Synthesis and applications of a new class of phosphorus donor ligands for asymmetric catalysis

Article abstract of DOI:10.1039/a701922j

The synthesis and applications to allylic substitutions of a range of novel ligands based on diazaphospholidines is described; enantiomeric excesses of up to 89% were achieved in an allylic substitution reaction.

Full text of DOI:10.1039/a701922j

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Synthesis and applications of a new class of phosphorus donor ligands for
asymmetric catalysis
a
a
b
a
Heather Tye, Donald Smyth, Colin Eldred and Martin Wills*
a
Department of Chemistry, University of Warwick, Coventry, UK CV4 7AL
b
Glaxo-Wellcome Research and Development Ltd, Glaxo-Wellcome Medicines Research Centre, Gunnels Wood Road, Stevenage,
Hertfordshire, UK SG1 2NY
6
The synthesis and applications to allylic substitutions of a
range of novel ligands based on diazaphospholidines is
described; enantiomeric excesses of up to 89% were achieved
in an allylic substitution reaction.
Latscha. Each intermediate bis(dimethylamino)phosphine was
heated under reflux with (R,R)-N,NA-dimethyl-1,2-diamino-
cyclohexane until no further dimethylamine could be detected
in the nitrogen stream from the reaction. At this point solvent
removal provided the pure ligands 1. Although always handled
under an inert atmosphere when in solution, each of the ligands
proved to be resistant to atmospheric oxidation when in solid
Recent years have seen dramatic developments in asymmetric
1
catalysis. Allylic substitution reactions in particular have been
the subject of attention from a number of research groups and
several excellent ligands have been developed for this particular
application. Of these, diphosphines and combined phosphine–
3 2
form. Treatment of 1c with BH ·SMe complex resulted in
formation of a highly stable borane complex 2 which could be
purified by chromatography. We have in previous work
demonstrated that related borane complexes could be used as a
2
amine donors have proven to be especially well suited to the
2
3
3
required role. As part of an ongoing programme directed at the
development of a range of phosphorus donor ligands with a
wide range of applications to asymmetric synthesis, we wished
to investigate diazaphospholidines 1 in this capacity. We
anticipated that such ligands would benefit from a high level of
conformational rigidity and would project a suitable chiral
environment within organometallic complexes of which they
may form a part. Furthermore we were aware of the facile
source of protected ligand (borane may be removed by an
amine), however in the case of 2 all attempts to remove the
borane resulted in decomposition.
We have applied the series of ligands thus produced to a
number of asymmetric transformations. In particular the ligands
appear to be particularly well disposed to the nucleophilic
allylic substitution reaction of 1,3-diphenyl-3-acetoxyprop-
1-ene 3. In most cases the substitution reaction with dimethyl
malonate (Scheme 2) gave good yields and, in the best cases,
excellent asymmetric inductions (Table 1). A number of
interesting trends become apparent upon analysis of the results.
In particular a general improvement and reversal of selectivity
is observed upon introduction of an ortho substituent. The level
of electron density in the aromatic ring does not appear to
influence the selectivity to any great extent (compare ligands 1a
and 1b). Although the best results, 89 and 78% ee in favour of
the R enantiomer, were achieved using the ligands 1c and 1d,
the same product enantiomer was obtained using ligands which
do not contain coordinating groups (i.e. 1e and 1f). This
suggests that all may share a common mode for directing the
asymmetric transformation. The importance of the size of the
ortho substituent is also difficult to gauge since the ethyl and
isopropyl substituted ligands 1e and 1f gave similar selectiv-
ities. We were unable to prepare the corresponding tert-butyl-
substituted reagent.
At present there is insufficient evidence to determine the
exact means by which asymmetric induction by the ligand is
achieved. It would appear that whilst the introduction of an
ortho substituent in the ligand is crucial to their success, the
observation of similar results from coordinating and non-
coordinating groups suggests that the ligand is probably only
appended to the palladium through the phosphorus atom. If this
is the case then their mechanism of action may have a parallel
with the phosphine ligand MOP, which has been demonstrated
2
synthesis of such materials from the corresponding C symmet-
4
ric chiral diamines. Although similar compounds have been
reported to act as effective chiral shift reagents, we were
unaware of any catalytic asymmetric transformations to which
they had been applied.5
The preparation of a series of ligands was achieved following
4
literature precedents (Scheme 1). The bis(dimethyl-
amino)phosphine precursors to 1a, 1b, 1c, 1e, 1h and 1i were
formed by the reaction of the corresponding lithiated aromatic
compound with preformed (Me N) PCl. The corresponding
2 2
precursors for 1d and 1f could not be prepared by this method.
However lithiation and transmetallation with zinc dichloride,
followed by reaction with phosphorus tirchloride and subse-
quently treatment with an excess of dimethylamine furnished
the required intermediates. The precursor to compound 1g was
synthesised following the published procedure of Drewelies and
Me
Me
H
H
HN
N
i
Ar P(NMe2)2
+
Ar
P
N
HN
H
H
Me
Me
1a Ar = Ph (100%)
b Ar = p-MeOC6H4 (96%)
c Ar = o-MeOC6H4 (100%)
d Ar = o-MeSC6H4 (98%)
OMe
to be effective for this application through the formation of a
Me
e Ar = o-EtC6H4 (95%)
1:1 phosphine–metal complex.7
Of significance is the pseudo-C
H
i
N
f
Ar = o-PrC6H4 (100%)
+
2
symmetry of the ligand and
P
g Ar = o-BrC6H4 (97%)
–
potential participation of a conformational rigidity conferred to
H3B
N
h Ar = o-MeOCH2C6H4 (97%)
MeO2C
Ph
CO2Me
MeO2C
CO2Me
Ph
H
Me
OAc
Ph
i
or
Ph Ph
2
i
Ar =
O
Ph
3
R
S
Scheme 2 Reagents and conditions: i, 1a–i, [Pd(h-C
malonate, (Me Si)N:CMe(OSiMe ), NaOAc, CH Cl
3 5
H
)Cl]
2
, dimethyl
Scheme 1 Reagents and conditions: i, PhMe, heat, 8–24 h
3
3
2
2
Chem. Commun., 1997
1053

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Table 1 Asymmetric addition of dimethyl malonate to 3 catalysed by
a–i
Table 2 Asymmetric addition of nitrogen nucleophiles catalysed by 1c
1
eea (%)
Ligand
(mol%)
ee (%)a
(config.)
Product
Solvent
t/h
42
20
5
168
8
8
Yield (%)
(config.)
Ligand Pd (mol%)
t/h
Yield (%)
4
a
2
CH Cl
2
68
49
77
67
51
67
45
48
63
78 (S)
73 (S)
68 (S)
78 (S)
61 (S)
61 (S)
76 (S)
68 (S)
58 (S)
1
1
1
1
1
1
1
1
1
1
1
1
a
b
c
c
c
c
d
e
f
10
10
10
10
5
20
20
20
10
10
4
20
20
20
20
20
20
16
16
16
20
12
20
24
16
16
24
24
20
97
71
97
89
85
94
90
84
91
85
84
92
28 (S)
23 (S)
89 (R)
83 (R)
85 (R)
82 (R)
78 (R)
59 (R)
56 (R)
66 (R)
51 (R)
35 (R)
4a
4a
4b
4b
4c
4d
4e
4f
THF
THF
2
CH Cl
2
THF
THF
2
CH
CH
CH
2
2
2
Cl
Cl
Cl
2
2
2
64
41
16
10
10
10
10
10
10
a
g
h
i
Enantiomeric excess determined by chiral HPLC using a chiralcel OD
column.
(a-methylbenzylamine of either configuration) appeared to
have no effect on the enantioselectivity of the reaction or the
sense of induction. Use of the cyclic amines pyrrolidine and
N-benzylpiperazine as nucleophiles resulted in the formation of
novel allylic amines 4e and 4f respectively, in excellent yields
but reduced enantioselectivities.
In conclusion a novel class of diazaphospholidine ligands has
been synthesised and their application to palladium-catalysed
allylic substitution has been demonstrated. Ongoing work is
directed towards the synthesis of improved ligands based on this
class for a variety of transition metal-catalysed asymmetric
transformations.
We thank the EPSRC and Glaxo-Wellcome Research and
Development for support of an Industrial CASE studentship (to
H. T.) and Dr J. Ballantine of the EPSRC National Mass
Spectroscopic service (Swansea) for HRMS analysis of certain
compounds.
a
Enantiomeric excess determined by 1H NMR spectroscopy using
(+)-Eu(hfc)
3
as a chiral shift reagent.
Me
H
H
X
Me
N
MeO
N
P
P
N
Me
N
H
H
Me
Fig. 1
R1
R2
OAc
Ph
N
i
Ph
Ph
Ph
1
2
3
(S)-4 a R = H, R = Bn
1
2
b R = H, R = (R)-CHMePh
1
2
c R = H, R = (S)-CHMePh
Footnote
1
2
d R = H, R = p-MeC6H4SO2
1
2
* E-mail: m.wills@warwick.ac.uk
e R –R = (CH2)4
1
2
f R –R = (CH2)2N(Bn)(CH2)2
References
1
2
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Scheme 3 Reagents and conditions: i, 1c, [Pd(h-C
NaOAc, THF or CH Cl
3 5 2
H )Cl] , R R NH,
1
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2
2
2
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failed to be formed using our general method (Scheme 1). If this
conformational preference is maintained in the palladium
complex then clearly this ortho group may be projected into the
region of the appended allylic group, and thus provide a means
to influence the reaction selectivity. Precisely how this effect is
transferred to the asymmetric reaction, however, is at present
unclear.
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attempted some studies of diazaphospholidines bearing larger
groups on the nitrogen atoms. The dibenzyl derivative of 1c
gave a product of 64% ee in 78% yield for the reaction depicted
in Scheme 2. The diisopropyl ligand failed to form using our
standard procedure, possibly due to steric hindrance.
2
039.
5
6
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Having identified 1c as the best of the series of ligands, we
have examined the use of nitrogen nucleophiles in the
substitution reaction (Scheme 3, Table 2). The results obtained
using benzylamine and sodium toluene-p-sulfonamide com-
9 N. Alcock, H. Tye and M. Wills, unpublished result.
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sense) than the selectivity achieved using dimethyl malonate as
nucleophile. The presence of a chiral centre in the nucleophile
Received in Cambridge, UK, 19th March 1997; Com.
7/01922J
1054
Chem. Commun., 1997