P-Chirogenic phosphonium salts: Preparation and use in Rh-catalyzed asymmetric hydrogenation of enamides

Article abstract of DOI:10.1016/S0040-4039(03)00668-3

P-Chirogenic trialkylphosphonium salts were prepared from the corresponding free phosphines by treatment with a strong acid (HBF₄ or HOTf). No racemization of the phosphonium salts occurred in methanol or water even at considerably high tempera

Full text of DOI:10.1016/S0040-4039(03)00668-3

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 3467–3469
P-Chirogenic phosphonium salts: preparation and use in
Rh-catalyzed asymmetric hydrogenation of enamides
Hiroshi Danjo, Wataru Sasaki, Takehiro Miyazaki and Tsuneo Imamoto*
Department of Chemistry, Faculty of Science, Chiba University, Yayoi-cho, Inage-ku, Chiba 263-8522, Japan
Received 21 February 2003; revised 7 March 2003; accepted 12 March 2003
Abstract—P-Chirogenic trialkylphosphonium salts were prepared from the corresponding free phosphines by treatment with a
strong acid (HBF4 or HOTf). No racemization of the phosphonium salts occurred in methanol or water even at considerably high
temperature. The salts were conveniently used in rhodium-catalyzed asymmetric hydrogenation of enamides. © 2003 Elsevier
Science Ltd. All rights reserved.
During our continuing studies on development of new
chiral phosphine ligands, we previously described ethyl-
ene- or methylene-bridged P-chirogenic trialkyldiphos-
phines, 1,2-bis(alkylmethylphosphino)ethanes (abbre-
viated as BisP*) and bis(alkylmethylphosphino)-
methanes (MiniPHOS).1 These phosphine ligands
exhibit high enantioselectivity in some transition metal-
catalyzed asymmetric reactions, especially when t-Bu-
BisP* or t-Bu-MiniPHOS are used. However, they are
air-sensitive owing to high electron density at phospho-
rus and are readily oxidized on contact with air. In
order to overcome the difficulty of storing them in inert
atmosphere, they are usually isolated as air-stable
borane complexes and the protecting boranato group is
removed prior to use.
(S)-tert-butylbenzylmethylphosphine–borane (1) was
deboranated by treatment with trifluoromethanesul-
fonic acid followed by potassium hydroxide to give
(S)-tert-butylbenzylmethylphosphine (2).3 Protonation
of free phosphine 2 was easily carried out by the use of
aqueous tetrafluoroboric acid to provide phosphonium
salt 3. In a similar manner, diphosphonium salts 6a,b
and 7a,b were prepared from the corresponding diphos-
phine–boranes 4 and 5, respectively, using tetra-
fluoroboric acid or trifluoromethanesulfonic acid.4 The
phosphonium salts 6a,b were air-stable white powder
and remained unchanged upon storing at room temper-
ature for at least several months. In contrast, salts 7a,b
proved difficult to be isolated pure, most likely due to
their greater lability.
Recently, Fu and his co-worker found that tetra-
fluoroboric acid acts as a good protecting agent for
air-sensitive trialkylphosphines such as tributylphos-
phine and tri-tert-butylphosphine.2 The resulting salts
are air-stable and easily liberate the trialkylphosphines
on contact with a weak Brønsted base. The authors
demonstrated that the salts can be conveniently used as
catalyst/reagent precursors in phosphine-catalyzed or
-mediated organic transformations without loss of reac-
tivity. Their report intrigued us to develop a convenient
protocol for P-chirogenic phosphine mediated process.
Herein we wish to describe preparation of P-chirogenic
trialkylphosphonium salts and their use as chiral lig-
ands in rhodium-catalyzed asymmetric hydrogenation.
It has been reported that racemization of P-chirogenic
phosphine was promoted by various reagents including
Several P-chirogenic trialkylphosphonium salts were
prepared from phosphine–boranes (Scheme 1). Thus,
Scheme 1. Reagents and conditions: (a) i. TfOH, toluene, 0°C
to rt, 30 min, ii. KOH, EtOH/H2O, 60°C, 3 h; (b) HBF4 aq.,
Et2O, rt, 10 min; (c) TfOH, Et2O, rt, 10 min.
* Corresponding author. Tel.: +81-43-290-2791; fax: +81-43-290-2791;
e-mail: imamoto@faculty.chiba-u.jp
0040-4039/03/$ - see front matter © 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0040-4039(03)00668-3

3468
H. Danjo et al. / Tetrahedron Letters 44 (2003) 3467–3469
acids.5 In particular, the acid-catalyzed racemization of
phosphine was strongly affected by the nature of its
conjugate base: for example, aqueous HBr induces
complete racemization of methylphenylpropylphos-
phine in methanol at 90°C within 5 h, whereas the
stereochemical integrity of the same phosphine remains
intact in aqueous HCl.
the reaction (entry 3). It should be noted that the
hydrogenation proceeded rapidly even in the absence of
base (entry 4). Although this fact is not fully under-
stood, we suppose that, under our reaction conditions,
the tetrafluoroboric acid salt enters in equilibrium with
free diphosphine (t-Bu-BisP*) which reacts with
[Rh(nbd)2]BF4 to form the thermodynamically more
stable complex [Rh(t-Bu-BisP*)(nbd)]BF4. On the other
hand, addition of a base was essential to promote the
hydrogenation with trifluoromethanesulfonic acid salt
6b. Thus, both excellent yield and enantioselectivity
were observed when 6b was used in the presence of
diisopropylethylamine (entry 5), whereas an abrupt
decrease of conversion and enantioselectivity was
observed in the absence of base (entry 6). Similar
results were obtained in the cases of MiniPHOS salts 7a
and 7b (entries 7–10).
In our hands, no significant decrease in the enan-
tiomeric purity of salt 3 was observed upon heating in
water or methanol in a sealed tube at 70°C up to 2
days. The enantiomeric excess of the corresponding
borane–adduct revealed to be identical (87–90% ee,
Scheme 2) to the one of the starting salt (90% ee).6
Finally, in sharp contrast to the reaction using the
tetrafluoroboric acid salt without a base (entries 4 and
8), use of the trifluoromethanesulfonic acid salt caused
sluggish reaction under the same reaction conditions
(entries 6 and 10). The remarkable difference in activity
may be ascribed to respective acid strength. Thus,
trifluoromethanesulfonic acid exhibits stronger acidity
than tetrafluoroboric acid and may form a more stable
phosphonium salt that does not readily liberate the free
phosphine necessary for the formation of the reactive
rhodium–diphosphine complex.
Scheme 2.
The optically active P-chirogenic phosphonium salts
were used in rhodium-catalyzed asymmetric hydrogena-
tion of methyl 2-acetamidocinnamate.7 The rhodium–
diphosphine complex was generated in situ by mixing 1
mol% of [Rh(nbd)2]BF4 with 1 mol% of diphosphonium
salt 6 or 7 in the presence or absence of a Brønsted
base. Hydrogenation was carried out in methanol under
3 atm of H2 at room temperature for 1 h. The results
are summarized in Table 1. In the case of tetra-
fluoroboric acid salt 6a, the reaction in the presence of
diisopropylethylamine proceeded smoothly and gave
the hydrogenation product with 99% ee (entries 1 and
2). However, addition of potassium carbonate retarded
Encouraged by these results, we next tried to use phos-
phonium salt 6a in the hydrogenation of various
olefinic compounds having acetylamino group at the
a-position under base-free conditions. Representative
results are summarized in Table 2. In all the cases
examined, the same sense of enantioselection was
observed in comparison with the results obtained by the
use of preformed [(S,S)-t-Bu-BisP*-Rh(nbd)]BF4 as a
precatalyst.1a It is worthy to note that hydrogenation of
methyl acetamidocinnamate went to completion even
under atmospheric pressure of H2 (entry 2). Excellent
yield and enantioselectivity were also obtained in the
case of dehydroamino acids without substituents at
b-position (dehydroalanine derivative, entry 3), whereas
hydrogenation of b,b-disubstituted dehydroamino acids
afforded lower stereoselectivity (entry 4). This protocol
also proved successful to hydrogenation of enamides
and dehydro b-amino acid derivatives (entries 6–9). It is
also noted that a (Z)-dehydro b-amino acid derivative
was reduced rapidly under these conditions (entry 9), in
contrast to the reduction catalyzed by isolated t-Bu-
BisP*–Rh complex (18 h at 20 atm of H2).8,9
Table 1. Rh-catalyzed asymmetric hydrogenation of
methyl acetamidocinnamate with P-chirogenic diphospho-
nium salts 6 and 7a
Entry
Salt
Base
Conv. (%)b
ee (%)c
1
2
3
4
5
6
7
8
9
6a
6a
6a
6a
6b
6b
7a
7a
7b
7b
i-Pr2NEt (2 mol%)
i-Pr2NEt (20 mol%) \99
K2CO3 (10 mol%)
None
i-Pr2NEt (2 mol%)
None
i-Pr2NEt (2 mol%)
None
i-Pr2NEt (2 mol%)
None
\99
94
99
–
\99
95
34
97
\99
99
Trace
\99
\99
13
\99
\99
\99
9
In conclusion, P-chirogenic trialkylphosphonium salts
have been prepared from free phosphines and strong
Brønsted acids. No appreciable stereomutation of these
chiral phosphonium salts occurs even upon heating in
protic solvent. The diphosphonium salts were conve-
niently used in rhodium-catalyzed asymmetric hydro-
genation of various enamides to provide excellent yields
and enantioselectivities in most cases.
10
16
a All reactions were carried out in methanol with
1 mol% of
[Rh(nbd)2]BF4, 1 mol% of salt and base under 3 atm of H2 pressure
at room temperature unless otherwise noted.
b Determined by 1H NMR.
c Determined by chiral GC or HPLC analysis.

H. Danjo et al. / Tetrahedron Letters 44 (2003) 3467–3469
3469
Table 2. Rh-catalyzed asymmetric hydrogenation of various enamides with diphosphonium salt 6aa
Entry
R1
R2
R3
Time (h)
Conv. (%)b
ee (%)c
(Config.)
1
Ph
Ph
H
H
H
H
CO2Me
CO2Me
CO2Me
CO2Me
Ph
4-MeOC6H4
4-O2NC6H4
Me
1
1.5
2
1
6
1
1
1
1
\99
94
98
\99
98
\99
\99
\99
89
\99
\99
96
70
94
\99
97
\99
64
(R)
(R)
(R)
(R)
(R)
(R)
(R)
(R)
(R)
2d
3
4
-(CH2)5-
5d
6
H
H
H
H
H
H
H
7
8
9
CO2Me
H
CO2Me
Me
a All reactions were carried out in methanol with 1 mol% of [Rh(nbd)2]BF4 and 1 mol% of 6a under 3 atm of H2 pressure at room temperature
unless otherwise noted.
b Determined by 1H NMR.
c Determined by chiral GC or HPLC analysis.
d The reaction was carried out under 1 atm of H2 pressure.
3
References
1.30 (d, JHP=9.5 Hz, 18H); 13C NMR (126 MHz, D2O) l
−2.1 (d, JCP=47.2 Hz), 10.6 (d, JCP=42.2 Hz), 28.2 (d,
1. (a) Imamoto, T.; Watanabe, J.; Wada, Y.; Masuda, H.;
Yamada, H.; Tsuruta, H.; Matsukawa, S.; Yamaguchi, K.
J. Am. Chem. Soc. 1998, 120, 1635–1636; (b) Yamanoi, Y.;
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CP=45.2 Hz); 31P NMR (200 MHz, D2O) l 27.7; IR
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(FAB) m/z 235 (M+−2BF4−H).
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6. The conditions for the determination of the enantiomeric
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CHIRALCEL OD-H; hexane/2-propanol=9/1; flow
rate=0.5 mL/min.
7. General procedure for asymmetric hydrogenation: A 50 mL
Fisher–Porter tube was charged with substrate (1 mmol),
[Rh(nbd)2]BF4 (10 mmol), and diphosphonium salt (10
mmol). The tube was connected to the hydrogen tank via
stainless steel tubing. The vessel was evacuated and filled
with hydrogen gas to a pressure of 3 atm. This operation
was repeated and the upper cock of the bottle was opened
to allow quick addition of anhydrous, degassed MeOH
(4–5 mL) and base (20 mmol) using a syringe. After four
vacuum/H2 cycles, the tube was pressurized to an initial
pressure of 3 atm. The tube was closed off and the mixture
was stirred at ambient temperature. After stirring for 1 h,
the mixture was passed through a silica gel column with
eluting EtOAc, and the filtrate was concentrated under
reduced pressure. The residue was submitted to HPLC or
GC analysis.
4. Preparation of diphosphonium salt 6a; a typical procedure:
To a dry toluene solution (10 mL) of (S,S)-1,2-bis(borana-
to(tert-butyl)methylphosphino)ethane (260 mg, 1.0 mmol)
was added trifluoromethanesulfonic acid (880 mL, 10
mmol) dropwise at 0°C under an Ar atmosphere. After 30
min, the mixture was allowed to warm to ambient temper-
ature and stirred, while monitoring the reaction by TLC,
until the starting phosphine–borane disappeared. The
volatiles were removed under reduced pressure, and a
solution of KOH (1.2 g, 20 mmol) in degassed EtOH–H2O
(10:1, 12 mL) was slowly added to the residue with stir-
ring. The mixture was stirred at 60°C for 2 h then cooled
to room temperature. Degassed Et2O (10 mL) was added,
and the mixture was dried over Na2SO4. The solution was
passed through a column (2 cm diameter) of basic alumina
(20 g) eluting with degassed Et2O (ca. 20 mL). To the
filtrate was added aqueous HBF4 (2.0 mL, 10 mmol) at
room temperature with vigorous stirring. After 30 min, the
precipitate was collected by filtration, washed with Et2O,
and dried under reduced pressure to give diphosphonium
salt 6a as white powder (374 mg, 91% yield): mp 272–
8. Yasutake, M.; Gridnev, I. D.; Higashi, N.; Imamoto, T.
Org. Lett. 2001, 3, 1701–1704.
9. Recently,
it
has
been
reported
that
(Z)-b-
(acylamino)acrylates were reduced under relatively mild
conditions in excellent enantioselectivity: (a) Lee, S.;
Zhang, Y. J. Org. Lett. 2002, 4, 2429–2431; (b) Tang, W.;
Zhang, X. Org. Lett. 2002, 4, 4159–4161; (c) Pen˜a, D.;
Minnaard, A. J.; de Vries, J. G.; Feringa, B. J. Am. Chem.
Soc. 2002, 124, 14552–14553.
1
274°C; [h]2D4 23.9 (c 0.1, H2O); H NMR (500 MHz, D2O)
2
l 2.68 (m, 2H), 2.51 (m, 2H), 1.89 (d, JHP=7.0 Hz, 6H),