An outstanding palladium system containing a C2-symmetrical phosphite ligand for enantioselective allylic substitution processes

Article abstract of DOI:10.1039/b813428f

The use of efficient Pd systems bearing C₂-symmetric chiral diphosphite ligands derived from carbohydrates in asymmetric allylic substitution reactions is described here, reaching TOFs > 22 000 h ^-1 in allylic alkylation and ca. 400 h^-1 in allylic amination, giving excellent enantioselectivities (ee > 99%) and kinetic resolution of the racemic substrate. The Royal Society of Chemistry.

Full text of DOI:10.1039/b813428f

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An outstanding palladium system containing a C2-symmetrical phosphite
ligand for enantioselective allylic substitution processes
a
b
b
c
´
Angelica Balanta Castillo, Isabelle Favier, Emmanuelle Teuma, Sergio Castillon,
a
a
a
b
´
Cyril Godard,* Ali Aghmiz, Carmen Claver* and Montserrat Gomez*
Received (in Cambridge, UK) 4th August 2008, Accepted 30th September 2008
First published as an Advance Article on the web 24th October 2008
DOI: 10.1039/b813428f
The use of efficient Pd systems bearing C2-symmetric chiral
diphosphite ligands derived from carbohydrates in asymmetric
allylic substitution reactions is described here, reaching TOFs 4
22 000 hÀ1 in allylic alkylation and ca. 400 hÀ1 in allylic
amination, giving excellent enantioselectivities (ee 4 99%)
and kinetic resolution of the racemic substrate.
Palladium-catalysed asymmetric allylic substitution is a versa-
tile and widely used process for the enantioselective formation
of carbon–carbon and carbon–heteroatom bonds. Over the
past decade, high enantiomeric excesses have been achieved
for these reactions, mainly using phosphorus and nitrogen
based ligands.1 However, these systems are generally ham-
pered by low reaction rates.1 In enantioselective allylic
substitution reactions, the use of catalysts containing C1- and
C2-symmetric diphosphite ligands was proved to be efficient.2
In particular, C1-diphosphites lead to highly active catalysts
(TOF 4 3000 hÀ1) yielding enantioselectivities up to 499%.2b
Although allylic substitution reactions have been widely
studied, relatively few catalysts have been reported for kinetic
resolution.3,4
Fig. 1 Chiral diphosphite ligands, 1 and 2.
Table 1 Pd-catalysed asymmetric allylic alkylation with 1a
Conv.
(%)b
Ee(I)
(%)c
Ee(II)
(%)c
Entry
Pd/1/rac-I
Time (min)
1
1/1.25/50
10
30
5
60
15
30
100
100
34
89
55
55
55
0
—
—
nd
nd
99 (S)
99 (S)
99 (S)
—
98 (S)
98 (S)
96 (S)
96 (S)
98 (S)
98 (S)
98 (S)
—
Here, we report the first use of C2-symmetric chiral diphos-
phite ligands 1 and 2 (Fig. 1) in asymmetric allylic alkylation
and allylic amination reactions using rac-1,3-diphenyl-3-
acetoxyprop-1-ene, rac-I as the substrate with evidence for
kinetic resolution at low Pd concentrations.
2d
3
1/1.25/100
1/1.25/5000
1/1.25/5000
1/1.25/10000
1/1.25/10000
1/1.25/10000 120
1/1.25/10000 15
1/1.25/10000 1440
4
5
6
7
8e
9e
Initially, the Pd-catalysed asymmetric allylic alkylation using
dimethyl malonate as a base and rac-1,3-diphenyl-3-acetoxy-
prop-1-ene, rac-I, as the substrate was investigated with the
ligand 1. The results are collected in Table 1. At low substrate to
palladium ratio (entry 1), total conversion was achieved in
10 minutes with 98% ee. Similar results were obtained using the
isolated complex [Pd(Z3-C3H5)(1)]PF6 as the catalytic precursor
(entry 2).w When the substrate/palladium ratio was increased to
5000, 34% conversion was obtained after 5 min of reaction
(entry 3, TOF = 20 400 hÀ1); and after 1 h, 89% conversion
was achieved (entry 4, TOF = 4450 hÀ1). In both cases,
excellent asymmetric induction was achieved (ee Z 96%). To
20
0
498 (S)
a
Reaction conditions: 1 mmol of substrate, 3 mmol of dimethyl
malonate, 3 mmol of N,O-bis(trimethylsilyl)acetamide (BSA); Pd/1 =
0.5 [Pd(m-Cl)(Z3-C3H5)]2 + 1.25 eq. of 1, a pinch of KOAc in 4 mL of
b
CH2Cl2 at room temperature. Conversion determined by 1H NMR
c
analysis. Enantiomeric excess determined by HPLC on a Chiracel-OJ
column. Absolute configuration, in parentheses, determined by optical
e
rotation.5 d Catalyst precursor = [Pd(Z3-C3H5)(1)]PF6. Mixture of I
and II obtained from entry 7 used as substrate.
the best of our knowledge, this is the highest TOF value
reported for an asymmetric allylic alkylation reaction. Interest-
ingly, the monitored reaction (analyses at up to 2 h of reaction)
using a substrate to palladium ratio of 10000 gave a constant
substrate conversion of 55% (entries 5–7) with a TOF = 22 000 hÀ1
after 15 minutes of reaction. The ee of the product II was
98% and optically pure (S)-I remained for the unreacted
substrate. To demonstrate the difference in reactivity between
both substrate enantiomers, the resulting reaction mixture
a
´
´
`
Departament de Quımica Fısica i Inorganica, Universitat Rovira i
Virgili, C/ Marcel.li Domingo s/n 43007 Tarragona Spain.
E-mail: cyril.godard@urv.cat; Fax: +34 977 559563;
Tel: +34 977 559575
b
c
´ ´
´
Laboratoire Heterochimie Fondamentale et Appliquee, UMR CNRS
5069, 118, route de Narbonne, 31062 Toulouse cedex 9, France.
E-mail: gomez@chimie.ups-tlse.fr; Fax: +33 561558204;
Tel: +33 561557738
´
Departament de Quımica Analıtica i Quımica Organica, Universitat
Rovira i Virgili, C/ Marcel.li Domingo s/n 43007 Tarragona Spain
´
´
`
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Table 2 Pd-catalysed asymmetric allylic amination with chiral ligand 1a
Entry
Pd/1/rac-I
Time (h)
Conv.b (%)
Ee(I)c (%)
Ee(III)c (%)
k(R-I)/k(S-I)d
1
2
3
4
5
6
1/1.25/50
1
1
2
4
7
24
100
16
26
40
55
60
—
98 (R)
—
1/1.25/2500
1/1.25/2500
1/1.25/2500
1/1.25/2500
1/1.25/2500
16 (S)
31 (S)
58 (S)
87 (S)
93 (S)
499 (R)
499 (R)
499 (R)
499 (R)
99 (R)
13.4
21.6
25.8
16.4
13.8
a
Reaction conditions: 1 mmol of substrate, 1 mmol of benzylamine; Pd/1 = 0.5 [Pd(m-Cl)(Z3-C3H5)]2 + 1.25 eq. of 1, in 4 mL of CH2Cl2 at room
temperature. Conversion determined by 1H NMR analysis. Enantiomeric excess determined by HPLC on a Chiracel-OD column. Absolute
configuration, in parentheses, determined by optical rotation.5 d kR/kS = ln[(1 À C/100)(1 À ee/100)]/ln[(1 À C/100)(1 + ee/100)] with C and ee
corresponding to the substrate I.7
b
c
containing the enantiopure (S)-1,3-diphenyl-3-acetoxyprop-1-
ene, (S)-I, was re-used as the substrate under the same
catalytic conditions (entries 8 and 9). After 24 h of reaction,
only 20% conversion was observed. This fact evidences that
the reaction rate for the transformation of the (S)-I is more
than 100 times slower than that of the corresponding (R)-I
enantiomer, confirming the efficient kinetic resolution that
occurred under these conditions.
highly depends on the nature of the nucleophile used. These
results suggest that the nucleophile not only participates in the
selectivity-determining step but could also be involved in the
decomposition of the ligand, which competes with the catalytic
reaction.
To investigate the effect of the environment around the
phosphite moieties, we have also used ligand 2 showing
opposite configuration at the C2 and C5 carbon atoms.
Surprisingly, very low conversions in the allylic alkylation
were obtained with this catalytic system (less than 5% con-
version after 1 h of reaction using rac-I/Pd = 50), indepen-
dently if the catalyst precursor was the preformed complex
[Pd(Z3-C3H5)(2)]PF6w or whether it was generated in situ. Such
a remarkable remote effect was previously reported for ligands
1 and 2 and their diphosphinite analogues in other transition
metal catalysed processes.6 The increased steric hindrance
induced by this ligand could explain these observations.
In conclusion, our preliminary results in asymmetric allylic
substitution reactions using diphosphite ligands with C2-
symmetry show that the catalytic system containing ligand 1 is
highly active, showing the highest turn over frequency values
The same catalytic system was also evaluated in the Pd-
catalysed allylic amination using benzylamine as the nucleo-
phile (Table 2). At low substrate to Pd ratio (entry 1), the
reaction was completed in 1 h with excellent ee (98%). When
this ratio was increased to 2500 (entries 2–5), evidence for
kinetic resolution was again observed. Indeed, the ee of the
product III was constant throughout the reaction ( Z 99%)
while that corresponding to the substrate I was increasing as
the reaction went on (entries 2–6), to reach 93% after 24 h with
a substrate conversion of 60% (entry 6). The ratio of the
reaction rates for the enantiomers (R)-I and (S)-I was found to
vary between ca. 8 and 26. Concerning the activity, the turn
over frequency of the reaction achieves 400 hÀ1 at 16%
conversion (entry 2) and ca. 250 hÀ1 for a substrate conversion
of 40% (entry 4). To the best of our knowledge, this is the
highest activity reported for this asymmetric allylic amination
process with such high enantioselectivity.
reported for asymmetric allylic alkylation (TOF = 22 000 hÀ1
)
and allylic amination (TOF = 400 hÀ1) processes with ex-
cellent ee values for the substituted products, II and III (up to
498%). Moreover, the effect of the substrate/nucleophile
ratio in the activity of these reactions points to a poison effect
of the good donor nucleophiles. Furthermore, the results
obtained with ligand 2 clearly show that small changes in
the ligand structure can drastically affect the catalytic activity.
Further kinetic and mechanistic studies are currently on-going
and will be reported at a later stage.
In addition, both the amount and the nature of the nucleo-
phile modify the rate of the allylic substitution. When a large
excess of dimethyl malonate in relation to the substrate (rac-I/
dimethyl malonate/BSA = 1/20/20) was used, the catalytic
activity dropped significantly (9% conversion versus 89%
obtained for rac-I/dimethyl malonate/BSA = 1/3/3 (entry 4,
Table 1)). Moreover, this effect was even more remarkable for
the allylic amination. Only a moderate excess of benzylamine
(rac-I/benzylamine = 1/3) led to a 15% conversion in com-
parison with 55% for rac-I/benzylamine = 1/1 (entry 5,
Table 2). This effect could be explained by the slow decom-
position of ligand 1 in the presence of a large excess of
nucleophile and base, as observed by 31P NMR spectroscopy.
Interestingly, the significant difference in activity for both
allylic substitution reactions using identical substrate to nucleo-
phile ratio clearly indicates that the kinetics of the reaction
We are grateful to the Spanish Ministerio de Educacion y
Ciencia (CTQ2007-62288/BQU, Consolider Ingenio 2010,
CSD2006-0003, ‘‘Juan de la Cierva’’ fellowship to C. G.) and
the Generalitat de Catalunya (2005SGR007777 Distinction for
Research Promotion, 2003 C. C.) for financial support.
Notes and references
w Synthesis of complexes [Pd(g3-C3H5)(1)]PF6 and [Pd(g3-C3H5)(2)]PF6.
In a purged Schlenk tube, 9 mg (0.025 mmol) of [Pd(Z3-C3H5)(m-Cl)]2
and 75 mg (0.05 mmol) of ligand (1 or 2) were dissolved in 5 mL of
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distilled dichloromethane. The solution was stirred for 30 min at room
temperature and 15 mg of NH4PF6 (0.09 mmol) dissolved in 1 mL of
dichloromethane was then added. After 24 h of stirring, washings with
degassed water were carried out (4 Â 5 mL). The organic phase was
dried over anhydrous Na2SO4, filtered off and the solvent removed
under reduced pressure. The pale yellow solid obtained was washed with
diethyl ether (3 Â 5 mL) and dried under reduced pressure. Yields: 1:
83%; yield of 2: 85%. High resolution LC/ESI-TOF/MS: m/z (100%)
= 1663.7945 ([M À PF6]+) for both complexes.
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[Pd(g3-C3H5)(1)]PF6: NMR H (CDCl3, 400 MHz) d in ppm: 7.0–7.6
(m, Ph), 5.66 (t, 1H, CH), 5.59 (t, 1H, CH), 5.26 (m, 1H, CH), 4.27
(br s, 2H), 3.98 (br s, 2H), 3.71 (d, 2H), 3.33 (d, 2H), 1.45 (s, 18H), 1.40
(s, 18H), 1.32 (s, 18H), 1.25 (s, 18H), 0.95 (s, 18H); 31P (CDCl3, 101.3
MHz, 298 K) 138.77 ppm (s), À150.9 ppm (PF6).
1
[Pd(g3-C3H5)(2)]PF6: NMR H (CDCl3, 400 MHz) d in ppm: 7.2–7.6
(m, Ph), 5.65 (br s, 1H, CH), 5.53 (br s, 1H, CH), 5.02 (m, 1H, CH),
4,61 (br s, 2H), 4.68 (br s, 2H), 3.79 (m, 2H), 3.76 (m, 2H), 1.46
(s, 18H), 1.37 (s, 18H), 1.33 (s, 18H), 1.26 (s, 18H), 0.95 (s, 18H); 31P
(CDCl3, 101.3 MHz, 298 K) 140.32 ppm (s), À161.3 ppm (PF6).
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Chem. Commun., 2008, 6197–6199 | 6199