Economic large-scale synthesis of o - And m -diphenylphosphinobenzoic acids

Article abstract of DOI:10.1055/s-0029-1218705

An efficient and simple to perform large-scale synthesis of o- and m-diphenylphosphinobenzoic acids is presented. In a single step, both useful carboxylic acid-functionalized phosphines can be accessed starting from the same inexpensive bulk chemicals o-chlorobenzoic acid, triphenylphosphine, and sodium. In both cases the formation of the desired product is controlled by the ratio of the starting materials only. Additionally, X-ray crystallographic data are reported for both products. Georg Thieme Verlag Stuttgart New York.

Full text of DOI:10.1055/s-0029-1218705

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1924
PRACTICAL SYNTHETIC PROCEDURES
Economic Large-Scale Synthesis of o- and m-Diphenylphosphinobenzoic Acids
Large-Scale
S
u
ynthesis of
o
s
-
and
m
-D
a
iphenylpho
n
sphinobenz
o
n
ic
A
cids e T. Kemme, Yvonne Schmidt, Christian U. Grünanger, Andy C. Laungani, Christian Herber, Bernhard Breit*
Albert-Ludwigs-Universität Freiburg, Institut für Organische Chemie und Biochemie, Freiburg Institute for Advanced Studies (FRIAS),
Albertstr. 21, 79104 Freiburg im Breisgau, Germany
Fax +49(761)2038715; E-mail: Bernhard.Breit@chemie.uni-freiburg.de
Received 17 February 2010
PSP
No185
Abstract: An efficient and simple to perform large-scale synthesis of o- and m-diphenylphosphinobenzoic acids is presented. In a single
step, both useful carboxylic acid-functionalized phosphines can be accessed starting from the same inexpensive bulk chemicals o-chlo-
robenzoic acid, triphenylphosphine, and sodium. In both cases the formation of the desired product is controlled by the ratio of the starting
materials only. Additionally, X-ray crystallographic data are reported for both products.
Key words: phosphorus ligand, catalysis, aromatic carboxylic acid, directing group, Birch conditions
O
O
Na (2 equiv), Ph3P (1 equiv)
OH
Procedure 1
Procedure 2
o-DPPBA (1)
OH
OH
NH3(l), −78 °C
PPh2
O
Cl
O
Na (4 equiv), Ph3P (2 equiv)
OH
m-DPPBA (2)
NH3(l), −78 °C
Cl
PPh2
Scheme 1
Phosphines are widely applied and important donor methodology has been the rather high costs of commercial
ligands for transition metal catalysis.1 Of particular use o-DPPBA.
are phosphines equipped with appropriate functional
groups, which allow for a modular ligand design through
attachment to a variety of chiral and achiral backbones.
The regioisomer of o-DPPBA (1) the m-diphenylphosphi-
nobenzoic acid (2, m-DPPBA) is the basis for a variety of
ligands (Figure 1), which have been applied for the Heck
Interesting examples of this class of ligands are the C2-
reaction and in allylic alkylation.9 Moreover, we recently
symmetric Trost ligands, widely applied for asymmetric
reported on the use of m-DPPBA (2) as a building block
palladium-catalyzed allylic substitution.2 These ligands
for supramolecular metallopeptide ligands for hydro-
are constructed by a modular design. Thus, chiral diols or
formylation and asymmetric hydrogenation.10
diamines are connected through an ester or an amide link-
age to the phosphine-binding post, with o-diphenylphos-
phinobenzoic acid (1, o-DPPBA) being the most
O
O
OH
important phosphine building block (Figure 1). Addition-
OH
ally, o-DPPBA (1) has found application as mediator in
Staudinger ligation reacions3 as well as catalyst- and
PPh2
PPh2
reagent-directing group in a number of transition-metal-
catalyzed and -mediated reactions.4 Among them are the
directed rhodium-catalyzed hydroformylation,5c,6 conju-
gate addition5 as well as the directed copper-mediated
allylic substitution with Grignard reagents.7 This method-
ology proved highly reliable for the construction of tertia-
ry and quaternary stereocenters providing exceptional
levels of acyclic stereocontrol, which has been applied in
several natural product syntheses.8 A drawback of this
1
2
Figure 1 The o- and m-diphenylphosphinobenzoic acids 1 and 2
Known total syntheses of m- and o-DPPBA (1,2) rely on
halogen–lithium exchange reactions, on the use of Grig-
nard reagents11 or on the applications of transition-metal-
mediated coupling reactions.12 Most of these syntheses
suffer from low yields, multistep processes, or expensive
starting materials.11–13
SYNTHESIS 2010, No. 11, pp 1924–1928
x
x.
x
x
.
2
0
1
0
Thus far the most practical approach to o-DPPBA (1) was
Advanced online publication: 15.03.2010
DOI: 10.1055/s-0029-1218705; Art ID: Z03910SS
reported by Rauchfuss et al.14 We herein present a signif-
© Georg Thieme Verlag Stuttgart · New York

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PRACTICAL SYNTHETIC PROCEDURES Large-Scale Synthesis of o- and m-Diphenylphosphinobenzoic Acids 1925
icant preparative improvement of the original Rauchfuss
synthesis of o-DPPBA (1) and furthermore demonstrate
that a simple change of stoichiometry in the reagents en-
abled unexpectedly the development of a new and effi-
cient one-step preparation of m-DPBBA (2) (Scheme 1).
Both syntheses start from inexpensive o-chlorobenzoic
acid and can be performed in large scale. Additionally, we
report X-ray crystallographic data of both the phosphine
carboxylic acids.
Table 1 Optimization of the Reaction Conditions
Entry Product Concn Na
Ph3P
Time Time Yield
(M)a
0.24
0.44
0.24
0.18
0.37
0.16
0.22
(equiv) (equiv) (h)b
(h)c
0.5
0.5
18
(%)
59
59
54
63
53
63
49
1
1
1
1
2
2
2
1
2
2
2
4
4
4
2
1
1
1
2
2
2
1
2.5
2.5
2.75
3
2
3
4
0.5
0.5
3
In order to simplify the original Rauchfuss procedure as
well as to minimize side products from phosphorus oxida-
tion several improvements have been made: Thus, the re-
action is run on a 1 liter scale in liquid ammonia without
the need of a dry ice condenser, which proved unneces-
sary. As an extremely important measure to the reliable
success of this reaction, a small counterflow of argon is
applied when adding reagents and substrates to the reac-
tion mixture in order to avoid the contamination with ox-
ygen. Furthermore, we found that it is sufficient to add the
substrates continuously spoonwise during a period of 3 to
5 minutes. THF was filtered over basic alumina oxide to
remove traces of peroxides prior to use and was added in
one portion instead of using a syringe. After the initial
crystallization we triturated the product with cold metha-
nol, followed by filtration and washing with cold metha-
nol, which directly yielded the pure product within only
two days. This trituration procedure avoided an additional
recrystallization and is essential in order to get rid of any
oxidized product.
5
3
6d
7e
12
2.5
0.5
a Concentration of o-chlorobenzoic acid in liquid ammonia.
b Stirring time before adding o-chlorobenzoic acid.
c Stirring time before adding THF.
d Results from literature.15
e Results from literature.14
corresponding carboxylate. In a next step, a nucleophilic
aromatic substitution with the best nucleophile diphe-
nylphosphide occurs via a corresponding Meisenheimer
type intermediate 3. Elimination of sodium chloride fur-
nishes after acidification o-DPPBA (1).
Conversely, when two equivalents of sodium amide are
generated by doubling the amounts of sodium and triphe-
nylphosphine an additional equivalent of sodium amide is
present, which induces a b-elimination within o-chlo-
robenzoate to generate the benzyne intermediate 4
(Scheme 2). Thereafter, 4 is attacked by the nucleophile
sodium diphenylphosphide in a regioselective manner
In a preliminary attempt to improve the yield of o-DPPBA
(1), we used an excess of triphenylphosphine and sodium.
Surprisingly, as a result of this experiment we did not ob-
serve the formation of o-DPPBA (1), but rather m-DPPBA
(2) as the exclusive product (Table 1, entry 4). Optimal re-
sults for m-DPPPBA (2) were obtained with two equiva-
lents of triphenylphosphine and four equivalents of
sodium. We also found that the concentration of the o-
chlorobenzoic acid substrate in liquid ammonia can be
doubled to 0.44 M without affecting the product yields
(Table 1, entries 1 and 2). A doubled concentration of the
reaction mixture towards m-DPPBA gave a lower yield
presumably due to the over concentrated reaction mixture
(Table 1, entry 5). In both reactions, extended reaction
times did not lead to better yields (Table 1, entries 3 and
6). However, it is noteworthy that our new and simplified
procedure provides significantly improved yields com-
pared to the original Rauchfuss procedure (Table 1, entry
7).
+ NH3
Na PPh2
Ph3P + 2 Na
Na NH2
+ Ph Na
Na
O
1. NaNH2 (– NH3)
2. Ph2PNa (SNAr)
CO2
Na
Na
O
Na
Cl
1
2
(– NaCl)
PPh2
PPh2
3
CO2
CO2H
Cl
PPh2
From a mechanistic point, the reaction divergence as a
function of stoichiometry of sodium and triphenylphos-
phine is interesting (Scheme 2). Thus, under Birch type
conditions triphenylphosphine is reduced to furnish sodi-
um diphenylphosphide and phenylsodium, which is a
strong base and will deprotonate ammonia instantaneous-
ly to provide one equivalent of sodium amide. To this
mixture is added one equivalent of o-chlorobenzoic acid,
which is instantaneously deprotonated by the strongest
base, under these conditions sodium amide, to furnish the
+ NH3 – NaNH2
O
O
O
1. 2 NaNH2
(– 2 NH3)
2. NaPPh
Na
O
Na
2
Na
4
PPh2
Scheme 2 Proposed mechanism for the formation of 1 and 2 from
o-chlorobenzoic acid
Synthesis 2010, No. 11, 1924–1928 © Thieme Stuttgart · New York

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1926
S. T. Kemme et al.
PRACTICAL SYNTHETIC PROCEDURES
presumably controlled by steric effects to furnish after
protonation m-DPPBA (2).
Both products are air stable and are obtained as light yel-
low powders. However, in solution in the presence of
oxygen slow oxidation of m- and o-DPPBA takes place.
Suitable single crystals from both o-DPPBA (1) and m-
DPPBA (2) could be obtained from saturated solutions in
methanol. Both were analyzed by X-ray crystallography.
The X-ray structure of o-DPPBA (1) is depicted in
Figure 2. o-DPPBA (1) co-crystallizes with methanol to
form 1:1 hydrogen bound adducts in the solid state. Con-
versely, m-DPPBA forms typical carboxylic acid dimers
in the crystal state (Figure 3).
Figure 2 Crystal structure of o-DPPBA (1)
In conclusion, the development of an improved practical
one pot synthesis of o-DPPBA (1) as well as a novel syn-
thesis of m-DPPBA (2) has been accomplished. Thus, in a
single step, both useful ligand precursors could be pre-
pared starting from the same inexpensive bulk chemicals
o-chlorobenzoic acid, triphenylphosphine and sodium.
Figure 3 Crystal structure of m-DPPBA (2)
All chemicals were used as received from commercial suppliers.
THF was filtered over basic Al2O3. All reactions were run under an
atmosphere of argon (argon 5.0, supplier: SWF, Friedrichshafen,
Germany). 1H, 13C, and 31P NMR spectra were recorded at r.t. on an
AMX 400 (Bruker) spectrometer in CDCl3 and C6D6. Elementary
analyses were performed on an Elementar vario EL (Elementar
Analysensysteme GmbH) and EI mass spectra were obtained on a
Finnigan MAT 8200 spectrometer. Crystal structures were obtained
on a Kappa CCD diffractometer (Nonius) and melting points were
determined using a Dr. Tottoli apparatus (Büchi).
added spoonwise during 3 min at –78 °C against a counterflow of
inert gas and stirring was continued for 30 min, then THF (350 mL,
filtered over Alox B) was added in one portion, the cooling bath was
removed, and the ammonia was allowed to evaporate overnight.
The dark orange-red solid residue was dissolved in H2O (1 L) under
mechanical stirring until a yellow suspension was formed. The
aqueous phase was washed with Et2O (1 × 250 mL and 1 × 200 mL)
and afterwards concd HCl (80 mL) was added until the aqueous
phase reached pH 1–2. The aqueous phase was extracted with
CH2Cl2 (3 × 200 mL, 1 × 100 mL) and the combined organic layers
were washed with H2O (400 mL). The solvent was evaporated care-
fully under reduced pressure (the solution effervesced heavily) until
no more solvent evaporated (200 mbar). The resulting syrup
(~100 mL) was mixed with MeOH (100 mL) and crystallization oc-
curred upon cooling overnight at 5 °C. The yellow crystals were
collected by filtration, triturated with cold MeOH (2 × 25 mL), fil-
tered, and washed with little cold MeOH. The solid was then dis-
solved two times in CH2Cl2 (300 mL each) to remove the residual
MeOH. The solvent was evaporated under reduced pressure and the
solid dried under air. From the combined mother liquor and MeOH
o-Diphenylphosphinobenzoic Acid (1)
Into a 1 L round-bottomed three-necked flask equipped with a me-
chanical stirrer was condensed ammonia (500 mL, dried over
NaOH/KOH) at –78 °C (dry ice acetone bath in a Dewar vessel). Na
(10.6 g, 460 mmol, 2.1 equiv) was then added in small pieces
against a continuous counterflow of inert gas (argon 5.0, SWF) dur-
ing 5 min. The resulting deep blue mixture was stirred for 10 min
and then Ph3P (58.4 g, 222 mmol, 1.0 equiv) was added continuous-
ly spoonwise against a counterflow of inert gas during 3 min. This
reaction mixture was stirred at –78 °C for 2.5 h until the color
turned to dark red. o-Chlorobenzoic acid (34.8 g, 222 mmol) was
Synthesis 2010, No. 11, 1924–1928 © Thieme Stuttgart · New York

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PRACTICAL SYNTHETIC PROCEDURES Large-Scale Synthesis of o- and m-Diphenylphosphinobenzoic Acids 1927
washings a second crop of crystals could be obtained and was treat-
Acknowledgment
ed in the same manner. The title compound (40.0 g, 59%) was ob-
This work was supported by the Fonds der Chemischen Industrie
tained as an amorphous yellow solid; mp 144–148 °C.
(fellowship to Y. S.), DFG (International Research Training Group,
IRTG 1038), the Alfried Krupp Award for young university
1H NMR (400 MHz, C6D6): d = 6.85–6.90 (m, 2 H, H-4, 5), 7.03–
7.09 (m, 7 H, C6H5 and H-3), 7.35–7.41 (m, 4 H, C6H5), 7.97–8.02
teachers of the Krupp Foundation (to B.B.), and BASF. We kindly
(m, 1 H, H-6).
thank Günther Leonhardt-Lutterbeck, Jürgen Leonhardt, Katja
Rießle, and Johanna Weipert for technical support and Dr. Jens
Geier for X-ray measurements.
13C NMR (100 MHz, C6D6): d = 128.7 (2 C), 128.8 (4 C), 131.8,
131.8, 132.6, 133.5 (d, J = 18.2 Hz), 134.4 (d, J = 21.1 Hz, 4 C),
134.7, 138.8 (d, J = 12.7 Hz, 2 C), 142.8 (d, J = 30.7 Hz), 171.1
(C=O).
References
31P NMR (161 MHz, C6D6): d = –3.74.
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Applications; Börner, A., Ed.; Wiley-VCH: Weinheim,
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MS (EI, 130 eV): m/z (%) = 306.1 (100, [M]+), 277.1 (96,
[Ph3PO]+), 229.1 (45, [M – C6H5]+), 199.0 (38), 183.0 (54), 152.0
(23), 104.9 (7), 79.6 (10).
(2) (a) Trost, B. M.; Van Vranken, D. L. Angew. Chem. Int. Ed.
1992, 31, 228. (b) Trost, B. M.; Li, L.; Guile, S. D. J. Am.
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Anal. Calcd for C19H15O2P: C, 74.50; H, 4.94. Found: C, 74.27; H,
5.94.
m-Diphenylphosphinobenzoic Acid (2)
Into a round-bottomed three-necked flask equipped with a mechan-
ical stirrer was condensed ammonia (600 mL, dried over NaOH/
KOH) at –78 °C (dry ice acetone bath in a Dewar vessel). Na
(10.3 g, 444 mmol, 4.0 equiv) was then added in small pieces
against a continuous counterflow of inert gas (argon 5.0, SWF) dur-
ing 5 min. The resulting deep blue mixture was stirred for 10 min
and then Ph3P (58.4 g, 222 mmol, 2.0 equiv) was added continuous-
ly in portions against a counterflow of inert gas during 5 min. This
reaction mixture was stirred at –78 °C for 3 h until the color turned
to dark red. o-Chlorobenzoic acid (17.4 g, 111 mmol) was added
spoonwise during 3 min at –78 °C against a counterflow of inert gas
and stirring was continued for 30 min. Then THF (350 mL, filtered
over Alox B) was added in one portion, the cooling bath was re-
moved and the ammonia was allowed to evaporate overnight. The
dark orange-red solid residue was dissolved in H2O (500 mL) under
mechanical stirring until a yellow suspension was formed. The
aqueous phase was washed with Et2O (2 × 200 ml) and afterwards
concd HCl (60 mL) was added until the aqueous phase reached
pH 1–2. The aqueous phase was extracted with CH2Cl2
(3 × 150 mL, 1 × 100 mL) and the combined organic layers were
washed with H2O (200 mL). The solvent was evaporated carefully
under reduced pressure (the solution effervesced heavily) until no
more solvent evaporated (200 mbar). The resulting syrup (~80 mL)
was then mixed with MeOH (60 mL) and crystallization occurred
upon cooling overnight at 5 °C. The yellow crystals were collected
by filtration, triturated with cold MeOH (2 × 25 mL), filtered and
washed with little cold MeOH. The resulting solid was dried under
air. From the combined mother liquor and MeOH washings a sec-
ond crop of crystals could be obtained and was treated in the same
manner. The title compound (21.5 g, 63%) was obtained as an
amorphous yellow solid; mp 148–150 °C.
Iourtchenkoa, A.; Sinoua, D. Tetrahedron Lett. 2002, 43,
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1H NMR (400 MHz, CDCl3): d = 7.31–7.38 (m, 10 H, 2 × C6H5),
7.42–7.46 (dddd, J = 0.7, 1.4, 7.6, 7.6 Hz, 1 H, H-5), 7.50–7.54
(dddd, J = 1.4, 1.4, 7.3, 7.3 Hz, 1 H, H-2), 8.05–8.11 (m, 2 H, H-4
and 6).
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(b) Herber, C.; Breit, B. Eur. J. Org. Chem. 2007, 3512.
(c) Rein, C.; Demel, P.; Outten, R. A.; Netscher, T.; Breit, B.
Angew. Chem. Int. Ed. 2007, 46, 8670. (d) Reiss, T.; Breit,
B. Org. Lett. 2009, 11, 3286. (e) Schmidt, Y.; Breit, B. Org.
Lett. 2009, 11, 4767.
13C NMR (100 MHz, CDCl3): d = 128.8, 128.8 (d, J = 7.1 Hz, 4 C),
129.1 (2 C), 129.6 (d, J = 7.0 Hz), 130.5, 133.9 (d, J = 19.8 Hz, 4
C), 135.3 (d, J = 21.9 Hz), 136.4 (d, J = 10.8 Hz), 138.7 (d, J = 13.7
Hz), 138.8 (d, J = 17.5 Hz, 2 C), 171.9 (C=O).
31P NMR (161 MHz, CDCl3): d = –5.50.
(9) (a) Amengual, R.; Genin, E.; Michelet, V.; Savignac, M.;
Genêt, P. Adv. Synth. Catal. 2002, 344, 393. (b) Kozlov, V.
A.; Aleksanyan, D. V.; Nelyubina, Y. V.; Lyssenko, K. A.;
Gutsul, E. I.; Puntus, L. N.; Vasil’ev, A. A.; Petrovskii, P.
V.; Odinets, I. L. Organometallics 2008, 7, 4062.
(c) Genin, E.; Amengual, R.; Michelet, V.; Savignac, M.;
MS (EI, 130 eV): m/z (%) = 306.1 (100, [M]+), 277.1 (96,
[Ph3PO]+), 183.0 (93), 152.0 (21), 107.9 (13).
Anal. Calcd for C19H15O2P: C, 74.50; H, 4.94. Found: C, 74.29; H,
5.00.
Synthesis 2010, No. 11, 1924–1928 © Thieme Stuttgart · New York