight molecules,
which are easy to purify and characterize.
Our interest in phosphorus chemistry led us to contem-
plate the possibility of using tetraarylphosphonium and
related phosphonium salts as potential solubility-control
groups for reagents and catalysts. Obviously, our goal was to
develop small stable entities that are soluble in well-defined
solvents but that precipitate completely when a minimum
amount of an orthogonal solvent is added. The alkyltriaryl-
phosphonium compounds are readily used as ylide precursors
for the Wittig reaction. A general characteristic of these
[
18]
reagents is their insolubility in diethyl ether. As diethyl
ether is a good solvent for most organic compounds, we first
considered quantifying the solubility of some arylphospho-
Figure 2. Precipitation/filtration/dissolution sequence of a solution of
Ph PBr and sudan red 7B. A) Ph PBr (250 mg), sudan red 7B (5 mg),
4
4
and CH Cl (1 mL); B) addition ofEt O (3 mL); C) filtrate; D) filtered
2
2
2
nium salts with various counterions (X = Br, ClO , PF ) in a
4
6
phosphonium salt (247 mg) after washing with Et
drying.
O (25 mL) and
2
system of CH Cl /Et O. Several arylphosphonium salts were
2
2
2
1
416
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Chemie
solid occurred (Figure 2B). Filtration produced a clear red
solution of the dye exempt of phosphonium (Figure 2C) and a
clean, white solid (Figure 2D).
are produced in this reaction. Phosphine 3 was mixed with
CBr and zinc dust, and the reaction mixture was heated
4
under reflux prior to the addition of aldehyde. Under these
conditions, the ylide was cleanly formed and high yields of the
1,1-dibromoalkenes were obtained (Table 1). The yields
In light of these promising properties, we evaluated the
ability of this group to control the solubility properties of a
supported reagent. To insure improved chemical stability, a
tetraarylphosphonium group was selected as the solubility-
control group. Furthermore, we assumed that the shielding of
the phosphorus center by the four aryl moieties should lead to
more reproducible solvent interactions and interionic dis-
tances that are largely responsible for the solubility proper-
Table 1: Synthesis of1,1-dibromoalkenes using the Corey–Fuchs reac-
tion with phosphine 3.
[a]
Entry
Yield [%]
[b]
1
6
7
8
9
94
[
19]
ties. Two recent reviews dealing with the advances in the
[
20]
separation-friendly reagents for the Mitsunobu reaction
[
[
[
b]
b]
b]
confirmed the great interest of the chemical community in
settling the problems of the elimination of phosphine oxide
and hydrazine by-products. We felt that the elaboration of a
phosphonium-supported triphenylphosphine moiety would
constitute an excellent model to evaluate the efficiency of the
tetraarylphosphonium species as a potentially useful solubil-
ity-control group. The desired compound 2 was synthesized
2
3
4
90
90
96
[
21]
using the Horner reaction,
which involved a nickel-
[
b]
c]
mediated coupling of bromophosphine 1 and triphenylphos-
phine (Scheme 1). A subsequent anion-exchange reaction led
either to the perchlorate or hexafluorophosphate salts 3 and 4.
5
6
10
11
96
98
[
[
d]
7
12
95
[
b]
b]
Scheme 1. Reagents and conditions: a) NiBr , PPh , PhCN, reflux, 4 h
8
9
13
14
85
96
2
3
(
78%); b) LiClO , MeCN, CH Cl , 15 min (95%); c) LiPF , MeCN,
4 2 2 6
CH Cl , H O, 1 h (95%).
2
2
2
[
Gratifyingly, the solubility of both the phosphine 3 and the
[a] After flash chromatography. [b] Phosphine
3
(2.5 equiv), CBr4
related phosphine oxide 5 closely followed that of the parent
tetraphenylphosphonium salt, thus indicating the predom-
inant influence of the solubility-control group (Figure 1,
curves f and g). Both compounds were precipitated quanti-
tatively when a two-volume excess of diethyl ether or less was
added.
(
2.5 equiv), Zn dust (2.5 equiv), CH Cl (0.2m), reflux (0.5 h); then
2
2
addition ofaldehyde, RT, 3 h. [c] Three equivalents ofall reagents, RT, 6 h.
[d] Six equivalents ofall reagents, RT, 6 h.
obtained with phosphine 3 are usually comparable with
those obtained with triphenylphosphine. When the reaction
was complete, the zinc salts were filtered and the addition of
Although the perchlorate ion is known to be both a
[
22]
powerful oxidant (perchloric acid ) and a solid-rocket
[
23]
propellant (ammonium perchlorate ), its nonlability in the
Et O to the filtrate to allow complete precipitation of the
2
[
24]
present compounds makes it slow to react. However, as
little chemistry is known regarding tetraarylphosphonium
perchlorate, a thermogravimetric experiment was performed
to ensure its dynamic thermal stability. The comparison
between phosphonium perchlorate and bromide showed
comparable behavior: decomposition occurred at a compa-
rable rate and very high temperature (3608C for the
phosphine oxide 5 by-product, followed by filtration, led to an
organic layer free of phosphine/phosphine oxide. Concen-
tration under reduced pressure afforded a quantitative
recovery of a very clean crude product for which the NMR
spectroscopic analysis did not show any traces of phosphoni-
um salts (Figure 3).
It is also possible to recycle phosphine 3 in high yield as
the only product of the reduction of the resulting phosphine
[
25]
perchlorate and 3808C for the bromide).
Nevertheless,
[
28]
care must be taken during their use because of the lack of
general data about phosphonium percholorate. Alternatively,
the hexafluorophosphate salt 4 could be used as well.
With phosphine 3 in hand, its reactivity, recovery, and
recyclability were initially tested in the Corey–Fuchs olefina-
oxide 5 with trichlorosilane and dimethylaniline [Eq. (1)].
Our next study was the Mitsunobu reaction involving
relatively hindered secondary alcohols using p-nitrobenzoic
[
29]
acid as the nucleophile. Although the optimal solvent for
this reaction is THF or toluene, the use of phosphine 3 forced
us to opt for a 2:1 mixture of toluene and dichloromethane.
[
26,27]
tion
as substantial amounts of triphenylphosphine oxide
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1417

Communications
excellent yield (Scheme 2). The desired product was therefore
obtained in five steps and 60% overall yield from 4-
chlorobenzaldehyde without the need to purify any of the
intermediates by chromatography.
The Mitsunobu reaction of 2-octanol with 4-nitrobenzoic
acid, phosphine 3 (1.5 equiv), and DEAD 24 (1.5 equiv) led to
the clean formation of the ester (Table 2, entry 3). Addition of
diethyl ether followed by filtration allowed quantitative
removal of the by-products. To the best of our knowledge,
this case is the first time that two supported reagents are used
simultaneously with such effectiveness. In a recent report,
Figure 3. Crude NMR spectrum for the Corey–Fuchs reaction (Table 1,
entry 7; quantitative mass recovery).
[33]
Hanson and co-workers
used five equivalents of both
reagents supported on a soluble ROMP polymer to esterify a
primary alcohol in 64% yield.
In conclusion, we have developed a highly reactive
triphenylphosphine and DEAD reagent supported on a
novel solubility-control group. The main advantage of this
system is the use of a novel low-molecular-weight support that
is soluble in solvents of medium polarities (CH CN, dimethyl
3
sulfoxide (DMSO), dimethylformamide (DMF), CH Cl ,
2
2
ClCH CH Cl, etc.) for the attachment of reagents and
2
2
insoluble in solvents of low polarities (Et O, PhMe, hexane)
2
The results are shown in Table 1, and they
indicate that the reactivity of phosphine 3 is
[
30]
quite similar to that of triphenylphosphine.
Interestingly, in this solvent system, the phos-
phine oxide 12 was precipitated, thus allowing a
visual indication of the reaction progress. When
the reaction was complete, 5 volumes of Et O
2
(
relative to CH Cl ) were added to complete
2 2
the precipitation of the phosphonium-derived
by-products. Filtration and concentration of the
crude mixture led to a phosphorus-free prod-
3
1
uct, as determined by P NMR spectroscopic
analysis. Conversely, the NMR spectroscopic
analysis of the phosphonium salt showed only
traces of the reaction products (less than 2%).
The Mitsunobu reaction of several alcohols led
to esters 15–18 in yields comparable to those
obtained with triphenylphosphine or other
supported phosphines (Table 1, entries 1–4)
and with complete inversion of configuration
Scheme 2. Synthesis ofthe DEAD reagent. Reagents and conditions: a) NiBr , PPh ,
2
3
PhCN, reflux, 2 h; b) LiClO , CH Cl , MeOH, 15 min, O , ꢀ788C then NaBH (77% for
4
2
2
3
4
two steps); c) triphosgene, pyridine, CH Cl , ꢀ788C then EtOOCNHNH , ꢀ788C!RT
2
2
2
(95%); d) pyridine, NBS, 08C, 0.5 h (91%).
for clean precipitation. In addition, the reagents display a
similar reactivity to their parent nonsupported analogues,
there is no need to use extra equivalents because of the
availability of all the reactive sites, and the reactions can
easily be followed by NMR spectroscopic and mass-spectro-
metric analysis. Furthermore, they are not hygroscopic
(completely insoluble in water) and are easily handled
solids that can be quickly and easily be filtered upon
precipitation. We are currently introducing additional
reagents, catalysts, and substrates on the phosphonium
support, and the results will be reported in due course.
(
determined by HPLC for 17).
The next step was to develop a diethyl azodicarboxylate
DEAD) reagent supported on the phosphonium solubility-
(
control group and examine whether it can be used in
conjunction with phosphine 3. The direct Horner reaction of
triphenylphosphine with 4-chlorobenzaldehyde did not give a
clean phosphonium salt. Alternatively, a double Horner
[
31]
reaction of 4,4’-dichlorostilbene led to the clean formation
of the bis(phosphonium) salt 21. After an anion-exchange
reaction and reductive ozonolysis, benzyl alcohol 22 was
obtained in an 77% overall yield from 20. The elaboration of
the DEAD reagent was accomplished by treatment of 22 with
triphosgene to generate the chlorocarbonyl pyridinium inter-
mediate followed by the addition of ethyl carbazate to lead to
hydrazine dicarboxylate 23. A final oxidation with N-bromo-
Received: October 11, 2005
Published online: January 20, 2006
Keywords: phosphonium ions · phosphorus · separation ·
.
[
32]
succinimide (NBS)
afforded the DEAD reagent 24 in
supported catalysts · Wittig reaction
1
418
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Chemie
Table 2: Mitsunobu reactions with phosphine 3.
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[
28] The compound is blue because of a possible reduction of the
ꢀ
ꢀ
ClO4 ion; an exchange with ClO4 gave a colorless compound.
[
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[
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[
[
[
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