Synthesis of symmetrical triarylphosphines from aryl fluorides and red phosphorus: Scope and limitations

Article abstract of DOI:10.1016/S0040-4039(01)01059-0

The reaction of aryl fluorides with phosphide anion, generated in situ from the reduction of red phosphorus by lithium metal in liquid ammonia, gave symmetrical triarylphosphines in fair to good yields. Phosphonodiamide, sulfonamide, 2-oxazolyl, and nitrile groups were stable to the reaction conditions, while nitro and bromo substituents were not. para-Substituted aryl fluorides gave higher yields than meta-substituted aryl fluorides, and ortho-substituted aryl fluorides failed to react.

Full text of DOI:10.1016/S0040-4039(01)01059-0

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 5373–5376
Synthesis of symmetrical triarylphosphines from aryl fluorides
and red phosphorus: scope and limitations
Terence L. Schull,* Susan L. Brandow and Walter J. Dressick
Center for Bio/Molecular Science and Engineering, Code 6950, U.S. Naval Research Laboratory, 4555 Overlook Avenue, SW,
Washington, DC 20375-5348, USA
Received 29 May 2001; revised 14 June 2001; accepted 15 June 2001
Abstract—The reaction of aryl fluorides with phosphide anion, generated in situ from the reduction of red phosphorus by lithium
metal in liquid ammonia, gave symmetrical triarylphosphines in fair to good yields. Phosphonodiamide, sulfonamide, 2-oxazolyl,
and nitrile groups were stable to the reaction conditions, while nitro and bromo substituents were not. para-Substituted aryl
fluorides gave higher yields than meta-substituted aryl fluorides, and ortho-substituted aryl fluorides failed to react. © 2001
Published by Elsevier Science Ltd.
Functionalized triarylphosphines are widely used as
ligands for transition metal complexes1 and as synthetic
intermediates for the preparation of novel materials.2
The classical method for preparing triarylphosphines
involves the reaction of Grignard reagents or aryl-
lithium reagents with phosphorus halides.3 More recent
methods include the palladium-catalyzed phosphination
of aryl triflates using triarylphosphines,4 the palladium-
catalyzed coupling of aryl halides with trimethylstan-
nyl- or trimethylsilyldiphenylphosphines,5 nucleophilic
phosphanylation of aryl fluorides in superbasic media,6
palladium-catalyzed P-C cross-coupling reactions of
primary and secondary phosphines with functionalized
aryl iodides,7 or a combination of nucleophilic phos-
phanylation and palladium-catalyzed P-C coupling.8
The surprising result of this preparation was that the
triarylphosphine was formed almost exclusively, even
when sub-stoichiometric amounts of the aryl fluoride
precursor were used. The selectivity of the reaction and
convenience of the preparation prompted us to investi-
gate whether this methodology was general in scope.
In a typical reaction,9 a suspension of red phosphorus
in liquid ammonia is stirred with three equivalents of
lithium metal in the presence of one equivalent of
tert-butanol, added slowly as a 10% solution in THF.
The presence of a proton donor accelerates the reduc-
tion of the red phosphorus and is believed to result in
an equilibrium mixture of H2P− and LiNH2.10 A THF
solution of the aryl fluoride is then added dropwise and
the reaction is stirred at reflux (−33°C).
Our interest in the symmetrical triarylphosphine P(4-
C6H4PO3Na2)3, triphenylphosphine triphosphonate
(TPPTP), led us to the development of a synthesis of
this compound,9 which combines the nucleophilic aro-
matic substitution chemistry of aryl fluorides with the
in situ formation of phosphide anion in liquid ammonia
using red phosphorus and alkali metals.10 In this way,
the use of the very expensive and toxic phosphine gas
was avoided.
With reactive substrates, an immediate color change is
observed, and the reaction mixture becomes a deep red
by the end of the addition. In these cases, the dry ice in
the Dewar condenser is not replenished, and the liquid
ammonia is allowed to slowly evaporate while stirring
the reaction mixture at room temperature overnight.
The work-up consists simply of adding water and ether
to the residual reaction mixture, filtering if necessary,
and separation of the phases.
We have found that the reaction is restricted to acti-
vated aryl fluorides containing electron-withdrawing
groups in the para- or meta-position. In contrast to
nucleophilic phosphanylations with PH3 in DMSO6a or
Ph2PK in DME or THF,11 the reaction failed for
ortho-substituted aryl fluorides, presumably because
Keywords: aryl fluoride; liquid ammonia; lithium phosphide; red
phosphorus; triarylphosphine.
* Corresponding author. Tel.: (202) 404-6043; fax: (202) 767-9594;
e-mail: tls@cbmse.nrl.navy.mil
0040-4039/01/$ - see front matter © 2001 Published by Elsevier Science Ltd.
PII: S0040-4039(01)01059-0

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T. L. Schull et al. / Tetrahedron Letters 42 (2001) 5373–5376
steric or electronic effects unfavorable to nucleophilic
aromatic substitution cannot be overcome at the low
reaction temperatures. Phosphonodiamide, sulfon-
amide, and 2-oxazolyl substituents were found to be
compatible with the reaction conditions, but a bromo
substituent was not. Nitrile groups may be used at low
temperatures (−78°C), while nitro groups were not tol-
erated even at low temperatures. The results are sum-
marized in Table 1.
The method is somewhat limited by the availability of
aryl fluoride precursors. For the preparation of phos-
phonate-substituted triaryl phosphines, fluoroaryl phos-
phonodiamides are the precursors of choice. In contrast
to phosphonodiesters,8,9,14 the phosphonodiamide moi-
ety is stable to the reaction conditions, yet can be
readily hydrolyzed to the corresponding phosphonic
acid by refluxing in dilute HCl.
Aryl phosphonodiamides are most easily prepared by
the reaction of an aryllithium reagent with N,N,N%,N%-
tetraalkylphosphonodiamidic halides. Thus, N,N,N%,N%-
tetramethyl-(4-fluorophenyl) phosphonodiamide was
readily prepared by metal–halogen exchange of 1-
bromo-4-fluorobenzene with n-butyllithium, and reac-
tion of the resulting 4-fluorophenyllithium with
N,N,N%,N%-tetramethyl phosphonodiamidic chloride in
THF at −78°C.9 However, this method failed for ortho-
or meta-bromofluorobenzenes because of competing
benzyne formation.
The use of 2-fluoropyridine as a substrate deserves
additional comment. The addition of 2-fluoropyridine
to the phosphide solution resulted in darkening of the
reaction mixture from yellow to brown to deep red,
characteristic of all the successful reactions. After
overnight stirring, 31P{1H} NMR analysis of the reac-
tion mixture showed very little product in the region
expected for a triarylphosphine. The major product
appeared at 14.6 ppm, with only a small peak at −4.4
ppm, assigned to P(2-Pyr)3, in approximately a 20:1
ratio.
The meta-substituted aryl fluoride precursor N,N,N%,N%-
The resonance at 14.6 ppm was consistent with the
formation of the known compound [(THF)2Li(m-
Pyr)2P] (1), l 13.0 (CDCl3), an unusual structure with a
divalent phosphorus atom.13
tetramethyl-(3-fluorophenyl)phosphonodiamide
was
prepared in low yield by the reaction of the Grignard
reagent derived from 1-bromo-3-fluorobenzene and
N,N,N%,N%-tetramethylphosphono diamidic chloride in
THF at reflux. A significant amount of the Grignard
homocoupling product difluorobiphenyl was formed
instead, which was identified by GC/MS analysis. The
sluggish reaction of Grignard reagents with the phos-
phonodiamidic chloride is in sharp contrast to the
reaction with aryllithium reagents.
Heating of the reaction mixture (2 h, reflux) changed
the ratio of the areas of the peaks assigned to 1 and
P(2-Pyr)3 to 2.5:1. Overnight heating resulted in
decomposition.
The ortho-substituted aryl fluoride precursor N,N,N%,N%-
tetraethyl-(2-fluorophenyl)phosphonodiamide was pre-
pared in a multistep sequence: Diethyl 2-fluorophenyl
phosphonate was prepared by the palladium-catalyzed
reaction of 1-bromo-2-fluorobenzene and diethyl phos-
phite.15 The ester was cleaved by transesterification with
bromotrimethylsilane16 followed by methanolysis to
give the free acid. The phosphonic acid was converted
to the phosphonyl dichloride by refluxing in thionyl
chloride, and finally to the diamide by treatment with
diethylamine.
Table 1. The reaction of phosphide anion with aryl
fluorides in liquid ammonia/THF
Entry Substrate
Producta
Yieldb
1
2-FC5H4N
[Li(2-Pyr)2P·2THF]c
(Not isolated)
2
3
4
5
6
7
8
9
2-FC6H4OMe
No reaction
Attempts to prepare aryl phosphonodiamides by the
palladium(0)-catalyzed coupling of bis(diethylamido)-
phosphite, (Et2N)2P(O)H,17 with aryl iodides
(Pd(PPh3)4/Et3N/THF or Pd(OAc)2-dppe/Et3N/THF)
were unsuccessful, as was the use of a Hiyama-type
2-FC6H4P(O)(NEt2)2 No reaction
3-FC6H4P(O)(NMe2)2 P[3-C6H4PO3H2]3·2H2O 37d
3-FC6H4-oxe
No reaction
4-FC6H4P(O)(NMe2)2 P[4-C6H4P(O)(NMe2)2]3 60
4-FC6H4-ox
P(4-C6H4-ox)3
P(4-C6H4SO2NEt2)3
P(4-C6H4CN)3
Uncharacterized mixture
Uncharacterized mixture
36
54
37f
4-FC6H4SO2NEt2
4-FC6H4CN
4-FC6H4Br
cross-coupling reaction18 with (Et2N)2P(O)SiMe3
19
(Pd2(dba)3/AsPh3/TBAF/THF).
10
11
4-FC6H4NO2
In our previous attempts to react a fluoroaryl phospho-
nate salt directly with phosphide anion in NH3/THF,9 it
was found that the low solubility of the disodium salt
led to no reaction of the aryl fluoride. In this study we
observed that the lithium salt of 4-fluorobenzoic acid,
prepared by carefully titrating a THF solution of 4-
fluorobenzoic acid with n-BuLi at −78°C, was soluble
in the reaction mixture. The lithium carboxylate was
a All products had satisfactory 31P and 1H NMR spectra.12
b Isolated yield after work-up and purification by column chromatog-
raphy or crystallization.
c Identified from 31P NMR analysis of reaction mixture (cf. Ref. 13).
d Isolated as phosphonic acid dihydrate after hydrolysis of crude
phosphonodiamide in 2.4 M HCl and crystallization.
e ox=4,5-dimethyl-2-oxazol-2-yl.
f Reaction carried out at −78°C.

T. L. Schull et al. / Tetrahedron Letters 42 (2001) 5373–5376
5375
not soluble in THF alone, so it was added in small
portions directly to the reaction mixture. The reaction
was quite sluggish, however, and did not go to comple-
tion. 31P NMR analysis of the crude product after
work-up showed approximately a 4:1 ratio of tertiary
and secondary phosphines, along with a small amount
of diarylphosphine oxide. 19F NMR analysis confirmed
the presence of some unreacted starting material as
well.20 The mixture of carboxylated phosphines and
starting material could not be satisfactorily purified.
For this reason we chose to prepare the more soluble
oxazoline derivatives of 3- and 4-fluorobenzoic acids.
4. (a) Kwong, F. Y.; Chan, K. S. Organometallics 2000, 19,
2058–2060; (b) Kwong, F. Y.; Chan, K. S. J. Chem. Soc.,
Chem. Commun. 2000, 1069–1070.
5. Tunney, S. E.; Stille, J. K. J. Org. Chem. 1987, 52,
748–753.
6. (a) Herd, O.; Langhans, K. P.; Stelzer, O.; Weferling, N.;
Sheldrick, W. S. Angew. Chem., Int. Ed. Engl. 1993, 32,
1058–1059; (b) Herd, O.; Hessler, A.; Langhans, K. P.;
Stelzer, O.; Sheldrick, W. S.; Weferling, N. J. Organomet.
Chem. 1994, 475, 99–111; (c) Bitterer, F.; Herd, O.;
Hessler, A.; Ku¨hnel, M.; Rettig, K.; Stelzer, O.;
Sheldrick, W. S.; Nagel, S.; Ro¨sch, N. Inorg. Chem. 1996,
35, 4103–4113.
Several attempts were made to convert 4-fluorobenzoic
acid to its 2-oxazoline derivative, either by refluxing the
benzoic acid with 2-amino-2-methylpropanol in tolu-
ene,21 or conversion of the benzoic acid to the acid
chloride, followed by condensation with 2-amino-2-
methylpropanol to form the amide, and cyclization
with thionyl chloride.22 In our hands, neither of these
procedures worked very well. The 2-oxazoline deriva-
tives, 4,4-dimethyl-2-(4-fluorophenyl)-2-oxazoline and
4,4-dimethyl-2-(3-fluorophenyl)-2-oxazoline, were even-
tually prepared by the palladium(0)-catalyzed
coupling23 of 4,4-dimethyl-2-(tri-n-butylstannyl)-2-oxa-
zoline with 1-bromo-4-fluorobenzene and 1-bromo-3-
fluorobenzene, respectively. Surprisingly, while the
para-substituted aryl fluoride reacted cleanly with phos-
phide anion, the meta-isomer did not react at all.
7. Herd, O.; Hessler, A.; Hingst, M.; Tepper, M.; Stelzer, O.
J. Organomet. Chem. 1996, 522, 69–76.
8. Machnitzki, P.; Nickel, T.; Stelzer, O.; Landgrafe, C. Eur.
J. Inorg. Chem. 1998, 1029–1034.
9. Dressick, W. J.; George, C.; Brandow, S. L.; Knight, D.
A.; Schull, T. L. J. Org. Chem. 2000, 65, 5059–5062.
10. (a) Brandsma, L.; Arbuzova, S.; de Lang, R.-J.;
Gusarova, N.; Trofimov, B. Phosphorus, Sulfur Silicon
1997, 126, 125–128; (b) Trofimov, B.; Gusarova, N.;
Brandsma, L. Main Group Chem. News 1996, 4, 18–24;
(c) Arbuzova, S. N.; Brandsma, L.; Gusarova, N. K.;
Trofimov, B. A. Recl. Trav. Chim. Pays-Bas 1994, 113,
575–576.
11. Hingst, M.; Tepper, M.; Stelzer, O. Eur. J. Inorg. Chem.
1998, 73–82.
12. Full experimental details for the preparation of P[4-
C6H4P(O)(NMe2)2]3 are given in Ref. 9. The preparation
of P[3-C6H4PO3H2]3·2H2O is described here for conve-
nience. To a suspension of red phosphorus (0.341 g, 0.011
mol) in liquid ammonia (ca. 100 mL) was added pieces of
lithium metal (0.290 g, 0.033 mol). After stirring for 10
min, a solution of t-BuOH (1.05 mL, 0.011 mol) in THF
(10 mL) was slowly added over the course of 70 min. The
deep blue color of the reaction mixture gradually dis-
charged, changing from blue to green to yellow. A solu-
tion of 3-FC6H4P(O)(NMe2)2 (3.45 g, 0.015 mol) in THF
(15 mL) was then added dropwise. Reflux was main-
tained for approximately four hours; thereafter the liquid
ammonia was allowed to evaporate overnight. To the
resulting deep red suspension was added deareated water
(20 mL) and ether (20 mL). After stirring vigorously for
several minutes, the phases were separated and the
aqueous phase was filtered through a pad of Celite.
(Note: for P(4-C6H4-ox)3, P(4-C6H4SO2NEt2)3, and P(4-
C6H4CN)3, the product is found in the organic phase,
and is isolated simply by filtering and removal of sol-
vent.) The pad was washed through with additional por-
tions of water, bringing the total volume of filtrate to 50
mL. The filtrate was acidified with 10 mL conc. HCl and
heated to boiling while sparging with nitrogen gas. A
gum was produced which eventually redissolved with
persistent stirring and heating, giving a pale yellow solu-
tion. Upon cooling an oil formed, from which a nearly
colorless supernate was decanted. Overnight cooling of
the supernate resulted in the formation of white crystals,
1.0 g after filtering and air drying. 31P NMR (CD3OD): l
In summary, we have shown that activated aryl
fluorides can react with phosphide anion in liquid
ammonia/THF to give tertiary phosphines in fair to
good yields. Although limited in scope, this method can
provide easy access to some functionalized triarylphos-
phines without the use of phosphine gas.
Acknowledgements
The authors gratefully acknowledge Dr. John Callahan
of the NRL Chemistry Division, Code 6115, for the
mass spectral analyses. Financial support for this work
was provided by the Office of Naval Research under
the NRL Core Funding program.
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1
15.7 (s, PO), −4.3 (s, P); H NMR (D2O/CD3OD): l 7.68
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T. L. Schull et al. / Tetrahedron Letters 42 (2001) 5373–5376
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.