Air-stable trialkylphosphonium salts: simple, practical, and versatile replacements for air-sensitive trialkylphosphines. Applications in stoichiometric and catalytic processes.

Article abstract of DOI:10.1021/ol016971g

Trialkylphosphines furnish unusual, sometimes unique, reactivity in a range of transformations. Unfortunately, their utility is compromised by their sensitivity to oxidation. We have examined a simple but powerful strategy for addressing this problem: convert air-sensitive trialkylphosphines into air-stable phosphonium salts via protonation on phosphorus. These robust salts serve as direct replacements for the corresponding phosphines (simple deprotonation under the reaction conditions by a Bronsted base liberates the trialkylphosphine) in a diverse set of applications. [reaction: see text]

Full text of DOI:10.1021/ol016971g

ORGANIC
LETTERS
2001
Vol. 3, No. 26
4295-4298
Air-Stable Trialkylphosphonium Salts:
Simple, Practical, and Versatile
Replacements for Air-Sensitive
Trialkylphosphines. Applications in
Stoichiometric and Catalytic Processes
Matthew R. Netherton and Gregory C. Fu*
Department of Chemistry, Massachusetts Institute of Technology,
Cambridge, Massachusetts 02139
gcf@mit.edu
Received October 29, 2001
ABSTRACT
Trialkylphosphines furnish unusual, sometimes unique, reactivity in a range of transformations. Unfortunately, their utility is compromised by
their sensitivity to oxidation. We have examined a simple but powerful strategy for addressing this problem: convert air-sensitive
trialkylphosphines into air-stable phosphonium salts via protonation on phosphorus. These robust salts serve as direct replacements for the
corresponding phosphines (simple deprotonation under the reaction conditions by a Brønsted base liberates the trialkylphosphine) in a diverse
set of applications.
Phosphines serve as useful catalysts, reagents, and ligands
in a wide array of important organic transformations. Until
now, triarylphosphines (e.g., PPh3), which are typically air-
stable, have been the predominant focus of study. Trialkyl-
phosphines, on the other hand, have been relatively neglected,
probably as a result in large part of the fact that many are
air-sensitive, which renders them more difficult to handle
than triarylphosphines. For example, the Encyclopedia of
Reagents for Organic Synthesis provides the following
description for P(n-Bu)3:1
“Improperly stored bottles of Bu3P are invariably con-
taminated with tributylphosphine oxide and butyl dibutyl-
phosphinate.... Oxygen should be rigorously excluded to
avoid free radical chain oxidation. Tributylphosphine is
pyrophoric....”
in electron-richness (in general, trialkylphosphines . tri-
2
arylphosphines) and shape/sterics. In particular, P(n-Bu)3
3
and P(t-Bu)3 have proved to be useful in a number of
(1) Diver, S. T. In Encyclopedia of Reagents for Organic Synthesis;
Paquette, L. A., Ed.; Wiley: New York, 1995; Vol. 7, pp 5014-5016.
(2) For example, see: (a) Reduction of disulfides: Ayers, J. T.; Anderson,
S. R. Synth. Commun. 1999, 29, 351-358. Grayson, M.; Farley, C. E. Chim.
Organ. Phosphore, Colloq. Int. C.N.R.S. 1969, 182, 275-284. (b) Reduction
of azides: Afonso, C. A. M. Tetrahedron Lett. 1995, 36, 8857-8858.
Szmuszkovicz, J.; Kane, M. P.; Laurian, L. G.; Chidester, C. G.; Scahill,
T. A. J. Org. Chem. 1981, 46, 3562-3564. (c) Catalyst for Baylis-Hillman
reaction: Yamada, Y. M. A.; Ikegami, S. Tetrahedron Lett. 2000, 41, 2165-
2169. Imagawa, T.; Uemura, K.; Nagai, Z.; Kawanisi, M. Synth. Commun.
1984, 14, 1267-1273. (d) Catalyst for acylation of alcohols: Vedejs, E.;
Bennett, N. S.; Conn, L. M.; Diver, S. T.; Gingras, M.; Lin, S.; Oliver, P.
A.; Peterson, M. J. J. Org. Chem. 1993, 58, 7286-7288. See also: Vedejs,
E.; Diver, S. T. J. Am. Chem. Soc. 1993, 115, 3358-3359.
(3) For early studies, see: (a) Buchwald-Hartwig reaction: Nishiyama,
M.; Yamamoto, T.; Koie, Y. Tetrahedron Lett. 1998, 39, 617-620. Hartwig,
J. F.; Kawatsura, M.; Hauck, S. I.; Shaughnessy, K. H.; Alcazar-Roman,
L. M. J. Org. Chem. 1999, 64, 5575-5580. (b) Suzuki reaction: Littke, A.
F.; Fu, G. C. Angew. Chem., Int. Ed. 1998, 37, 3387-3388. Littke, A. F.;
Dai, C.; Fu, G. C. J. Am. Chem. Soc. 2000, 122, 4020-4028. (c) Heck
reaction: Littke, A. F.; Fu, G. C. J. Org. Chem. 1999, 64, 10-11. Littke,
There is, however, growing evidence that trialkylphos-
phines can furnish reactivity that is not generally accessible
with triarylphosphines; this dichotomy presumably arises
from differences between these two families of phosphines
10.1021/ol016971g CCC: $20.00 © 2001 American Chemical Society
Published on Web 12/05/2001

important processes, including palladium-catalyzed couplings
and Baylis-Hillman reactions. Unfortunately, P(n-Bu)3 and
P(t-Bu)3 cannot readily be handled in air because of the ease
with which they undergo oxidation.
It occurred to us that a simple but powerful strategy for
handling these phosphines would be to protect them as their
conjugate acids. According to this approach, an oxidation-
stable, easily handled phosphonium salt would be employed
as a catalyst/reagent precursor, and a weak base (e.g., (i-
Pr)2NEt) in the reaction mixture would liberate the desired
phosphine through simple acid-base chemistry.4,5
A survey of the literature revealed a precedent for the use
of a phosphonium salt as a precursor to a phosphine reagent.
In 1991, Whitesides applied tris(2-carboxyethyl)phosphine
hydrochloride as a water-soluble stoichiometric reducing
agent for disulfides.6 To the best of our knowledge, however,
the versatility of this phosphonium-salt strategy has not been
determined.
In this Letter, we establish the generality of this approach,
focusing on the phosphonium salts of P(n-Bu)3 and P(t-Bu)3.
We show that [(n-Bu)3PH]BF4 and [(t-Bu)3PH]BF4 are stable
to oxygen and to moisture and that they can be stored in air
for long periods of time (>4 months) without any detectable
deterioration. Furthermore, we demonstrate that these phos-
phonium salts can be used interchangeably with the phos-
phines themselves in a broad spectrum of processes ranging
from catalytic applications (palladium-catalyzed couplings,
acylations of alcohols, and Baylis-Hillman reactions) to
stoichiometric transformations (reductions of disulfides and
azides). We anticipate that this study will spark the develop-
ment of a wide array of applications of trialkylphosphonium
salts (trialkylphosphines) in organic synthesis.
simply serve as a spectator in the reaction of interest). Both
8
9
[(n-Bu)3PH]BF4 and [(t-Bu)3PH]BF4 have been reported
previously, as have many congeners with different counter-
ions. To date, the utility of these phosphonium salts in
synthetic organic chemistry has not been examined.
[(n-Bu)3PH]BF4 and [(t-Bu)3PH]BF4 can be synthesized
in near-quantitative yield simply by mixing a solution of the
phosphine in CH2Cl2 with a solution of aqueous HBF4 (48
wt %; ∼$40/kg from Alfa-Aesar).10 Separation of the phases
and concentration of the organic layer provide analytically
pure phosphonium salt. Alternatively, the salts will soon be
available from Strem Chemicals.11
Neither [(n-Bu)3PH]BF4 (mp 51-52 °C) nor [(t-Bu)3PH]-
BF4 (mp 261 °C, dec) shows any sign of deterioration after
1
exposure to air for several months (31P, 13C, and H NMR;
elemental analysis). Indeed, NMR spectroscopy reveals no
significant decomposition even after heating [(t-Bu)3PH]BF4
in air at 120 °C for 24 h. In view of the sensitivity of the
free phosphines, the air-stability of these salts is particularly
remarkable.12 Neither salt is hygroscopic.
Applications of [(n-Bu)3PH]BF4. P(n-Bu)3 has been
employed in synthetic organic chemistry in a number of
useful ways, including as a nucleophilic catalyst2c,d and as a
stoichiometric reducing agent.2a,b As one test of the phos-
phonium-salt strategy, we have examined the substitution
of P(n-Bu)3 with [(n-Bu)3PH]BF4 in several of these ap-
plications.13
P(n-Bu)3 serves as a mild reducing agent for a range of
functional groups. For example, Anderson has described the
synthesis of thioacetates via the reaction of disulfides with
P(n-Bu)3, followed by acylation with acetic anhydride (eq
1).2a,14 We have applied this procedure to the reduction of
diphenyl disulfide, and we have determined that [(n-Bu)3PH]-
BF4/(i-Pr)2NEt furnishes a yield identical to that provided
by the phosphine itself (eq 1).
Phosphonium Salts. Preparation and Stability. The pKa
values of the conjugate acids of P(n-Bu)3 and P(t-Bu)3 are
8.4 and 11.4, respectively.7 To maximize the likelihood that
the chemistry of the phosphonium salts will mimic that of
the free phosphines, we chose to investigate salts for which
the counterion is noncoordinating (and therefore likely to
A. F.; Fu, G. C. J. Am. Chem. Soc. 2001, 123, 6989-7000. Shaughnessy,
K. H.; Kim, P.; Hartwig, J. F. J. Am. Chem. Soc. 1999, 121, 2123-2132.
(d) Stille reaction: Littke, A. F.; Fu, G. C. Angew. Chem., Int. Ed. 1999,
38, 2411-2413. Littke, A. F.; Schwarz, L.; Fu, G. C. Manuscript in
preparation. (e) Arylation of carbonyl compounds: Kawatsura, M.; Hartwig,
J. F. J. Am. Chem. Soc. 1999, 121, 1473-1478. (f) Arylation of alcohols:
Mann, G.; Incarvito, C.; Rheingold, A. L.; Hartwig, J. F. J. Am. Chem.
Soc. 1999, 121, 3224-3225. (g) Hiyama reaction: Denmark, S. E.; Wu,
Z. Org. Lett. 1999, 1, 1495-1498. (h) Sonogashira reaction: Hundertmark,
T.; Littke, A. F.; Buchwald, S. L.; Fu, G. C. Org. Lett. 2000, 2, 1729-
1731. Bo¨hm, V. P. W.; Herrmann, W. A. Eur. J. Org. Chem. 2000, 3679-
3681. (i) Kumada reaction: Bo¨hm, V. P. W.; Weskamp, T.; Gsto¨ttmayr,
C. W. K.; Herrmann, W. A. Angew. Chem., Int. Ed. 2000, 39, 1602-1604.
(j) Negishi reaction: Dai, C.; Fu, G. C. J. Am. Chem. Soc. 2001, 123, 2719-
2724.
(8) (a) Muskopf, J. W.; Bertram, J. L.; Walker, L. L. U.S. Patent 5,-
140,079, 1992. (b) Perron, R.; Mutez, S. U.S. Patent 4,927,957, 1990. (c)
Grenouillet, P.; Neibecker, D.; Tkatchenko, I. U.S. Patent 4,889,949, 1989.
(9) Jia, G.; Morris, R. H. J. Am. Chem. Soc. 1991, 113, 875-883.
(10) Roberts, N. K.; Wild, S. B. J. Am. Chem. Soc. 1979, 101, 6254-
6260.
(11) Dr. Mike Strem, personal communication.
(12) Approximately half of the trialkylphosphine is consumed in 20 min
for P(n-Bu)3 and 4 min for P(t-Bu)3, when a 0.1 M solution in THF is
vigorously stirred in air. In contrast, the corresponding phosphonium salts
show no decomposition after weeks in solution.
(4) Dialkylphosphine oxides have been employed as precursors to
dialkylphosphinous acids, via tautomerization: Li, G. Y. Angew. Chem.,
Int. Ed. 2001, 41, 1513-1516.
(5) In situ deprotonation has been used to generate metal-carbene
complexes from imidazolium salts. For example, see: Zhang, C.; Huang,
J.; Trudell, M. L.; Nolan, S. P. J. Org. Chem. 1999, 64, 3804-3805. Huang,
J.; Nolan, S. P. J. Am. Chem. Soc. 1999, 121, 9889-9890.
(6) Burns, J. A.; Butler, J. C.; Moran, J.; Whitesides, G. M. J. Org. Chem.
1991, 56, 2648-2650.
(7) For an extensive compilation of pKa values for tertiary phosphines,
see: Rahman, M. M.; Liu, H.-Y.; Eriks, K.; Prock, A.; Giering, W. P.
Organometallics 1989, 8, 1-7.
(13) Notes: (a) Each reaction was first conducted according to the
published conditions. Then, it was repeated using [(n-Bu)3PH]BF4/base in
place of P(n-Bu)3, with all other reaction parameters unchanged. (b) In each
instance, the Brønsted base was required in order for the phosphonium salt
to serve as a suitable substitute for the phosphine.
(14) The PBu3-mediated reduction of a disulfide to a thiol is a key step
in Bristol-Myers Squibb’s synthesis of Vanlev, a vasopeptidase inhibitor
that is currently in Phase 3 clinical trials: Scott, John W. Presented at Chiral
USA 2000, Boston, MA, 2000.
4296
Org. Lett., Vol. 3, No. 26, 2001

Trialkylphosphines such as P(n-Bu)3 are often employed
in the reduction of azides to amines,2b,15,16 which can be
tosylated in situ to produce sulfonamides (eq 2). For n-octyl
Table 1. Suzuki Cross-Couplings Using [(t-Bu)3PH]BF4
azide, P(n-Bu)3 and [(n-Bu)3PH]BF4/(i-Pr)2NEt achieve this
one-pot transformation with similar efficiency (eq 2).
P(n-Bu)3 has been applied in organic synthesis not only
as a stoichiometric reagent but also as a catalyst. For
example, Ikegami has recently described the use of P(n-Bu)3/
PhOH in Baylis-Hillman reactions (eq 3).2c We have
a Isolated yields; average of two runs. b Literature yields, using P(t-Bu)3
(ref 3b), are reported in parentheses.
coupling reactions.3 However, as with P(n-Bu)3, the air-
sensitivity of P(t-Bu)3 has impeded the application of this
useful reagent. As a second test of the phosphonium-salt
strategy, we have investigated the replacement of P(t-Bu)3
with [(t-Bu)3PH]BF4 in a representative cross section of
palladium-catalyzed processes.17
Because most palladium-catalyzed coupling reactions that
employ P(t-Bu)3 as a ligand also require Brønsted-base
additives, we envisioned that simply substituting the P(t-
Bu)3 in the original Pd2(dba)3/P(t-Bu)3 protocols with [(t-
Bu)3PH]BF4 would lead to comparable results. To furnish
support for this hypothesis, we undertook a series of 31P
NMR studies.
In the absence of a Brønsted base, the addition of Pd2-
(dba)3 to a solution of [(t-Bu)3PH]BF4 in THF (δ 52; slightly
soluble) leads to no change in the 31P NMR spectrum. After
KF, Cy2NMe, CsF, or HN(i-Pr)2 is added, the resonance for
[(t-Bu)3PH]BF4 disappears, and one new signal appears (δ
86), corresponding to Pd(P(t-Bu)3)2.18 In the case of amines,
this transformation occurs rapidly at room temperature and
is accompanied by precipitation of the ammonium tetrafluo-
roborate salt. In the case of non-amine (heterogeneous) bases,
the reaction is slower, requiring up to 2 h to proceed to
completion.
We have evaluated four palladium-catalyzed coupling
processes for which Pd/P(t-Bu)3 has been shown to be an
active catalyst (Suzuki,3b Heck,3c Stille,3d and Sonogashira3h
reactions). In each instance, we have replaced P(t-Bu)3 with
an equimolar amount of [(t-Bu)3PH]BF4, and we have kept
the quantities of all other components the same.
established that [(n-Bu)3PH]BF4/PhONa affords the desired
product with an isolated yield that is comparable to that
furnished by Ikegami’s procedure (eq 3). Within minutes of
mixing [(n-Bu)3PH]BF4 with PhONa, a white precipitate
(NaBF4) appears, signaling that free phosphine has been
generated.
Another process for which P(n-Bu)3 serves as a catalyst
is the acylation of alcohols by anhydrides, a reaction
discovered by Vedejs (eq 4).2d We have determined that [(n-
Bu)3PH]BF4, in the presence of a mild base such as NaOBz
or (i-Pr)2NEt, is as effective as the phosphine itself (eq 4).
Applications of [(t-Bu)3PH]BF4. During the past few
years, P(t-Bu)3 has emerged as an unusually powerful ligand
for a broad spectrum of palladium- and nickel-catalyzed
(15) The PMe3-mediated reduction of an azide to an amine is a key step
in Bristol-Myers Squibb’s synthesis of epothilone B-lactam (BMS-247550),
an anticancer agent that is currently undergoing clinical trials: Borzilleri,
R. M.; Zheng, X.; Schmidt, R. J.; Johnson, J. A.; Kim, S.-H.; DiMarco, J.
D.; Fairchild, C. R.; Gougoutas, J. Z.; Lee, F. Y. F.; Long, B. H.; Vite, G.
D. J. Am. Chem. Soc. 2000, 122, 8890-8897. Other methods (including
PPh3) for reducing the azide are less effective. We have synthesized [Me3-
PH]BF4 (from PMe3 and HBF4 (52 wt % in Et2O) in THF) and determined
that, like [(n-Bu)3PH]BF4 and [(t-Bu)3PH]BF4, it is an air-stable, crystalline
solid (mp 212-213 °C).
The data in Table 1 establish that air-stable [(t-Bu)3PH]-
(17) We have recently established that use of air-stable Pd(P(t-Bu)3)2,
sometimes in conjunction with Pd2(dba)3, can circumvent the need to handle
P(t-Bu)3 in palladium-catalyzed coupling reactions: (a) Dai, C.; Fu, G. C.
J. Am. Chem. Soc. 2001, 123, 2719-2724. (b) Littke, A. F.; Fu, G. C. J.
Am. Chem. Soc. 2001, 123, 6989-7000.
(16) For an overview of the Staudinger reaction, see: Gololobov, Y.
G.; Kasukhin, L. F. Tetrahedron 1992, 48, 1353-1406.
Org. Lett., Vol. 3, No. 26, 2001
4297

Table 2. Heck Reactions Using [(t-Bu)3PH]BF4
Table 3. Stille Cross-Couplings Using [(t-Bu)3PH]BF4
a Isolated yields; average of two runs. b Literature yields, using P(t-Bu)3
(ref 3d), are reported in parentheses.
a Isolated yields; average of two runs. b Literature yields, using P(t-Bu)3
(ref 3c), are reported in parentheses. c The E olefin is produced with >20:1
E:Z selectivity.
unusual, sometimes unique, reactivity in an array of pro-
cesses. Unfortunately, the practical utility of many trialky-
lphosphines is compromised by their sensitivity to oxidation,
which can render them difficult to handle. To address this
problem, we have examined a simple but powerful strategy:
conversion of air-sensitive trialkylphosphines into storable,
air-stable phosphonium salts by way of protonation on
phosphorus.
We have demonstrated that these robust salts can indeed
serve as direct replacements for the corresponding phos-
phines; simple deprotonation under the reaction conditions
by a Brønsted base liberates the trialkylphosphine. Thus,
phosphonium salts are interchangeable with phosphines in
a diverse set of processes ranging from stoichiometric to
catalytic uses. We anticipate that this study will provide a
powerful stimulus to the development of applications of
trialkylphosphines in organic synthesis.
BF4 is indeed a suitable substitute for air-sensitive P(t-Bu)3
in Suzuki cross-coupling reactions. Thus, we obtain com-
parable (within 5%) isolated yields for a cross section of
aryl and vinyl halides under the same mild conditions. Table
2 demonstrates that the phosphonium salt may also be used
instead of the free phosphine in Heck couplings of chlorides
and bromides, with similar or even improved efficiency (up
to 14% higher yield). Furthermore, we can replace P(t-Bu)3
with [(t-Bu)3PH]BF4 in Stille reactions of aryl halides (Table
3). Finally, we have determined that the phosphine and the
phosphonium salt are interchangeable in Sonogashira cou-
plings of aryl bromides (eq 5), furnishing comparable
yields.19
Acknowledgment. Support has been provided by Bristol-
Myers Squibb, Merck, the National Institutes of Health
(National Institute of General Medical Sciences, R01-
GM62871), the Natural Sciences and Engineering Research
Council of Canada (postdoctoral fellowship to M.R.N.),
Novartis, and Pfizer. We thank Frontier Scientific for
donating arylboronic acids.
Conclusions. Trialkylphosphines are beginning to emerge
as important reagents in organic synthesis as a result of their
(18) (a) Otsuka, S.; Yoshida, T.; Matsumoto, M.; Nakatsu, K. J. Am.
Chem. Soc. 1976, 98, 5850-5858. (b) Yoshida, T.; Otsuka, S. Inorg. Synth.
1990, 28, 113-119.
(19) Notes: (a) For the couplings in Tables 1-3 that require elevated
temperature, the reaction mixtures are first stirred at room temperature for
1 h, and then they are heated to the indicated temperature. This ensures
that free P(t-Bu)3 is available to coordinate to the low-valent metal complex.
(b) For each coupling process in Tables 1-3 and eq 5, the reaction proceeds
to completion in comparable time with Pd/P(t-Bu)3 and Pd/[(t-Bu)3PH]BF4.
Supporting Information Available: Experimental pro-
cedures and compound characterization data. This material
is available free of charge via the Internet at http://pubs.acs.org.
OL016971G
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Org. Lett., Vol. 3, No. 26, 2001