BINOL-based diphosphonites as ligands in the asymmetric Rh-catalyzed conjugate addition of arylboronic acids

Article abstract of DOI:10.1021/ol010219y

matrix presented BINOL-based diphosphonites having achiral backbones are useful ligands in the Rh-catalyzed conjugate addition of arylboronic acids to α,β-unsaturated carbonyl compounds. The nature of the achiral backbone determines the direction and degr

Full text of DOI:10.1021/ol010219y

ORGANIC
LETTERS
2001
Vol. 3, No. 25
4083-4085
BINOL-Based Diphosphonites as
Ligands in the Asymmetric Rh-Catalyzed
Conjugate Addition of Arylboronic Acids
Manfred T. Reetz,* Dominique Moulin, and Andreas Gosberg
Max-Planck-Institut fu¨r Kohlenforschung, Kaiser-Wilhelm-Platz 1,
D-45470 Mu¨lheim/Ruhr, Germany
reetz@mpi-muelheim.mpg.de
Received October 2, 2001
ABSTRACT
BINOL-based diphosphonites having achiral backbones are useful ligands in the Rh-catalyzed conjugate addition of arylboronic acids to
r,â-unsaturated carbonyl compounds. The nature of the achiral backbone determines the direction and degree of enantioselectivity, with er
values of up to 99.5:0.5 possible.
We have previously shown that BINOL-based diphospho-
nites of the type 1-2 are excellent ligands in the Rh-
catalyzed asymmetric hydrogenation of prochiral olefins
(er ) 97:3 to 99:1).1 It was therefore of interest to test these
a reaction first reported by Hayashi and Miyaura using
BINAP as the chiral ligand.2
The ligands 1-2 were prepared in good yields as previ-
ously reported.1 The synthesis of the diphosphonites 3 and
and related diphosphonites such as 3 and 4 in other types of
transition metal catalyzed reactions. Herein we report their
use in the asymmetric Rh-catalyzed conjugate addition of
arylboronic acids to R,â-unsaturated carbonyl compounds,
(1) (a) Reetz, M. T.; Gosberg, A.; Goddard, R.; Kyung, S.-H. Chem.
Commun. (Cambridge) 1998, 2077-2078. (b) Reetz, M. T. Pure Appl.
Chem. 1999, 71, 1503-1509. (c) Reetz, M. T.; Gosberg, A. German patent
application 19840279.1 (04/09/1998).
10.1021/ol010219y CCC: $20.00 © 2001 American Chemical Society
Published on Web 11/16/2001

4 also posed no problems.1c In the present study all ligands
were based on (R)-BINOL.
Table 1. Rh-Catalyzed Conjugate Addition of 10a to 9 (5:1)
mol % conversion
configuration
entry ligand of Rh
(%)
er
of 11a
1
2
3
4
5
6
7
8
9
1a
1b
2a
2b
2c
2d
3
3
3
3
3
3
3
3
3
100
100
89
84
100
77
100
100
100
100
97.5:2.5
71.5:28.5
75.5:24.5
91:9
92.5:7.5
89:11
99.5:0.5
98.5:1.5
95.5:4.5
98.5:1.5
S
R
S
S
S
S
S
R
S
R
4b
3
4
0.3
0.3
10
In exploratory experiments the model reaction of cyclo-
hexenone 9 with phenylboronic acid 10a was performed
using Rh(acac)(C2H4)2 as the rhodium source and a diphos-
phonite as the ligand (1:1) under conditions described by
Hayashi and Miyaura2 (3 mol % of Rh; 5 molar excess of
10a; presence of H2O in dioxane, 1:10; 100 °C; 5 h).
a Configurational assignment was made by comparison with authentic
samples. b In this case 1.2 equiv of 10a.
pinpoint presently, it may to be related to increased flexibility
of the backbone of the Rh-complex of ligand 4 and/or
different bite angles. Indeed, ligand 1b, which can be
expected to be more flexible than 1a, also shows opposite
enantioselectivity (Table 1, entry 2), although the effect is
less pronounced.
Several parameters were then varied in order to learn more
about the reaction, especially concerning the role of water.
Hayashi and Miyaura postulate a hydroxy-rhodium species
as the actual catalysts.2g,h We therefore studied the influence
of water on the reaction of 9 with 10a using ligand 1a. In
the absence of any water, conversion was still complete, but
the er value decreased from 97.5:2.5 to 92:8. This may well
be due to different catalytic species. In other cases no
significant influence on enantioselectivity was observed.
Another aspect of the original procedure based on BINAP
has to do with the necessity of using an excess of phenyl-
boronic acid (10a), with conversion to 11 decreasing from
99% to 64% upon lowering the 10/9 ratio from 5:1 to
1.4:1.2a This has been ascribed to protonation of a phenyl-
rhodium intermediate with undesired formation of benzene.2
In our case it is usually not necessary to use a great excess
of reagent 10a. For example, when employing ligand 4, 99%
conversion to the described product is observed by using
just 1.2 equiv of 10a. Another advantage of the diphosphonite
ligand system concerns the fact that several of these ligands
lead to catalysts which are particularly active, the reaction
of 9 with 10a requiring only 0.3 mol % of Rh/3 or Rh/4
(Table 1, entries 9 and 10). Although a reaction time of 5 h
was chosen for all reactions in the standard protocol, many
of them are over within half an hour. Alternatively, the
reaction can even be run at room temperature/36 h, leading
to 100% conversion and 95.5:2.5 to 98.5:1.5 er values using
3 mol % of Rh/4. In the case of the reaction using 3 mol %
of Rh/BINAP, only 41% conversion (99.5:0.5 er) is observed.
The conjugate addition was then extended to include
arylboronic acids 10b-g. Although not all of the ligands
were tested, the generality of the process was demonstrated
(Table 2). In some of the cases the er values are slightly
lower than in the BINAP system.2 However, it needs to be
pointed out that upon using Rh/BINAP the electron-rich
The immediate conclusion concerns the observation that
diphosphonites, which are not as electron-rich as diphos-
phines (e.g., BINAP), are well suited for this transformation.
Moreover, Table 1 shows that the nature of the achiral
backbone of the ligands (all containing (R)-BINOL at
phosphorus) influences the stereochemical outcome. Whereas
in the previously reported Rh-catalyzed hydrogenation fer-
rocene-based ligands 2 are the best,1 the ethano- and
phenylene-bridged ligands 1a and 3 are clearly superior in
the present reaction, resulting in er values of 97.5:2.5 and
99.5:0.5, respectively, in favor of (S)-11a (Table 1). Thus,
ligand 3 is as efficient as BINAP (er ) 98.5:1.5).2a
Surprisingly, ligand 4 leads to the opposite enantiomer (R)
with excellent selectivity (er ) 98.5:1.5; Table 1, entry 8).
This means that it is possible to control the absolute
configuration of the product either by the choice of (R)- or
(S)-BINOL in the synthesis of the ligands or by the choice
of the achiral backbone alone. Although the source of the
stereochemical switch when going from 3 to 4 is difficult to
(2) (a) Takaya, Y.; Ogasawara, M.; Hayashi, T.; Sakai, M.; Miyaura, N.
J. Am. Chem. Soc. 1998, 120, 5579-5580. (b) Hayashi, T.; Senda, T.;
Takaya, Y.; Ogasawara, M. J. Am. Chem. Soc. 1999, 121, 11591-11592.
(c) Hayashi, T.; Senda, T.; Ogasawara, M. J. Am. Chem. Soc. 2000, 122,
10716-10717. (d) Sakuma, S.; Sakai, M.; Itooka, R.; Miyaura, N. J. Org.
Chem. 2000, 65, 5951-5955. (e) Takaya, Y.; Senda, T.; Kurushima, H.;
Ogasawara, M.; Hayashi, T. Tetrahedron: Asymmetry 1999, 10, 4047-
4056. (f) Kuriyama, M.; Tomioka, K. Tetrahedron Lett. 2001, 42, 921-
923. (g) Hayashi, T. Synlett 2001, 879-887. (h) Itooka, R.; Iguchi, Y.;
Miyaura, N. Chem. Lett. 2001, 7, 722-723.
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Org. Lett., Vol. 3, No. 25, 2001

determined sign of the specific rotation is given, as was
reported by Hayashi and Miyaura.2a
Table 2. Rh-Catalyzed Conjugate Addition of 10b-g to 9a
entry
reagentb
ligand
conversion (%)
er
1
2
3
4
5
6
7
8
10d
10e
10b
10c
10d
10e
10f
10g
1a
1a
3
3
3
3
3
3
88
82
96
100
87
88
95.5:4.5
93.5:6.5c
96.5:3.5
97:3
97.5:2.5
97:3
Finally, it was of interest to test the R-acetamido acrylic
acid ester 16 because stereochemistry is not only determined
in the phenyl insertion step but also in the protonation. This
type of transformation is known using phenyltin reagents,3
but an asymmetric catalytic version has not been reported.
Using the BINAP-based Rh catalyst,2 we observed 100%
conversion to the phenylalanine derivative 17, but the product
turned out to be racemic. In the case of phosphonites,
conversion under the standard conditions was also quantita-
tive. Moreover, significant albeit not perfect enantioselec-
tivity resulted. The best er was observed with ligand 2c (85:
15 in favor of (S)-17) which was increased to 88.5:11.5 in
the presence of 3 equiv of NaF:
75
93
95.5:4.5
94.5:5.5
a 3 mol % of Rh. b 5 equiv. c Determined by HPLC on Chiralcel OD-H.
arylboronic acid 10d affords none of the desired adduct 11d
(only protonation with formation of anisol),2 whereas Rh/3
results in excellent conversion and enantioselectivity (entry
5, Table 2).
We then studied the reaction of phenylboronic acid (10a)
with other substrates, 12-15. Again, although not all ligands
were tested, it was found that 3 and 4 are usually the most
active and selective, leading to products having opposite
absolute configuration (Table 3). Noteworthy is the fact that
both cyclic and acyclic substrates react rapidly and selec-
tively. In two cases the absolute configuration is presently
unknown, which means that only the polarimetrically
In conclusion, BINOL-based diphosphonites are useful
ligands in the Rh-catalyzed conjugate addition reactions.
Advantages include simple synthesis, high catalyst activity,
and useful levels of enantioselectivity. It is also clear that
variation of the achiral backbone can be used to tune the
ligands, with even reversal of enantioselectivity being
observed. Since the trends in the present reaction are quite
different from those observed previously in the case of
hydrogenation,1 the question regarding the universal chiral
diphosphonite cannot be answered. We are currently studying
other types of transition metal catalyzed processes using
BINOL-based diphosphonites.1c
Table 3. Rh-Catalyzed Conjugate Reactions of 10aa
conversion
entry substrate ligand
(%)
er
configuration
1
2
3
4
5
6
7
8
9
12
12
12
13
13
13
13
14
14
14
15
15
1a
2a
3
1a
2a
3
63
100
58
100
100
100
100
83
91:9
76.5:23.5
94.5:5.5
92.5:7.5
79.5:20.5
92.5:7.5
98:2
96:4
85:15
97:3
98:2
S
S
S
(-)b
(-)b
(-)b
(+)b
S
S
S
(-)b
(+)b
4
1a
2c
3
3
4
Supporting Information Available: Experimental pro-
cedures and full characterization for typical compounds 3
and 11a. This material is available free of charge via the
Internet at http://pubs.acs.org.
100
100
82
10
11
12
85
66:34
a All reactions were carried out in dioxane/H2O (10:1) at 100 °C for 5
h using 3 mol % of Rh/L*. Configurational assignment was made by
comparison with authentic samples. b Sign of specific rotation.
OL010219Y
(3) Huang, T.-S.; Li, C.-J. Org. Lett. 2001, 3, 2037-2039 and references
therein.
Org. Lett., Vol. 3, No. 25, 2001
4085