Palladium catalysed enantioselective phosphination reactions using secondary phosphine-boranes and aryl iodide

Article abstract of DOI:10.1039/b501078k

Preliminary results dealing with the enantioselective version of the C-P cross-coupling reaction between dissymmetric secondary phosphine-borane complexes and aryl iodide derivatives are presented. To gain information on the enantiodiscriminating step, di

Full text of DOI:10.1039/b501078k

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Palladium catalysed enantioselective phosphination reactions using
secondary phosphine-boranes and aryl iodide{
Ste´phanie Pican and Annie-Claude Gaumont*
Received (in Cambridge, UK) 24th January 2005, Accepted 4th March 2005
First published as an Advance Article on the web 15th March 2005
DOI: 10.1039/b501078k
conversion was completed with 2, however with 1, the reaction was
sluggish (6% conv.). Even at 60 uC, the reaction with 1 was
sluggish (35% conv.). Since we had previously observed that the
rate-limiting step was the reductive elimination,5 we selected a
ligand having a greater bite angle, which should favour the
reductive elimination. Thus, using racemic BINAP and a
palladium source [Pd2dba3 or Pd(OAc)2], a complete transforma-
tion of the precursor 1 into the expected arylation product 3
was observed after 48 hours. Although both palladium
sources are effective precatalysts, Pd(OAc)2 was preferred
since the use of Pd2dba3 resulted in the formation of a side
product which was identified as the hydrophosphination adduct
of dba.
Preliminary results dealing with the enantioselective version of
the C–P cross-coupling reaction between dissymmetric second-
ary phosphine-borane complexes and aryl iodide derivatives are
presented. To gain information on the enantiodiscriminating
step, direct observation of an intermediate involved in the
catalytic cycle has been achieved by 31P NMR spectroscopy.
Since several decades, phosphines have played a key role in the
development of asymmetric catalysis. Among these, P-chirogenic
ligands have been less studied, mainly because of the difficulties
encountered in their synthesis. They are mainly prepared by
resolution processes or by using a stoichiometric amount of a
chiral auxiliary.1 Recently, in a remarkable work, Glueck has
demonstrated that P-chirogenic phosphines could also be prepared
by asymmetric catalysis using a catalytic amount of a chiral
auxiliary.2 Thus, an enantioenriched tertiary phosphine was
obtained with enantiomeric excesses varying from 53 to 78% via
phosphination of a phenyl halide using a racemic bulky secondary
phosphine [i.e. methyl(triisopropylphenyl)phosphine] as precursor,
in conjunction with NaOSiMe3 as base and a chiral palladium
catalyst. Then, Helmchen successfully applied this kind of
methodology to the synthesis of a family of enantioenriched
triarylphosphines (ee between 25 and 93%) involving coupling
phenyl(o-biphenyl)phosphine with an ortho-substituted aryl
iodide.3
After purification of the coupling products (3 and 4) by silica gel
chromatography in air, conditions for the separation of the two
enantiomers of each coupling product were defined by HPLC.6
ð1Þ
We then investigated the C–P cross-coupling reaction between
racemic phosphine 1 and m-iodoanisole mediated by various
enantiopure ligands, using Pd(OAc)2, K2CO3 and CH3CN as
previously stated. The reaction was monitored by 31P NMR
spectroscopy. Whatever the identity of the ligand, the reaction was
sluggish at room temperature and heating at 40 uC proved more
convenient. The reactions were stopped before reaching 50%
conversion by quenching with an aqueous solution and each ee
was measured by HPLC after purification by silica gel chromato-
graphy.{ Selected results are reported below. With phosphine 1
and (R)-BINAP (L1), (S)-PHANEPHOS (L2), the bisoxazoline7
L3, or (R)-(S)-PPFA (L4), racemic 3 was obtained. Even,
(R,R)-Me-DuPHOS (L5), the ligand of choice used by Glueck,2
gave racemic product in our reaction. Nevertheless, four ligands
gave promising enantioselectivities: (S,S)-BDPP (L6) (17%),
(R,R)-Et-FerroTANE8 (L7) (12%), the bisthiazoline9 L8 (13%)
and the phosphine-oxazoline10 L9 (27%). All results are
summarized in Fig. 1.
Our group has recently been involved in the C–P bond forming
reactions by using either the hydrophosphination reaction4 or the
metal catalysed C–P cross-coupling reaction. In the latter case, we
began our investigation by examining the catalytic cycle of the
Pd(0) mediated cross-coupling reaction between an aryl iodide and
diphenylphosphine-borane.5 Herein we report our preliminary
results on the enantioselective version of this reaction using simple
unhindered racemic secondary phosphine-borane precursors 1 and
2 and chiral catalysts.
We first examined the racemic version of the reaction in order to
determine conditions allowing the separation of the 2 enantiomers
of the cross-coupling product. Preliminary coupling conditions
tested were based on those reported for the coupling of
diphenylphosphine-borane.5 Thus, we reacted respectively, for
24 hours, tert-butylphenylphosphine-borane 1 and o-anisylphenyl-
phosphine-borane 2 with m-iodoanisole in CH3CN at room
temperature in the presence of dpppPdCl2 (5 mol%) and two
equivalents of K2CO3 [eqn. (1)]. Under these conditions, the
Screening of other parameters (base and solvent) with the ligand
giving the best results (e.g. phosphine-oxazoline L9) was then
performed. With a more polar solvent (DMSO), a similar
enantioselectivity was obtained. However using less polar
solvents (CH2Cl2, THF or toluene) was always detrimental to
the ee. Replacing K2CO3 by Cs2CO3 in CH3CN showed no
improvement.
{ Electronic supplementary information (ESI) available: HPLC chroma-
togram for 3 and crystallographic data for 7b. See http://www.rsc.org/
suppdata/cc/b5/b501078k/
*annie-claude.gaumont@ensicaen.fr
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Chem. Commun., 2005, 2393–2395 | 2393

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precursor signals and the quantitative formation of the transme-
tallation adduct at 270 uC.
ð2Þ
The distinctive 31P NMR spectrum, shown in Fig. 2, reveals the
trans relationship of the two phosphorus atoms and is consistent
with the proposed structure 7. The transmetallation adduct
was obtained as an equimolar amount of the two expected
diastereomers (7a and 7b) indicating no kinetic resolution in
the reaction between the phospha-anion intermediate and
complex 6. The mixture was then allowed to reach rt slowly (5 h)
and 31P NMR spectra were recorded regularly. No variation of the
diastereomeric ratio (50:50) was observed during the warming. To
promote the reductive elimination, the mixture was gently heated
in the NMR probe at 55 uC. Even at this temperature, complex 7
proved to be stable and did not produce the cross-coupling
product or any decomposition product. Interestingly, during the
heating, a modification of the diastereomeric ratio was observed
by 31P NMR, leading to a final ratio of 23:77. Only a
thermodynamic equilibrium between the 2 diastereomers can
account for the observed ratio modification. This result seems
to indicate that, for this example, the stereoselectivity of the
reaction is governed more by thermodynamic factors than by
kinetic ones.
Fig. 1 Conversions and enantioselectivities in the C–P cross-coupling
between 1 and m-iodoanisole using various chiral ligands (L1–L9).
Using the best defined conditions [L9, Pd(OAc)2, CH3CN and
K2CO3], the influence of temperature on ee was studied. Upon
lowering the temperature from 40 uC to room temperature (20 uC),
we were pleased to measure a satisfactory enantiomeric excess of
45%. Using a lower temperature (0 uC) resulted in an extremely
slow reaction (2% conversion after 3 weeks).
Since complex 7 was stable at rt, we were able to separate the
two diastereomers 7a and 7b by flash chromatography using
CH2Cl2 as eluant. A single crystal of the major diastereomer was
grown from slow evaporation of a CH2Cl2–heptane solution
allowing the confirmation of the structure of the transmetallation
adduct 7 (Fig. 3) and establishing the absolute configuration of
the phosphido-borane P centre which is (S) for the main
diastereomer (7b).
We then turned our attention to o-anisylphenylphosphine-
borane 2 in order to obtain information on the influence of the
substituents on the ee. Using the conditions defined for 1 [L9,
Pd(OAc)2, CH3CN, K2CO3, 40 uC], low enantioselectivity was
obtained with 2 (3% compared to the 27% measured with
phosphine 1). Surprisingly, by lowering the temperature to rt, the
ee was not improved.
To gain understanding of this result, we undertook a study of
the catalytic cycle, following the preliminary work done using the
racemic version.5 Thus, one equivalent of complex 5 (previously
prepared according to a method reported by Brown11 for similar
structures) and an excess of racemic phosphine-borane 2 (3
equivalents) were treated with a base (Me3SiOK) in THF-d8 at
270 uC [eqn. (2)].
Low temperature 31P NMR monitoring of the reaction showed
a complex mixture from which transmetallation intermediates were
too ill-defined to be characterized. The mixture was then allowed
to reach rt slowly and 31P NMR revealed a clear formation at 0 uC
of the coupling product 4, indicating that reductive elimination
had occurred.
To characterize the transmetallation adducts, the rate of the
reductive elimination was decreased using iodopentafluoroben-
zene. Thus complex 6, prepared as previously, was reacted with
Fig. 2 31P NMR spectrum of transmetallation adducts 7a and 7b in
THF-d8 at 270 uC; assignments: d ppm 26.8 (d, J 5 351 Hz, P2), 0.9 (d,
J 5 343 Hz, P4), 17.9 (d, J 5 351 Hz, P1), 18.9 (d, J 5 343 Hz, P3).
an excess of
Monitoring of the reaction by low temperature 31P NMR
spectroscopy showed, this time, the clean disappearance of the
2 [eqn. (2)] and Me3SiOK at 270 uC.
2394 | Chem. Commun., 2005, 2393–2395
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Ste´phanie Pican and Annie-Claude Gaumont*
Laboratoire de Chimie Mole´culaire et Thio-organique, UMR CNRS
6507, ENSICAEN, Universite´ de Caen, 6 bd du Mare´chal Juin,
14050 Caen, France. E-mail: annie-claude.gaumont@ensicaen.fr;
Fax: +33 2 31 45 28 77; Tel: +33 2 31 45 28 73
Notes and references
{ Representative procedure for enantioselective C–P cross-coupling reactions.
In a Schlenk tube, the ligand (0.022 mmol) and palladium acetate (2 mg,
8.9 1023 mmol) were stirred for 15 min at room temperature in 1 mL of
acetonitrile. To this solution were added m-iodoanisole (23 mL, 0.2 mmol),
potassium carbonate (54 mg, 0.39 mmol) and phosphine-borane 1 or 2
(0.2 mmol). The mixture was heated for a time ‘‘t’’ at the desired
temperature T. The reaction was followed by 31P NMR and stopped before
reaching 50% conversion by quenching with an aqueous solution. The
product 3 or 4 was extracted with diethyl ether and the organic layer dried
over magnesium sulfate. The solvent was removed under reduced pressure
and the crude product purified by silica gel chromatography using toluene
as eluant. Ee was measured by HPLC.
§ The following crystal structure has been deposited at the Cambridge
Crystallographic Data Centre and allocated the deposition number CCDC
227137. See http://www.rsc.org/suppdata/cc/b5/b501078k/ for crystallo-
graphic data in CIF or other electronic format. Crystal data for 7b:
˚
Fig. 3 X-Ray structure of the complex 7b.§ Selected bond lengths (A)
and angles (u): Pd(1)–C(25), 2.010(3); Pd(1)–N(1), 2.107(3); Pd(1)–P(1),
2.3005(10); Pd(1)–P(2), 2.3504(10); C(25)–Pd(1)–N(1), 178.32(13); C(25)–
Pd(1)–P(1), 93.37(10); N(1)–Pd(1)–P(1), 86.02(9); C(25)–Pd(1)–P(2),
88.71(10); N(1)–Pd(1)–P(2), 91.88(9); P(1)–Pd(1)–P(2), 177.87(4).
PdP2C43H39BF5NO2?C5H12, Mr 5 948.05, trigonal, P32, a 5 11.9662(3),
˚
3
c 5 26.4783(5) A, V 5 3283.5(1) A , Z 5 3, Dx 5 1.438 mg m23
,
˚
l(MoKa) 5 0.71073A, m 5 5.58 cm21, F(000) 5 1464, T 5 120 K. The
˚
sample (0.35 6 0.32 6 0.32 mm) is studied on a NONIUS Kappa CCD
with graphite monochromatized MoKa radiation. Structure refined with
SHELXL9713: 541 variables and 6578 observations with I . 2.0s(I);
To confirm this result, the reaction was performed again under
the same conditions but using strictly stoichiometric amounts of
phosphine-borane 2 and complex 6 (1 to 1 equivalent). Under
these conditions, the results obtained were exactly the same as
those obtained previously (a 50:50 ratio and a 23:73 ratio were
measured for the two diastereomers respectively at 270 uC and
+55 uC) confirming the thermodynamic equilibrium. These results
indicate that there is a temperature required for the equilibration
between the two transmetallation adducts. Below this temperature
the cross-coupling product is obtained with a low ee, assuming that
P–C bond formation by reductive elimination proceeds with
retention of configuration.12
R 5 0.031, Rw 5 0.075 and Sw 5 1.071 , Dr , 1.0 e A23. Absolute
˚
configuration determined with the Flack parameter: 20.05(2). Atomic
scattering factors from International Tables for X-ray Crystallography.14
Ortep views realized with PLATON98.15
1 See for example: K. M. Pietrusiewicz and M. Zablocka, Chem. Rev.,
1994, 94, 1375; K. V. L. Cre´py and T. Imamoto, Top. Curr. Chem.,
2003, 229, 1.
2 J. R. Moncarz, N. F. Laritcheva and D. S. Glueck, J. Am. Chem. Soc.,
2002, 124, 13356.
3 C. Korff and G. Helmchen, Chem. Commun., 2004, 530.
4 D. Mimeau and A. C. Gaumont, J. Org. Chem., 2003, 68, 7016;
D. Mimeau, O. Delacroix and A. C. Gaumont, Chem. Commun., 2003,
2928.
5 A. C. Gaumont, M. B. Hursthouse, S. J. Coles and J. M. Brown, Chem.
Commun., 1999, 63.
In summary, conditions allowing the C–P cross-coupling
between a racemic secondary phosphine-borane and an aryl
iodide have been examined. A great difference between 2 simple
phosphine precursors, an alkyl-aryl derivative (tert-butylphenyl-
phosphine-borane 1) and a diaryl derivative (o-anisylphenylpho-
sphine-borane 2), has been observed. Under the conditions
defined [CH3CN, K2CO3, rt, Pd(OAc)2 and ligand L9],
phosphine 1 was coupled with a satisfactory ee of 45% while
6 CHIRALPAK1 AD Column; eluent for 3: n-heptane–propan-2-ol
(97:3), 1 mL min21, 28 uC; eluent for 4: n-heptane–propan-2-ol (95:5),
1 mL min21, 5 uC.
7 [R(R*,R*)]-(+)-2,29-Isopropylidenebis(4-benzyl-2-oxazoline).
8 A. Marinetti, F. Labrue and J. P. Genet, Synlett, 1999, 1975; U. Berens,
M. J. Burk, A. Gerlach and W. Hems, Angew. Chem. Int. Ed., 2000, 39,
1981.
9 (R,R)-2,29-(1-Methylethylidene)bis[4,5-dihydro-4-ethylthiazoline]:
I. Abrunhosa, M. Gulea, J. Levillain and S. Masson, Tetrahedron:
Asymmetry, 2001, 12, 2851.
phosphine
2 gave under the same conditions a racemic
10 (R)-(+)-2-[2-(Diphenylphosphino)phenyl]-4-(1-methylethyl)-4,5-dihy-
drooxazole: G. Helmchen and A. Pfaltz, Acc. Chem. Res., 2000, 33, 336;
A. Pfaltz, Acta Chem. Scand., 1996, 50, 189.
11 Complexes 5 and 6 were prepared according to the preparation
procedure of iodo[1,3-bis(diphenylphosphino)propane](phenyl)-palla-
dium, see: J. M. Brown and P. J. Guiry, Inorg. Chim. Acta., 1994,
220, 249.
12 J. R. Moncarz, T. J. Brunker, D. S. Glueck, R. D. Sommer and
A. L. Rheingold, J. Am. Chem. Soc., 2003, 125, 1180; J. R. Moncarz,
T. J. Brunker, J. C. Jewett, M. Orchowski, D. S. Glueck, R. D. Sommer,
K. C. Lam, C. D. Incarvito, T. E. Concolino, C. Ceccarelli,
L. N. Zakharov and A. L. Rheingold, Organometallics, 2003, 22, 3205.
13 G. M. Sheldrick, SHELXL-97, Program for refinement of crystal
structures, University of Go¨ttingen, Germany, 1997.
14 International Tables for X-ray Crystallography, ed. A. J. C. Wilson,
Kluwer Academic, Dordrecht, 3rd series, 1992, vol. C.
15 A. L. Spek, PLATON98, A Multipurpose Crystallographic Tool, Utrecht
University, Utrecht, 1998.
coupling product. A mechanistic investigation suggests that, at
least for the diaryl derivative, the enantiodiscrimination could
arise from thermodynamic control. Extensive exploration of
this reaction to obtain more mechanistic details of the
enantioselective C–P cross coupling reaction will be reported in
due course.
The authors thank CNRS, Ministe`re de la recherche, Conseil
Re´gional de Basse-Normandie and FEDER (Fonds Europe´ens de
De´veloppement Economique Re´gional) for their financial support.
Margareth Lemarie´ (LCMT, UMR CNRS 6507, CAEN) and Dr
Lo¨ıc Toupet (UMR CNRS 6626, Rennes) are respectively
acknowledged for HPLC analysis and determination of X-ray
structure. I. Abrunhosa and M. Gulea are acknowledged for a
loan of ligand L8.
This journal is ß The Royal Society of Chemistry 2005
Chem. Commun., 2005, 2393–2395 | 2395