An axially chiral phosphine ligand based on restricted rotation in N-arylimides

Article abstract of DOI:10.1016/S0040-4039(01)01482-4

Described is the preparation, resolution, and absolute configuration of a new axially chiral monodentate phosphine ligand. The chirality of the ligand is derived from restricted rotation about a central N_imide-C_aryl bond, resulting i

Full text of DOI:10.1016/S0040-4039(01)01482-4

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 7185–7187
An axially chiral phosphine ligand based on restricted rotation in
N-arylimides
Yizhao Chen, Mark D. Smith and Ken D. Shimizu*
Department of Chemistry and Biochemistry, University of South Carolina, Columbia, SC 29208, USA
Received 18 July 2001; revised 9 August 2001; accepted 10 August 2001
Abstract—Described is the preparation, resolution, and absolute configuration of a new axially chiral monodentate phosphine
ligand. The chirality of the ligand is derived from restricted rotation about a central NimideꢀCaryl bond, resulting in enantiomeric
atropisomers that are stable and separable up to >120°C. Finally, the ability of the new axially chiral phosphine ligand is
demonstrated in a Pd-catalyzed allylic alkylation reaction. © 2001 Elsevier Science Ltd. All rights reserved.
Chiral phosphines are important molecules in effecting
asymmetric transformations as ligands for transition
metal catalysts and as chiral nucleophilic catalysts.1,2
One of the most successful classes of chiral phosphines
have been the axially chiral biaryls, as exemplified by
the monodentate MOP3 and the bidentate BINAP.4
The synthesis of new axially chiral biaryls, however,
remains a challenge due to the difficulties in forming
the central sterically hindered CarylꢀCaryl bond.5 There-
fore, we have set out to develop the chemistry of more
synthetically accessible axially chiral molecules based
on the restricted rotation in N-arylimides.6,7 Presented,
herein, is the synthesis, resolution, structural analysis,
and asymmetric transformations of axially chiral
monophosphine 1 based upon an N-arylimide frame-
work.
highly asymmetric environment. The steric repulsion of
the phenyl groups of the diphenylphosphine and the
adjacent imide group orient the phosphine lone pair
toward the imide surface. This conformation is benefi-
cial as the coordination of a metal center by the phos-
phine atom would ‘enshroud’ it in the highly
asymmetric environment over the imide ring in which
one face would be shielded by the phenyl substituents
that project up from the imide surface. In contrast, a
structurally similar axially chiral monophosphine
reported by Virgil et al. positions the phosphine lone
pair over a relatively flat aromatic surface.8
One of the primary advantages of monophosphine 1 is
that it can be rapidly synthesized from common start-
ing materials (Scheme 1).9 In contrast to the biaryls, the
central bond is readily formed by heating an appropri-
ately substituted aniline with a cyclic anhydride. For
example, condensation of aminophosphine 4 with 2,2-
diphenylsuccinic anhydride 5 proceeds in high yield
(81%) to give ( )-1 simply be heating the neat compo-
nents together in vacuo at 150°C.10 The requisite
aminophosphine 4 was synthesized from the corre-
sponding chloroaniline 2 via a nickel-mediated phosphi-
nation and reduction with Na/naphthalene.11
The chirality in monophosphine 1 arises from restricted
rotation about the central CarylꢀNimide single bond. This
structurally hindered bond is readily synthesized by
condensation of an ortho-substituted aniline and a
cyclic anhydride. The resulting N-arylimide rotamers
are highly stable and are axially chiral enantiomers.
Ligand 1 was designed to place its phosphine atom in a
Racemic phosphine 1 was resolved by coordination
with enantiomerically pure (+)-di-m-chlorobis[(R)-2-[1-
(dimethylamino)ethyl]phenyl-C2,N]dipalladium(II) (6)
(Scheme 1).12 The resulting diastereomeric Pd-com-
plexes (R,R)-7 and (S,R)-7 were kinetically stable and
readily separable by flash chromatography.13 In fact, a
large difference in polarity of the diastereomers was
observed (DRf=0.20), yielding evidence of the highly
asymmetric environment present in phosphine 1. The
* Corresponding author. Tel.: (803) 777-6523; fax: (803) 777-9521;
e-mail: shimizu@psc.sc.edu
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)01482-4

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Y. Chen et al. / Tetrahedron Letters 42 (2001) 7185–7187
Scheme 1. Synthesis and resolution of monophosphine ( )-1.
individual diastereomers of were treated with
NH2CH2CH2NH2 to release the enantiomerically pure
(R)-(−)-1 or (S)-(+)-1. Acidification of the aqueous
extracts with HCl allowed recovery of the valuable
enantiomerically pure Pd-complex (R)-6 in >80% yield.
conformationally independent molecules were observed
in the unit cell, which differ slightly in the dihedral
angle about the CarylꢀP bonds. The observed conforma-
tions are almost identical to those calculated by molec-
ular modeling. The cyclic imide and aryl planes are
nearly perpendicular (89.7 and 86.0°). Both conformers
also maintain the indented orientation in which the
phosphine lone pair is pointing into the asymmetric
over the imide ring. This leads to a chirally enshrouded
environment in which approach from one face of the
phosphine is hindered by the steric bulk of the 3,3-
diphenyl groups.
7
The conformational stability of phosphine 1 was evalu-
ated by examination of the monophenyl analogs 8 and
9. Restricted rotation in 8 and 9 is more easily observed
as the atropisomers are diastereomers (phenyl up and
phenyl down) and are easily separable by flash chro-
matography (silica gel) and differentiated on the basis
1
of H NMR. Models suggest that the missing phenyl
The high quality of the X-ray data set and the presence
of the phosphorous heavy atom enabled determination
of the absolute stereochemistry from the anomalous
X-ray scattering data.16 The (+)-enantiomer was
assigned an (S)-stereochemistry with a corresponding
Flack parameter of 0.01(5).17 For completeness, the
group is too far away from the N-aryl group to signifi-
cantly alter the rotational barrier.
Phosphine 8 is directly analogous to phosphine 1, hav-
ing both a diphenyl phosphine and a methyl group
ortho to the imide ring. The diastereomers of phosphine
8 were highly stable and no interconversion was seen
even on heating at 110°C (toluene reflux) for 2 days.
This sets a lower limit of the rotational barrier of >40
kcal/mol.14 By comparison the diastereomers of phos-
phine 9, which lacks an ortho-methyl group, rotates
slowly a room temperature. The diastereomers of 9
were initially separable at room temperature (23°C) but
rapidly began to interconvert on standing for >10 min,
corresponding to a rotational barrier of only 21 kcal/
mol.
The three-dimensional structure of phosphine 1 was
established by X-ray crystallography (Fig. 1).15 Enan-
tiomerically pure crystals were obtained by recrystal-
lization of the resolved enantiomers from acetone. Two
Figure 1. X-Ray crystal structures of ( )-1.

Y. Chen et al. / Tetrahedron Letters 42 (2001) 7185–7187
7187
Table 1. Reaction conditions and results of the Pd-catalyzed allylic alkylation using (−)-1a
Entry
Pd (mol%)
(R)-1 (mol%)
Nuc. (equiv.)
BSAb (equiv.)
Solvent (mL)
Conversion (%)
Time (h)
ee %c
1
2
3
4
5
5
5
5
5
5
40
40
20
20
20
5
3
3
3
3
10
6
6
6
4
THF (0.2)
36
99
71
23
14
64
48
47
24
24
9
32
42
52
55
CH2Cl2 (0.2)
CH2Cl2 (0.2)
CH2Cl2 (0.2)
CH2Cl2 (0.2)
a Reactions were all carried out using 200 mL of acetate 10 at rt.
b N,O-Bis(trimethylsilyl)acetamide.
c ee was measured by chiral HPLC (ChiralPak AD).
8. Dai, X.; Wong, A.; Virgil, S. C. J. Org. Chem. 1998, 63,
2597–2600.
9. Characterization data for ( )-1: 1H NMR (300 MHz,
CDCl3) l 7.42–7.10 (m, 20H), 7.05 (s, 1H), 6.71 (s 1H),
3.68 (d, 1H, J=18.0 Hz), 3.36 (d, 1H, 18.0 Hz), 2.18 (s,
3H), 1.80 (s, 3H). IR (KBr) 3478, 2924, 1716, 1368, 749,
698 cm−1; found (HRMS, FAB) m/z 539.2014; calcd for
C36H30NO2P: 539.2030; mp 138–143°C, [h]2D5=−81.5 (c
2.38, CH2Cl2).
Scheme 2.
(−)-enantiomer was likewise crystallized and assigned as
the (R)-enantiomer with a Flack parameter of 0.08(9).
10. Miller, C. A.; Long, L. M. J. Am. Chem. Soc. 1951, 73,
4895–4898.
11. Cooper, M. K.; Downes, J. M.; Duckworth, P. A. Inorg.
Synth. 1989, 25, 129.
12. Purchased from Aldrich.
13. Yasuike, S.; Okajima, S.; Yamaguchi, K.; Seki, H.;
Kurita, J. Tetrahedron: Asymmetry 2000, 11, 4043–4047.
14. Calculated from the Eyring equation assuming an ideal
value of A=2.08×1010.
The ability of monophosphine 1 to effect asymmetric
transformations was tested in the well studied Pd-cata-
lyzed allylic alkylation reaction (Scheme 2).18
Monophosphine 1 is able to induce moderate enan-
tioselectivity with a high of 55% ee (Table 1, entry 5).
Higher reactivity and selectivity was observed in
CH2Cl2 as opposed to THF. In addition, it was found
that the reaction appeared to give higher selectivities at
lower conversions. While overall the selectivity is mod-
erate using monophosphine in comparison to bidentate
phosphine ligands, it is on par with that observed other
chiral monodentate phosphine ligands.3,19 We are cur-
rently in the process of surveying the selectivity of
monophosphine 1 in other asymmetric reactions in
which monodentate phosphine ligands have out per-
formed their bidentate cousins.3,20,21
15. Crystal data for phosphine (+)-1: C36H30NO2P, space
group P21, a=12.8739(7), b=12.8245(7), c=17.8403(10)
3
,
,
A, i=94.5560(10)°, volume=2936.1(3) A , Z=4. A yel-
low plate crystal of approximate dimensions 0.45 mm×
0.36 mm×0.11 mm was used for X-ray crystallographic
analysis. The X-ray intensity data were measured at 293
K using a Bruker SMART APEX CCD-based diffrac-
tometer system equipped with a Mo target X-ray tube
,
(u=0.71073 A). The structure was solved and refined
using the Bruker SHELXTL (Version 5.1) software pack-
age. The final anisotropic full-matrix least-squares refine-
ment converged at R1=0.0438, wR2=0.0644 (I>2|I),
using 11588 independent reflections. Hydrogen atoms
were refined using a riding model. Refinement of the
absolute structure parameter (Flack parameter) indicated
the compound to be enantiomerically pure.
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