Pallado-catalysed hydrophosphination of alkynes: Access to enantio-enriched P-stereogenic vinyl phosphine-boranes

Article abstract of DOI:10.1039/b607434k

Preliminary results dealing with the synthesis of non-racemic P-stereogenic vinylphosphine-boranes by hydrophosphination of alkynes in the presence of a chiral catalyst are reported. The Royal Society of Chemistry 2006.

Full text of DOI:10.1039/b607434k

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Pallado-catalysed hydrophosphination of alkynes: access to enantio-
enriched P-stereogenic vinyl phosphine–boranes{
Benoˆıt Join,a David Mimeau,b Olivier Delacroixa and Annie-Claude Gaumont*a
Received (in Cambridge, UK) 25th May 2006, Accepted 9th June 2006
First published as an Advance Article on the web 26th June 2006
DOI: 10.1039/b607434k
Preliminary results dealing with the synthesis of non-racemic
P-stereogenic vinylphosphine–boranes by hydrophosphination
of alkynes in the presence of a chiral catalyst are reported.
Phosphines are the main ligands in homogeneous catalysis.1
Although many chiral phosphines are found in the literature, only
few among them are P-stereogenic, i.e. with the chirality centre at
the phosphorus atom. This low availability can be explained by the
difficulties encountered in their synthesis. P-stereogenic phosphines
are mainly prepared by resolution processes or via asymmetric
Scheme 1 Hydrophosphination of 1-ethynylcyclohexene.
toluene).17 A range of chiral ligands having various steric and
electronic properties such as ferrocenylbisphosphine (L1), ferroce-
nylphosphine-amine (L2), phosphine-oxazoline (L3), thiazoline
amine (L4), bisphosphine with central (L5, L6, L7, L10, L11),
planar (L8) or axial chirality (L9) were first tested (Fig. 1).
The procedure was quite simple.{ The ligand L and palladium
acetate were mixed together in toluene and stirred 15 mn prior to
introduction of 1 and alkyne. The mixture was then heated at 35 uC
synthesis using stoichiometric amounts of chiral auxiliaries.2–6
A
more elegant approach relies on the use of asymmetric catalysis.
However, only few examples have been reported until now.7–13
In our group, we are interested in the formation of C–P bonds
by the metallo-catalysed C–P cross coupling reactions10,14 or by
the atom economical hydrophosphination reactions.15–18 Dealing
with hydrophosphination reactions, our work is mainly focused on
the less studied addition of phosphines to unactivated unsaturated
compounds19 i.e. alkenes and alkynes. With alkynes, we developed
two procedures allowing to prepare the anti-Markovnikov adducts
by addition of a secondary phosphine–borane to an alkyne under
thermal conditions and the Markovnikov derivatives by using a
metallo-catalysed activation.17 We thus reasoned that the reaction
between a racemic secondary phosphine–borane and a chiral
palladium catalyst should give an access to P-stereogenic
phosphines assuming a transfer of chirality from the catalyst to
the product. We report here our preliminary results on the
synthesis of tertiary vinylphosphine derivatives by palladium
catalysed asymmetric hydrophosphination of alkynes. To the best
of our knowledge, there is no example of catalyzed asymmetric
hydrophosphination providing P-stereogenic vinylphosphines in
the literature.
The reaction between methylphenylphosphine–borane 1, a
representative alkylarylphosphine and 1-ethynylcyclohexene was
chosen as a model case (Scheme 1). The reactions were performed
under kinetic resolution conditions, i.e. with 0.5 equiv. of alkyne
for 1 equiv. of phosphine 1.
First sets of experiments were performed under the conditions
optimized for the racemic version (Pd(OAc)2, diphosphine,
aLaboratoire de Chimie Mole´culaire et Thio-organique, UMR CNRS
6507, ENSI-CAEN, and Universite´ de Caen, 6 bd du Mare´chal Juin,
14050, Caen, France. E-mail: annie-claude.gaumont@ensicaen.fr;
Fax: 0033 2 31 45 28 77; Tel: 0033 2 31 45 28 73
bLaboratoire de Synthe`se et d’Electrosynthe`se Organique, UMR CNRS
6510 Universite´ de Rennes, Campus de Beaulieu, 35042, Rennes, France
{ Electronic supplementary information (ESI) available: 1H, 11B, 13C and
31P NMR spectra of 2, HPLC chromatogram of enantio-enriched 2. See
DOI: 10.1039/b607434k
Fig. 1 Conversion of 1 into 2 and ee using enantiopure ligands.
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and the conversion was followed by 31P NMR. After 17 h, the
product was purified on silica gel chromatography under air and
conditions for the separation of the two enantiomers were defined
by HPLC. It should be pointed out that purification was made
easier by the presence of the borane, which protects the phosphine
from oxidation.20 Important ligand effects in catalytic activity and
in enantioselectivity were revealed by this screening (Fig. 1). A
reasonable conversion of 30% (50% max. due to kinetic resolution
conditions) was obtained with ferrocenyl ligand (L1), phosphine
oxazoline (L3) and bisphosphine (L5). Other ligands afforded a
rather low conversion (¡10%) except BINAP (L9), for which a
conversion of 20% was measured. With thiazoline (L4), no
conversion was observed.21 Low enantiomeric excesses (,10%)
were obtained with all the electron poor bisarylphosphines
whatever the kind of chirality involved: central (L5, L6, L7), axial
(L9) and planar (L8) ones. With arylphosphine-amine ligands L2
and L3, ee slightly higher than 10% were obtained. Mixed alkyl-
aryl bisphosphine (L1) showed promising ee (close to 20%). These
preliminary results indicate that electron rich substituents on the
phosphorus atom play a determining role in the enantioselection
step. To validate this assumption, a rigid and electron rich ligand,
the bis-phospholane (R,R)-MeDUPHOS (L10), was tested. A
rather low conversion of 12% was obtained. Nevertheless, a
promising ee of 30% was measured by HPLC. We thought that
increasing the steric hindrance by using (R,R)-i-PrDUPHOS (L11)
could favour the enantiodiscrimination even if the conversion
could suffer. As expected a lower conversion was observed (8%)
but without any benefit to the ee. Enantiomers of L10 and L11,
respectively (S,S)-MeDuphos (L12) and (S,S)-i-PrDuphos (L13)
gave the other enantiomer with similar ee.
Fig. 2 Conversion of 1 into 2 and ee using different solvents.
to test more polar solvents (Fig. 2). Dichloromethane proved to be
detrimental both for the activity and the selectivity even if the
solubility of the precatalyst was good. In a more polar solvent such
as acetonitrile, a high solubility of the precatalyst was observed,
but no conversion was obtained. An explanation can arise from
the high coordinating ability of acetonitrile, which is able to
compete with the alkyne in the catalytic cycle. With these results in
hand, we selected a less coordinating polar solvent (tetrahydro-
furan) than acetonitrile. As expected, a high solubility of the
catalyst was observed. However, the conversion and the selectivity
were slightly lower than those obtained in toluene. Consequently
toluene was retained to carry on the study.
Influence of the temperature on the activity and the enantio-
selectivity was then evaluated (Fig. 3). This set of tests was carried
out in toluene and the reactions were stopped after 17 h.
Since low ee could result from autocatalysis (phosphine–boranes
1 and 2 playing the role of an achiral ligand),22 compounds 1 and
racemic 2 were both tested as ligands with Pd(OAc)2. Almost no
conversion was observed (,3%) indicating that autocatalysis may
be disregarded under these conditions.
At temperature lower than 35 uC, the conversion was too low to
allow isolation and purification of the product, precluding
measurement of the ee. At higher temperature (50 uC), the
conversion increased dramatically (35 vs. 12% at 35 uC),
presumably because of a better solubility of the precatalyst in this
solvent. Furthermore a slight increase of enantioselectivity was
observed (42 vs. 30% at 35 uC). Increasing further on the
temperature (60 and 65 uC) proved to be detrimental for both
activity and enantioselectivity. This drop of activity and selectivity
can be attributed to the decomplexation of phosphine–borane 1
leading to the corresponding free phosphine, which is less reactive
than 1 and can furthermore compete with the ligand for palladium
In order to improve the catalytic activity and the selectivity of
the reaction, influence of other parameters such as palladium
source, ligand/metal ratio, solvent and temperature were studied.
(R,R)-MeDUPHOS, which gave the best ee, was used in these
tests. Given that palladium acetate required first to be reduced to
generate the active species, a palladium(0) source (Pd2(dba)3) was
used. After 17 h at 35 uC in toluene, a conversion of 16% and a
lower enantioselectivity of 19% were measured. Moreover, a by-
product was detected (d(31P) = 19 ppm). The NMR signals of the
by-product are consistent with the hydrophosphination adduct of
dibenzylidene acetone (dba). To avoid this side-reaction, Pd(OAc)2
was preferred.
Influence of the metal/ligand ratio on the enantioselectivity was
then studied. The first set of tests was performed with a 1 : 1.5
metal : ligand ratio. Increase of the amount of ligand to 2 equiv.
(10 mol%) led to similar conversion and selectivity, while a
decrease to 1 equiv. (5 mol%) induced a considerable drop of
selectivity (17 vs. 30% ee with 1.5 equiv.). These results could be
explained by the fact that part of the ligand is used to reduce the
Pd(II) into the catalytically active Pd(0) species.
The preliminary enantioselective hydrophosphination reactions
were performed in toluene. Solubility of the palladium precatalyst
being rather low in this solvent, we thought that the poor
conversion could result from this low solubility. We thus decided
Fig. 3 Conversion of 1 into 2 and ee using different temperatures.
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1
+
?
complexation. Monitoring of the reaction by 31P NMR of crude
samples confirmed the partial decomplexation of phosphine–
borane 1 when heated at these temperatures.
JBH = 95.3 Hz). HMRS calc. for C15H19P ([M 2 BH3] : 230.1227, found:
230.1224).
1 R. Noyori, Asymmetric Catalysis in Organic Synthesis, J. Wiley & Sons
Ltd, New York, 1994.
2 S. Juge´, M. Stephan, J.-A. Laffitte and J.-P. Geneˆt, Tetrahedron Lett.,
1990, 31, 6357.
3 A. R. Muci, K. R. Campos and D. A. Evans, J. Am. Chem. Soc., 1995,
117, 9075.
4 M. Pietrusiewicz and M. Zablocka, Chem. Rev., 1994, 94, 1375.
5 K. V. L. Cre´py and T. Imamoto, Adv. Synth. Catal., 2003, 345, 1 & 2.
6 M. J. Johansson and N. C. Kann, Mini. Rev. Org. Chem., 2004, 1, 233.
7 V. S. Chan, I. C. Stewart, R. G. Bergman and F. D. Toste, J. Am.
Chem. Soc., 2006, 128, 2786.
8 C. Scriban and D. S. Glueck, J. Am. Chem. Soc., 2006, 128, 2788.
9 N. F. Blank, K. C. McBroom, D. S. Glueck, W. S. Kassel and
A. L. Rheingold, Organometallics, 2006, 25, 1742, and references
therein.
Influence of the amount of alkyne was finally tested. The
reaction was conducted under the best conditions previously
defined [(Pd(OAc)2, (R,R)-MeDuphos, toluene, 50 uC, 17 h] on
using 1.2 equiv. of alkyne instead of 0.5 equiv. As expected, a
strong increase in conversion was obtained (70%) for a similar ee.
In conclusion, we have reported the first palladium catalysed
asymmetric hydrophosphination of non-activated alkynes. High
conversion (70%) and enantiomeric excess up to 42% were
obtained. Mechanistic investigations are currently under progress
in order to gain information on the enantiodiscriminating step and
will be reported in due course.
10 S. Pican and A.-C. Gaumont, Chem. Commun., 2005, 2393.
11 C. Korff and G. Helmchen, Chem. Commun., 2004, 530.
12 C. Scriban, I. Kovacik and D. S. Glueck, Organometallics, 2005, 24,
4871, and references therein.
13 A. Motta, I. L. Fragala` and T. J. Marks, Organometallics, 2005, 24,
4995, and references therein.
14 A. -C. Gaumont, M. J. Hursthouse, S. J. Coles and J. M. Brown, Chem.
Commun., 1999, 97.
15 D. Mimeau, O. Delacroix and A.-C. Gaumont, Chem. Commun., 2003,
2928.
Notes and references
{ Typical procedure for metallocatalysed hydrophosphination reaction: In a
Schlenk tube, flamed under vacuum and flushed with nitrogen, Pd(OAc)2
(1.25 6 1025 mol, 3 mg, 5 mol%) and (R,R)-MeDUPHOS (1.9 6
1024 mol, 6 mg, 7.5 mol%) were introduced. After three vacuum/N2 cycles,
200 mL of toluene were added and the mixture was stirred at 50 uC during
20 min. Then methylphenylphosphine–borane 1 (2.5 6 1024 mol., 35 mL),
ethynylcyclohexene (3 6 1024 mol, 33.5 mL, 1.2 equiv.) and toluene (50 mL)
were added to the solution. The mixture was stirred for 17 h at 50 uC and
then directly purified by silica gel chromatography (AcOEt–heptane–
toluene, 2 : 6 : 2, Rf = 0.6) affording pure hydrophosphination product 2.
Ee values were measured by HPLC using an AD-RH column (H2O–
MeCN, 63 : 37, flow 1 mL min21, t1 = 61 min, t2 = 66 min) at 25 uC.
31P NMR (161 MHz, CDCl3): d 11.61 (dm, 1JPB = 65.3 Hz); 1H NMR
(400 MHz, CDCl3): d 7.75–7.60 (m, 2H); 7.55–7.40 (m, 3H); 5.92 (d,
3JHPtrans = 36.2 Hz, 1H); 5.82 (d, 3JHPcis = 18.1 Hz, 1H); 5.77–5.71 (m, 1H);
16 D. Mimeau, O. Delacroix, B. Join and A.-C. Gaumont, C. R. Chim.,
2004, 7, 845.
17 D. Mimeau and A.-C. Gaumont, J. Org. Chem., 2003, 68, 7016.
18 B. Join, O. Delacroix and A.-C. Gaumont, Synlett, 2005, 1881.
19 For a recent review on hydrophosphination of unactivated unsaturated
compounds, see: O. Delacroix and A.-C. Gaumont, Curr. Org. Chem.,
2005, 9, 1851.
20 A.-C. Gaumont and B. Carboni, Science of Synthesis, Thieme, Stuttgart,
2005, vol. 6, ch. 16, p. 485.
21 M. Gulea is acknowledged for a loan of ligand L4; I. Abrunhosa,
M. Gulea, J. Levillain and S. Masson, Tetrahedron: Asymmetry, 2001,
12, 2851.
2
2.10–1.85 (m, 4H); 1.69 (d, JHP = 9.8 Hz, 3H); 1.65–1.52 (m, 2H); 1.52–
1
1.43 (m, 2H); 0.95 (qm, JHB = 95.3 Hz, 3H). 13C NMR (101 MHz,
CDCl3): d 143.35 (d, 1JCP = 45.1 Hz); 134.72 (d, 2JCP = 6.2 Hz); 131.81 (d,
2JCP = 9.5 Hz); 131.28 (d, 4JCP = 2.2 Hz); 131.00 (d, 1JCP = 55.0 Hz); 130.16
(d, 3JCP = 5.8 Hz); 129.06 (d, 3JCP = 10.0 Hz); 126.57 (d, 2JCP = 10.7 Hz);
22 C. Darcel, E. B. Kaloun, R. Merde`s, D. Moulin, N. Riegel,
S. Thorimbert, J. P. Geneˆt and S. Juge´, J. Organomet. Chem., 2001,
624, 333.
3
1
28.53 (d, JCP = 3.0 Hz); 25.91 (s); 22.99 (s); 22.05 (s); 12.15 (d, JCP
=
40.7 Hz). 11B NMR (128 MHz, CDCl3): d 233.53 (dq, JBP = 65.3 Hz,
1
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Chem. Commun., 2006, 3249–3251 | 3251