Switching on and off metalation sites in triarylphosphines by manipulating substrate coordination

Article abstract of DOI:10.1055/s-1998-2099

The inductive electron-withdrawing effect of the positively charged phosphorus atom in triarylphosphine-borane adducts is largely compensated by the steric congestion caused in its vicinity. Therefore, trihydro(triphenylphosphonio)borate reacts only sluggishly even with superbasic reagents and products derived from ortho-metalated intermediates by their trapping with electrophiles are formed only in poor yield. On the other hand, the borane adducts of (3-anisyl)diphenylphosphine and (3- fluorophenyl)diphenylphosphine can be readily deprotonated at the hetero- adjacent para position and converted into final products in high yields. The phosphorus-remote regioselectivity of these phosphine-borane zwitterions is complementary to that previously observed with the corresponding phosphine oxides.

Full text of DOI:10.1055/s-1998-2099

SYNTHESIS
July 1998
983
Switching On and Off Metalation Sites in Triarylphosphines by Manipulating
Substrate Coordination
Olivier Desponds, Cyril Huynh, Manfred Schlosser*
Institut de Chimie organique de l'Université, Bâtiment de Chimie (BCh), CH-1015 Lausanne, Switzerland
Fax +41(21)6923965
Received 15 August 1997
Abstract: The inductive electron-withdrawing effect of the posi-
Species structurally related to triphenylphosphine oxide
such as N-(triphenylphosphonio)anilide8 and (triphe-
nylphosphonio)methanide9 can equally be submitted to an
ortho-selective hydrogen/metal exchange. We wondered
how triarylphosphine–borane10 adducts would behave in
this respect. Since the preparation of such zwitterions is as
simple as their cleavage back to the components, they
could act as turntables promoting the site-controlled elec-
trophilic substitution of aromatic phosphines.
tively charged phosphorus atom in triarylphosphine–borane
adducts is largely compensated by the steric congestion caused in
its vicinity. Therefore, trihydro(triphenylphosphonio)borate reacts
only sluggishly even with superbasic reagents and products
derived from ortho-metalated intermediates by their trapping with
electrophiles are formed only in poor yield. On the other hand, the
borane adducts of (3-anisyl)diphenylphosphine and (3-fluorophe-
nyl)diphenylphosphine can be readily deprotonated at the hetero-
adjacent para position and converted into final products in high
yields. The phosphorus-remote regioselectivity of these phos-
phine–borane zwitterions is complementary to that previously
observed with the corresponding phosphine oxides.
The parent compound trihydro(triphenylphosphonio)bo-
rate was found not to react with phenyllithium at all and
with the superbasic mixture11,12 of butyllithium and potas-
sium tert-butoxide only sluggishly. While much starting
material was recovered, only 19% of (2-iodophe-
nyl)diphenylphosphine (4) were obtained after iodination.
Extended reaction times had obviously caused an alcoho-
late assisted deborylation.13 On the other hand, the super-
base promoted metalation proceeded rapidly and
smoothly when (3-anisyl)diphenylphosphine–borane was
employed as the substrate, and no spontaneous deboryla-
tion occurred. However, (4-iodo-3-methoxyphenyl)di-
phenylphosphine–borane (5; 62%) rather than the expect-
ed 2-iodo isomer was formed upon iodination. Similarly,
the 3-fluoro analog exclusively afforded (3-fluoro-4-io-
dophenyl)diphenylphosphine–borane (6; 78%). This
time, tert-butyllithium sufficed to bring about the metala-
tion, no superbasic reagent being required.
Key words: ortho-metalation, optional site selectivities, super-
bases, phosphine–borane adducts, phosphine ligands
Triphenylphosphine oxide undergoes selective monomet-
alation at one of its six ortho positions when treated with
phenyllithium in diethyl ether or tetrahydrofuran1, 2 [53%
of 2-(diphenylphosphino)benzoic acid1 and 73% of (2-io-
dophenyl)diphenylphosphine oxide2 (1) after reaction
with dry ice and iodine, respectively]. The simultaneously
occurring aryl/aryl exchange remains unnoticed unless
isotopically labeled substances are employed.3, 4 The in-
troduction of an electronegative atom or group into the
meta position of the substrate enhances the acidity at the
doubly activated site flanked by the two substituents to
such an extent that deprotonation can already be accom-
plished with lithium diisopropylamide. Thus, (3-ani-
syl)diphenylphosphine oxide5,6 and (3-fluorophenyl)-
diphenylphosphine oxide7 easily undergo ortho-lithiation
and subsequent iodination to afford precursors to Ullmann-
coupled biaryls [76% of (2-iodo-3-methoxyphenyl)diphe-
nylphosphine oxide (2)5 and 85% of (3-fluoro-2-iodophe-
nyl)diphenylphosphine oxide (3)7, respectively].
(3-Anisyl)diphenylphosphine and (3-fluorophenyl)diphe-
nylphosphine can be submitted to a hydrogen/metal inter-
conversion at the 4-position using butyllithium in the
presence of potassium tert-butoxide and, respectively,
tert-butyllithium even without prior coordination. Under

SYNTHESIS
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984
tiplet). MS were obtained by chemical ionization in an ammonia at-
mosphere at 100 °C source temperature. Elemental analyses were
executed by the laboratory of I. Beetz, D-96301 Kronach.
the conditions of direct metalation, however, the yields
are poor (44% and 37%, respectively) and the structural
integrity is imperfect (aryl/alkyl substitution at phospho-
rus being a major side reaction).
(3-Fluorophenyl)diphenylphosphine–Borane:
A solution of (3-fluorophenyl)diphenylphosphine7 (56 g, 0.20 mol) in
THF (0.25 L) was added, over the course of 30 min, to an ice-cold
suspension of borane (0.21 mol) in THF (0.37 L) which had been
prepared15 from NaBH4 (8.1 g, 0.21 mol) and BF3•ΟΕt2 (30 mL, 34 g,
0.24 mol). After 3 h at 0°C, the mixture was filtered and the solvent
evaporated. The white powder left behind was washed with chilled
water (2 × 0.20 L) and dried on burned clay. The crude product was
triturated with hot i-PrOH (40 mL) to afford white crystals; mp
108–111°C (mp 109–111°C after recrystallization from hexane/tolu-
ene 2:1); yield: 48 g (81%).
The differences in reactivity and site selectivity exhibited
by triarylphosphine oxides and triarylphosphine–borane
adducts are striking. Manifestly, efficacious coordination
of organometallic reagents requires the presence of non-
bonding (“free”) electron pairs at the phosphorus-attached
center. The electrostatic attraction provided by the nega-
tively charged boron atom is not enough. Obviously, met-
als seek to get engaged in partially covalent bonds (i.e.
space-oriented interactions with electrons) at both ground
and transition states. A description of such structures in
terms of ion pair or ion multiplet assemblies may lead to
wrong conclusions.
1H NMR: δ = 7.2 (6 H, m), 7.4 (6 H, m), 7.3 (1 H, m), 7.19 (1 H, t, J
= 8.2 Hz, broad), 1.3 (3 H, m, broad).
31P NMR: δ = 21.8.
MS (CI): m/z (%) = 310 (0.8, M+ + NH4 – 2), 294 (0.9, M+), 293 (4.1,
M+ – 1), 280 (100), 201 (8.1), 183 (13).
In conclusion, the diphenyl(trihydroborato)phosphonio
group establishes little, if any, coordinative interaction
with organometallic reagents. It does activate an aromatic
ring to which it is attached, but it does so only by inductive
electron withdrawal. However, this effect is not powerful
enough to overcompensate to a sufficient extent the steric
hindrance caused by this bulky substituent. As a conse-
quence, no or little ortho-metalation is observed. On the
other hand, phosphonioborates with an electronegative
meta-substituent (e.g., fluorine or methoxy) readily un-
dergo a hydrogen/metal exchange reaction at the para-po-
sition, the phosphonio unit providing long-range
assistance. By analogy, para-heterosubstituted phospho-
nioborates can be assumed to be attacked at the meta and,
again, not at the ortho position.
Anal. calcd for C18H17BFP (294.12) C 73.51, H 5.83; found C 73.76,
H 5.79.
(3-Methoxyphenyl)diphenylphosphine–Borane:
Obtained analogously by allowing (3-methoxyphenyl)diphenyl-
phosphine5 (60 g, 0.20 mol) to react with borane (0.21 mol) in THF
(0.37 L). After 1 h at 0°C, the mixture was worked up as described
above to afford white crystals; mp 125–127°C (mp 126.5–128°C af-
ter recrystallization from benzene/hexane 1:1); yield: 56 g (91%).
1H NMR: δ = 7.58 (4 H, ddm, J = 10.9, 7.0 Hz), 7.51 (2 H, tq, J = 7.5,
1.4 Hz), 7.43 (4 H, tm, J = 7.3 Hz), 7.35 (1 H, td, J = 7.8, 3.1 Hz), 7.1
(2 H, m), 7.03 (1 H, dm, J = 8.2 Hz), 3.77 (3 H, s), 1.3 (3 H, m, broad).
31P NMR: δ = 21.7.
MS (CI): m/z (%) = 307 (100, M+ + 1), 293 (1.9), 231 (3.2), 199 (3.1),
152 (2.5).
Anal. calcd for C19H20BOP (306.15) C 74.54, H 6.58; found C 74.80,
H 6.53.
(2-Iodophenyl)diphenylphosphine (4):
Starting materials were purchased from Fluka (CH-9470 Buchs), Al-
drich (D-89552 Steinheim) and Merck (D-64271 Darmstadt), unless
literature sources or details of the preparation are given. BuLi in hex-
ane (1.5 M and “11.5 M”, i.e. containing the organometallic reagent
to the extent of 90%) was supplied by CheMetall (D-60271 Frank-
furt), t-BuOK by Callery (Pittsburgh, PA 15230). All commercial re-
agents were used without further purification. Air and moisture
sensitive compounds were stored in Schlenk tubes or Schlenk bu-
rettes. They were protected by and handled under an atmosphere of
99.995% pure N2 (glassware: Glasgerätebau Pfeifer, D-98711
Frauenwald). Et2O and THF were dried by distillation from sodium
wire after the characteristic blue color of in situ generated sodium
diphenyl ketyl 14 persisted. Ethereal extracts were dried with Na2SO4.
The temperature of dry ice/MeOH baths is indicated as –75°C and r.t.
(22–26°C) as 25°C. Mps are reproducible after resolidification and
are corrected. Silica gel (Merck Kieselgel 60) of 70–230 mesh
(0.06–0.20 mm) particle size was used for column chromatography.
The solid support was suspended in hexane and, when all air bubbles
had escaped, was sluiced into the column. When the level of the liquid
was still some 3–5 cm above the silica layer, the dry powder, obtained
by adsorption of the crude product mixture on 15–20 g silica gel and
subsequent evaporation of the solvent, was poured on top of the col-
umn.
At –75°C, t-BuOK (2.2 g, 20 mmol) in THF (20 mL) and a solution
of triphenylphosphine–borane15 (5.5 g, 20 mmol) in THF (50 mL)
were consecutively added to BuLi, from which the commercial sol-
vent (hexane) had been stripped off (20 mmol). After 20 h at –75°C,
the mixture was treated with I2 (5.1 g, 20 mmol) in THF (20 mL) be-
fore the temperature was raised to 0°C. After vigorous shaking with
10% aq Na2S2O3 (50 mL), the organic solvent was evaporated and the
aqueous phase extracted with CH2Cl2 (3 × 20 mL). The combined or-
ganic layers were washed with brine (80 mL) and dried. Evaporation
of the solvent afforded 5.7 g of yellow needles. The 31P NMR spec-
trum revealed the presence of triphenylphosphine–borane (δ = 20.8)
and a new product (δ = 8.3) in the approximate ratio of 4:3. The latter
was obtained pure after chromatography (silica gel, 0.15 kg, Et2O/
pentane 1:9). Adduct 4 was isolated as a white crystalline material
(platelets); mp 117–120°C (lit.16 mp 119–120°C); yield:1.5 g (19%).
1H NMR: δ = 7.89 (1 H, ddd, J = 8.0, 3.2, 1.2 Hz), 7.3 (11 H, m), 6.99
(1 H, td, J = 7.7, 1.7 Hz), 6.79 (1 H, dt, J = 7.6, 1.2 Hz).
31P NMR: δ = 8.8.
Upon oxidation with H2O2 (see below) and recrystallization from
EtOAc, (2-iodophenyl)diphenylphosphine oxide (1) was obtained;
mp 157–160°C (lit.2 mp 159–161°C); yield: 0.46 g (30%).
1H NMR spectra were recorded at 400 MHz and 31P NMR spectra
were recorded at 162 MHz, chemical shifts (δ scale) referring to TMS
(internal standard) and 85% aq H3PO3 (external standard), respective-
ly. All samples were dissolved in CDCl3. Coupling constants (J) are
measured in Hz. Coupling patterns are abbreviated as s (singlet), d
(doublet), t (triplet), q (quartet), td (triplet of doublets), and m (mul-
(4-Iodo-3-methoxyphenyl)diphenylphosphine–Borane (5):
At –75°C, THF (25 mL) and t-BuOK (2.8 g, 25 mmol) were added to
BuLi, from which the commercial solvent (hexane) had been stripped
off (25 mmol). A solution of (3-methoxyphenyl)diphenylphos-
phine–borane (7.7 g, 25 mmol) in THF (25 mL) was added dropwise
over the course of 20 min. After 2 h at –75°C, the mixture was treated

SYNTHESIS
July 1998
985
with I2 (6.3 g, 25 mmol), as described in the preceding procedure. Af-
ter washing with 10% aq Na2S2O3 (50 mL), the product was extracted
with CH2Cl2 (3 × 30 mL). The H NMR spectrum of the yellow oil
Anal. calcd for C18H13FIP (406.17) C 53.23, H 3.23; found C 53.28,
H 3.20.
1
obtained revealed the presence of the starting material (methoxy sig-
nal at δ = 3.77) and of (4-iodo-3-methoxyphenyl)diphenylphos-
phine–borane (methoxy signal at δ = 3.81) in ca. ratio of 1:5. The
former impurity was removed by trituration with hot i-PrOH (10 mL)
to give an off-white fine powder; mp 120–123°C (mp 130–132°C af-
ter recrystallization from hexane/benzene 1: 1); yield: 6.7 g (62%).
1H NMR: δ = 7.82 (1 H, dd J = 7.9, 2.6 Hz), 7.6 (6 H, m), 7.5 (4 H,
m), 7.11 (1 H, dd, J = 12.1, 1.7 Hz), 6.74 (1 H, ddd, J = 10.1, 7.8,
1.6 Hz), 3.81 (3 H, s), 1.2 (3 H, large m).
(4-Iodo-3-methoxyphenyl)diphenylphosphine Oxide:
Under stirring, 30% aq H2O2 (1.1 mL, 1.2 g, 11 mmol) was slowly
added to a suspension of (4-iodo-3-methoxyphenyl)diphenylphos-
phine (4.2 g, 10 mmol) in MeOH (15 mL) kept at 0°C. After 1 h at
25°C, sat. aq Na2SO3 (4 mL) and 2 M HCl (1 mL) were added. After
1 h, the organic solvent was evaporated and the aqueous phase was
extracted with CH2Cl2 (3 × 10 mL). The combined organic layers
were washed with brine (20 mL) and dried. Evaporation of the solvent
afforded white crystals; mp 180–183°C (mp 186–187.5°C after re-
crystallization from benzene); yield: 3.7 g (86%).
31P NMR: δ = 21.9.
MS (CI): m/z (%) = 448 (2.2, M+ + NH4 – 2), 432 (1.8, M+), 431 (5.2),
418 (71), 292 (100).
Anal. calcd for C19H19BIOP (432.05) C 52.82, H 4.43; found C 53.21,
H 4.35.
1H NMR: δ = 7.83 (1 H, dd, J = 7.8, 3.3 Hz), 7.66 (4 H, ddt, J = 12.1,
7.0, 1.5 Hz), 7.55 (2 H, tq, J = 7.4, 1.5 Hz), 7.5 (4 H, m), 7.30 (1 H, dd,
J = 12.8, 1.6 Hz), 6.76 (1 H, ddd, J = 11.6, 7.9, 1.7 Hz), 3.86 (3 H, s).
31P NMR: δ = 28.8.
MS (CI): m/z (%) = 450 (0.2, M+ + NH4 – 2), 434 (70, M+), 433
+
(3-Fluoro-4-iodophenyl)diphenylphosphine–Borane (6):
At –75°C, THF (50 mL) was added to t-BuLi (25 mmol), from which
the commercial solvent (pentane) had been stripped off. This solution
was siphoned through a cannula in the course of 30 min to (3-fluo-
rophenyl)diphenylphosphine–borane (7.4 g, 25 mmol) in THF
(50 mL) kept at –75°C. After 2 h at –75°C, I2 (6.3 g, 25 mmol) in
THF (25 mL) was added, the dry ice bath removed and the mixture
allowed to reach 0°C. After vigorous shaking with 10% aq Na2S2O3
(50 mL), the organic solvent was evaporated and the aqueous phase
extracted with CH2Cl2 (3 × 30 mL). The combined organic layers
were washed with brine (60 mL) and dried. Evaporation to dryness af-
forded the crude product (9.7 g) which was triturated with hot i-PrOH
(7 mL); mp 117–121°C (mp 124–125°C after recrystallization hex-
ane/toluene 2:1); yield: 8.2 g (78%).
(100), 307 (21).
Anal. calcd for C19H16IO2P (434.21) C 52.56, H 3.71; found C 52.79,
H 3.92.
(3-Fluoro-4-iodophenyl)diphenylphosphine Oxide:
Obtained analogously from (3-fluoro-4-iodophenyl)diphenylphos-
phine (4.7 g, 12 mmol); mp 116–119°C (mp 119–120°C after recrys-
tallization from hexane/toluene 1:2); yield: 4.5 g (93%).
1H NMR: δ = 7.87 (1 H, ddd, J = 8.2, 6.1, 3.3 Hz), 7.66 (4 H, ddt, J
= 12.3, 7.1, 1.7 Hz), 7.59 (2 H, tq, J = 7.7, 1.7 Hz), 7.49 (4 H, tdt, J
= 8.1, 3.2, 1.6 Hz), 7.33 (1 H, ddd, J = 12.2, 7.8, 1.7 Hz), 7.20 (1 H,
ddd, J = 11.2, 8.1, 1.7 Hz).
31P NMR: δ = 27.9.
MS (CI): m/z (%) = 422 (63, M+), 421 (100), 345 (6.6), 295 (74).
Anal. calcd for C18H13FIOP (422.17) C 51.21, H 3.10; found C 51.10,
H 3.19.
1H NMR: δ = 7.82 (1 H, ddd J = 8.0, 6.1, 2.6 Hz), 7.6 (6 H, m), 7.5
(4 H, m), 7.20 (1 H, ddd, J = 10.9, 8.0, 1.8 Hz), 7.08 (1 H, ddd, J =
10.1, 8.0, 1.8 Hz), 1.3 (3 H, m, broad).
31P NMR: δ = 22.1.
MS (CI): m/z (%) = 436 (1.3, M+ + NH4 – 2), 420 (1.5, M+), 406
+
This work was supported by the Schweizerische Nationalfonds zur
Förderung der wissenschaftlichen Forschung, Bern (grant 20-
41'887-94). The authors are indebted to Dr. R. Schmid, Basel, for
valuable suggestions and comments.
(100), 280 (49), 183 (21).
Anal. calcd for C18H16BFIP (420.01) C 51.47, H 3.84; found C 51.46,
H 4.01.
(4-Iodo-3-methoxyphenyl)diphenylphosphine:
A solution of (4-iodo-3-methoxyphenyl)diphenylphosphine–borane
(10 g, 23 mmol) in Et2NH (80 mL) was heated under reflux for 4 h.
After evaporation to dryness, the residue was dissolved in CH2Cl2
(100 mL), washed with 2 M HCl (2 × 50 mL) and brine (2 × 50 mL)
and dried. Evaporation of the solvent afforded the product as a white
powder which was crystallized from i-PrOH; mp 124–127°C (mp
127–128°C after recrystallization from EtOH/benzene 4:3); yield:
5.1 g (53%).
(1) Schaub, B.; Jenny, T.; Schlosser, M. Tetrahedron Lett. 1984,
25, 4097.
(2) Desponds, O.; Schlosser, M. J. Organomet. Chem. 1996, 507,
257.
(3) Desponds, O. Chimia 1996, 50, 639.
(4) Pitteloud, C., Diploma work, Université de Lausanne, 1996.
(5) Schmid, R.; Foricher, J.; Cereghetti, M.; Schönholzer, P. Helv.
Chim. Acta 1991, 74, 370.
(6) See also: Brown, J. M.; Woodward, S. J. Org. Chem. 1991, 56,
6803.
1H NMR: δ = 7.71 (1 H, dd, J = 7.9, 1.6 Hz), 7.3 (10 H, m), 6.75 (1 H,
dd, J = 8.1, 1.7 Hz), 6.58 (1 H, ddd, J = 8.1, 6.4, 1.6 Hz), 3.72 (3 H, s).
31P NMR: δ = –4.2.
(7) Jendralla, H.; Li, C.-h.; Paulus, E. Tetrahedron: Asymmetry
1994, 5, 1297.
MS (CI): m/z (%) = 434 (0.6, M+ + NH4 – 2), 418 (100, M+), 341 (2.8),
292 (25).
Anal. calcd for C19H16IOP (418.21) C 54.57, H 3.86; found C 54.83,
H 3.91.
(8) Stuckwisch, C. G. J. Org. Chem. 1976, 41, 1173.
(9) Schaub, B.; Schlosser, M. Tetrahedron Lett. 1985, 26, 1623.
(10) Schmidbaur, H. J. Organomet. Chem. 1980, 200, 287.
(11) Schlosser, M. J. Organomet. Chem. 1967, 8, 9.
(12) Schlosser, M. Modern Synth. Methods 1992, 6, 227.
(13) Imamoto, T.; Oshiki, T.; Onozawa, T.; Kusumoto, T.; Sato, K.
J. Am. Chem. Soc. 1990, 112, 5244.
(14) Ziegler, K.; Crössmann, F.; Kleinert, H.; Schäfer, O. Liebigs
Ann. Chem. 1929, 473, 1ff, specifically p 20.
Metzger, H.; Müller, E.; In Houben-Weyl, 4th ed., Vol. 1/2;
Müller, E. Ed.; Thieme: Stuttgart, 1959; pp 337–338.
(15) Moore, R. C.; White, S. S.; Kelly, H. C. Inorg. Synth. 1970, 12,
109.
(3-Fluoro-4-iodophenyl)diphenylphosphine:
Obtained analogously from (3-fluoro-4-iodophenyl)diphenylphos-
phine–borane (9.2 g, 22 mol); mp 63–64°C; yield: 5.2 g (58%).
1H NMR: δ = 7.69 (1 H, ddd, J = 8.1, 6.2, 1.6 Hz), 7.4 (6 H, m), 7.3
(4 H, m), 6.90 (1 H, ddd, J = 8.2, 6.3, 1.5 Hz), 6.82 (1 H, ddd, J = 9.5,
7.2, 1.8 Hz).
31P NMR: δ = –5.4.
MS (CI): m/z (%) = 423 (0.4, M+ + NH4), 406 (100, M+), 329 (2.8),
280 (30).
(16) Tunney, S. E.; Stille, J. K. J. Org. Chem. 1987, 52, 748.