PalladIum-catalyzed enantioselective allylic phosphination

Article abstract of DOI:10.1002/anie.200801287

(Chemical Equation Presented) A new cat. for chiral phosphines: A highly enantioselective allylic phosphination reaction is realized using the Pd-Josiphos(L) catalyst system. This C-P bond forming reaction provides a new access to chiral phosphines (see scheme) that may be further functionalized. Cy=cyclohexyl, dba=trans,trans-dibenzylideneacetone.

Full text of DOI:10.1002/anie.200801287

Communications
DOI: 10.1002/anie.200801287
Allylic Phosphination
Palladium-Catalyzed Enantioselective Allylic Phosphination**
Pietro Butti, Raphal Rochat, Aaron D. Sadow, and Antonio Togni*
Chiral phosphines are pre-eminent ligands in asymmetric
catalysis and are utilized in applications ranging from
laboratory syntheses to industrial processes.[1] Despite their
wide-spread use in enantioselective catalysis, there are
surprisingly few syntheses of chiral phosphines by enantiose-
lective methods. Thus, it is of interest to develop such
reactions because catalytic asymmetric transformations in
There are, however, several examples of non-enantiose-
lective catalytic syntheses of allylic phosphonates, which all
involve Pd0- or Ni0-catalyzed coupling of phosphonates and
allylic substrates.[8] Furthermore, Moreno Maæas and co-
workers have synthesized allylic phosphonium salts by the
reaction of allylic pyridinium salts and triphenylphosphine in
the presence of [Pd(PPh3)4].[9] Most notably, this complex was
shown 25 years ago by Fiaud to catalyze the reaction of
lithium diphenylphosphide with aliphatic allylic acetate
derivatives to afford the corresponding substitution prod-
ucts.[10] However, to our knowledge these transition-metal-
catalyzed reactions do not appear to have ever been
attempted in the presence of chiral ligands. Finally, the
advent of organocatalytic processes in recent years has led to
the development of an enantioselective 1,4-addition of
secondary phosphines to a,b-unsaturated aldehydes, giving
products in up to 98% ee.[11]
À
which the P C bond and stereogenic centers are simulta-
neously formed might allow access to new chiral motifs, give
more efficient syntheses of valuable chiral ligands, and
stimulate the development of new enantioselective processes.
À
Recently, a few strategies for catalytic P C bond forma-
tions have emerged that give enantiomerically enriched
phosphines.[2] It is noteworthy that these systems frequently
À
find close parallels in N C bond formations. For example,
organolanthanide compounds catalyze both intramolecular
hydroaminations and hydrophosphinations, apparently
through analogous mechanisms.[3] Also, our group has de-
scribed a nickel(II) catalyst which is active for asymmetric
hydroamination and hydrophosphination of vinyl nitriles.[4]
Finally, of particular relevance are palladium-catalyzed aryl–
X/E–H (E = N, P) coupling reactions, which have shown
tremendous synthetic utility.[5] Thus, new catalytic asymmetric
phosphine synthesis might be guided by examples from the
corresponding amine chemistry. In this context, it is of interest
to note that although asymmetric allylic amination is a
prominent method for the preparation of chiral amines,[6]
there are no reports of asymmetric allylic phosphination
(Scheme 1). Additionally, a pendant allylic group would offer
Based on previous work in the area of asymmetric allylic
substitutions[12] and on our hydroamination/hydrophosphina-
tion chemistry,[4] we began to pursue asymmetric allylic
phosphination. We initially examined reactions of 1,3-diphe-
nylallyl ethyl carbonate (1a; Scheme 2) and diphenylphos-
phine (2) in the presence of chelating chiral ferrocenyl P,N
ligands and palladium precursors. The P,N ligands, especially
1-{1-[2-(diphenylphosphino)ferrocenyl]ethyl}-3-(tertbutyl)-1-
H-pyrazole (3; see Figure 1) have been shown to be effective
ligands for Pd-catalyzed asymmetric allylic aminations of the
same substrate.[13] The reaction was conveniently monitored
1
by NMR spectroscopy (31P{1H}, 31P, H, 31P–1H HMQC), the
results of which indicate that the reaction proceeds to full
conversion of the secondary phosphine substrate after
approximately 48 h at 408C. However, the reactions were
not selective (Scheme 2), giving the allylic phosphine product
4, the product formed by dehydrocoupling of the secondary
phosphine, 5,[14] and a small amount of the vinyl isomer 6
resulting from a 1,3-hydrogen shift.
Scheme 1. General formulation of allylic phosphination. LG=leaving
group.
In the hope that a less-basic leaving group would inhibit
the formation of the side products and increase selectivity for
the chiral allylic phosphine, the allylic acetate 1b (Scheme 2)
was investigated as the substrate. In the presence of 3
(6 mol%) and [Pd(dba)2] (5 mol%; dba = dibenzylideneace-
the possibility of further functionalizations, and allylic
alkylations and aminations have been shown to be useful in
synthesis.[7]
[*] P. Butti, R. Rochat, Prof. Dr. A. D. Sadow,[+] Prof. Dr. A. Togni
Departement Chemie und Angewandte Biowissenschaften
ETH Zürich, 8093 Zürich (Switzerland)
Fax: (+41)44-632-1310
E-mail: togni@inorg.chem.ethz.ch
[+] Current address: Department of Chemistry
Iowa State University, Ames (USA)
[**] This research was supported by the ETH Zürich.
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
Scheme 2. Products observed in asymmetric allylic phosphination.
R’=P h (4).
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Angewandte
Chemie
tone) in dichloromethane at 408C, diphenylphosphine and 1b
react in 24 h to afford the desired allylic phosphine 4,
accompanied by side products accounting for 44% yield.
These have been identified as the diphosphine 5 (26%), the
vinyl isomer 6 (10%) and the reduced derivative 7 (8%).
Unfortunately, under these conditions the reaction affords
product 4 with a enantiomeric excess of only 17%.
propen-1-ol (1c) as allylic substrate, leads to a highly
enantioselective product formation (96% ee), however with
incomplete conversion. Replacing the phenyl substituents by
cyclohexyl groups in the substrate (1d) gives a disappointing
result, in terms of yield (20%), product distribution, and
enantioselectivity (40% ee).
We also investigated an additional set of Josiphos-related
ligands (Figure 1) in the reaction leading to 4. Ligand 10 is a
Josiphos bearing 3,5-bis(trifluoromethyl)phenyl substituents
instead of phenyl. This ligand has an increased difference in
A stoichiometric reaction, in which the palladium prod-
ucts could be detected, reveals the likely reason for the low
1
selectivities obtained upon catalytic phosphination. The H
and 31P{1H} NMR spectrum of a mixture of the catalyst
precursor [Pd{h3-(1,3-Ph2C3H3)}(3)]SbF6 and 1 equivalent of
diphenylphosphine shows resonance signals corresponding to
the non-coordinated ligand 3 after 10 min at room temper-
ature in [D8]THF. This result indicates that the secondary
phosphine Ph2PH and [Pd(h3-(1,3-Ph2C3H3)(3)]SbF6 rapidly
react by ligand substitution rather than the expected nucle-
ophilic attack, thus forming achiral, but catalytically active
species, such as the [Pd(h3-allyl)(R2PH)2]+ ion.
Therefore, we sought catalysts containing ligands that are
less labile than ligand 3 in the presence of excess secondary
phosphines. In contrast to P,N ligands, chiral bis(phosphines)
are expected to form more stable complexes with palladium
and thus ligand exchange in the presence of a large excess of
secondary phosphine might be less favorable. Therefore, (R)-
1-[(S)-2-(diphenylphosphino)ferrocenyl]ethyldicyclohexyl-
phosphine ((R)-(S)-Josiphos, 8; Figure 1) was investigated as
chiral ligand in the title reaction of racemic 1,3-diphenylallyl
acetate (1b). Note that allylic amination and alkylations were
among the first asymmetric reactions for which Josiphos has
been found to be a highly effective ligand.[12b,15]
The catalyst may be generated in situ either from the
ligand and [Pd(dba)2] or from the isolable complex [Pd(h3-
(1,3-Ph2C3H3)(8)]SbF6 (9). We initially focused our interest on
the optimization of the reaction with diphenylphosphine as
the nucleophile with equimolar amounts of 1b in different
solvents, leading to 4 (Table 1). Qualitatively, the reaction
appears to produce less side products and to be more selective
(up to 96% ee) in solvents such as benzene and toluene. It is
interesting to note that the reaction with 1,3-diphenyl-2-
Figure 1. Josiphos-type ligands of (R)–(S) configuration used in this
study.
the donor ability of the two phosphorus atoms and leads to a
faster catalytic reaction with a selectivity comparable to that
obtained with Josiphos (Table 2, compare with Table 1). For
comparison, we also examined R-binap ([1,1’-binaphthalene]-
2,2’diylbis(diphenylphosphine)) as a classical representative
of C2 symmetric diphosphines. The reaction is somewhat
sluggish with this ligand and the main product is formed as
only 56% of a product mixture that is obtained in relatively
low yield. Moreover, the enantioselectivity does not go
beyond approximately 39% ee, with the sense of chiral
induction corresponding to that of (R)-(S)-Josiphos. We
encountered a very similar situation when the enantiomeri-
cally enriched product 4 (ca. 95% ee) was used as chiral
Table 1: The effect of various solvents on product distribution and
enantioselectivity in the formation of 4 catalyzed by the Pd(Josiphos)
system.[a]
Table 2: The effect of the chiral ligands on product distribution and
enantioselectivity in the Pd-catalyzed formation of (E)-1-diphenylphos-
phino-1,3-diphenylpropene.[a]
Substrate Solvent
Prod. Distrib. Yield of 4 [%][c] (ee of 4 [%])
(% 4:5:6:7)[b]
Ligand
t [h]
Prod. Distrib.
Yield of 4 [%][c]
(ee of 4 [%])
(% 4:5:6:7)[b]
1b
1b
1b
1b
1b
1b
1c
1d
C6H6
89:11:0:0
78:11:4:7
73:6:7:14
84:6:6:4
70:1:1:19
79
74
68
81
68
75
54
20
94[d] (96[e])
79[d] (81[e])
87[d] (91[e])
51[d] (49[e])
78[d] (83[e])
65[d] (68[e])
97[d] (96[e])
n.d.[d] (40[e])
10
11
12
13
4
52
188
50
52
52
97:1:1:1
79:6:6:9
92
78
40
65
48
42
50
82[d] (85[e])
69[d] (68[e])
80[d] (82[e])
82[d] (89[e])
38[d] (39[e])
11[d] (11[e])
18[d] (20[e])
toluene
CH2Cl2
THF
MeOH
dioxane 77:15:6:2
71:3:9:17
72:20:3:5
56:11:13:20
49:12:11:28
51:9:12:26
R-binap
4[f]
C6H6
C6H6
96:4:0:0
42:40:0:18
4[g,h]
52
[a] Reaction Conditions: 5 mol% [Pd(dba)2], 5.2 mol% ligand, 408C,
CH2Cl2. [b] Products distribution is given as ratio between: 4:5:6:7, see
Scheme 2. [c] Yield of isolated product, based on Ph2PH. [d] Determined
by HPLC, see Supporting Information for details. [e] Determined by
31P{1H}-NMR, see Supporting Information for details. [f] ca. 95%
enantiomeric purity. [g] 10.4 mol% ligand.
[a] Reaction conditions: 5 mol% [Pd(dba)2], 5.2 mol% 8, 408C. [b] Prod-
ucts distribution is given as ratio between: 4, 5, 6, 7; see Scheme 2.
[c] Yield of isolated product, based on Ph2PH. [d] Determined by HPLC,
see Supporting Information for details; n.d.=not determined. [e] Deter-
mined by 31P{1H}-NMR, see Supporting Information for details.
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Communications
ligand. This is a strong indication that the reaction does not
display any significant autocatalytic effect.
Four additional secondary phosphines were used as
nucleophiles in the Pd(Josiphos)-catalyzed reaction of 1b.
Whereas dicyclohexylphosphine (14) gave a relatively slow
reaction and afforded the new allylic phosphine in low
enantioselectivity (45% ee, 5H-benzo[b]phosphindole (15)
afforded the desired product in 84% isolated yield and
80% ee (Table 3). Note that with this cyclic phosphine full
Table 3: Pd(Josiphos)-catalyzed allylic phosphination with five different
phosphines as nucleophiles.[a]
Figure 2. ORTEPdiagram of compound 19 used for the determination
of the absolute configuration of 4. Only the hydrogen atom at the
newly generated stereogenic center is shown at its calculated position;
thermal ellipsoids set at 30% probability.
R2PH
t [h]
Prod. Distrib.
Yield of 4 [%][c]
(ee of 4 [%])[d]
(% 4:5:6:7)[b]
2
14
15
16
17
48
74
0.3
48
48
89:11:0:0
65:28:6:1
84:14:0:2
91:6:1:2
79
44
84
85
82
96
45
80
83
42
88:8:2:2
[a] Reaction Conditions: 5 mol% [Pd(dba)2], 5.2 mol% 8, 408C, C6D6.
[b] Products distribution is given as ratio between: 4:5:6:7, see
Scheme 2. [c] Yield of isolated product, based on R2PH. [d] Determined
by 31P{1H}-NMR, see Supporting Information for details.
conversion was reached after approximately 20 min, indicat-
ing a rate increase by approximately two orders of magnitude
as compared with both diphenyl- and dicyclohexylphosphine.
However, also in this case the same type of byproducts was
observed, with the dehydrocoupling product of the nucleo-
phile accounting for 14%. Not surprisingly, bis(2-naphthyl)-
phosphine (16) gave the product in fairly high enantioselec-
tivity (83% ee) and good yield. On the other hand, with the
bulkier bis(2-tolyl)phosphine (17) the product could only be
obtained with 42% ee, despite both satisfactory yield and
product distribution.
Since no reliable conditions could be found for the direct
chromatographic separation of the enantiomers of the
product, two different methods relying on derivatization
were used to determine the enantiomeric excess. The first one
consists in measuring the diastereomeric ratio of the products
19 formed by treating the enantiomerically enriched 4 with
bis-(chloro[2-[1-(dimethylamino)ethyl]ferrocenyl-C,N]-palla-
dium(II)) (18), derived from (S)-[1-(dimethylamino)ethyl]-
ferrocene. The major diastereomer of 19 was characterized by
X-ray crystallography. Thus, the absolute configuration of the
major enantiomer of 4 could be determined to be R by
internal comparison (see Figure 2).
Figure 3. ORTEPdiagram of the phosphine sulfide R-20. Hydrogen
atoms are omitted for clarity, except for that at C(1); thermal ellipsoids
are set at 30% probability.
In conclusion, we have shown that secondary phosphines
may be used as nucleophiles in Pd-catalyzed enantioselective
allylic substitution reactions. When using Josiphos as chiral
ligand and 1,3-diphenylallyl acetate as substrate the new
chiral allylic phosphine is obtained in good yield and up to
96% ee. Despite the current relatively narrow scope of the
reaction, it may become a new method for the preparation of
chiral, highly enantiomerically enriched phosphines that are
otherwise difficult to synthesize.
Experimental Section
Representative Procedure for Pd-Catalyzed Allylic Phosphination:
1,3-diphenylallyl acetate (29 mg, 0.115 mmol, 1.00 equiv) was added
to a mixture of Josiphos (4.8 mg, 8.046 mmol, 0.07 equiv) and [Pd-
(dba)2] (3.3 mg, 5.747 mmol, 0.05 equiv) in 1 mL of the chosen solvent
and the orange solution was stirred for 30 min. The secondary
phosphine HPR2 (0.115 mmol, 1.00 equiv) was then added and the
mixture was heated to 408C in an oil bath. To remove the catalyst and
byproduct 5 the reaction solution was worked-up in a glove box by
filtration through a short plug of silica gel (0.5 g) using toluene as an
eluent. After removing the solvent in vacuo the product was isolated
as a colorless solid.
The second method consisted in analyzing by chiral HPLC
the phosphine sulphide 20 obtained by the reaction of 4 with
elemental sulfur. Crystals of the R enantiomer of this com-
pound were obtained by slow diffusion of hexane into a
concentrated CH2Cl2 solution of
(Figure 3).
a sample at 96% ee
The Supporting Information contains experimental procedures
for the synthesis of selected new compounds. CCDC-668371 (19) and
4880 www.angewandte.org
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CCDC-654095 (20) contain the supplementary crystallographic data
for this paper. These data can be obtained free of charge from The
Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/
data_request/cif.
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Received: March 17, 2008
Published online: May 21, 2008
Keywords: allylation · allylic phosphination ·
.
asymmetric catalysis · palladium · phosphane ligands
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