Catalytic cycle of rhodium-catalyzed asymmetric 1,4-addition of organoboronic acids. Arylrhodium, oxa-π-allylrhodium, and hydroxorhodium intermediates

Article abstract of DOI:10.1021/ja012711i

The catalytic cycle of asymmetric 1,4-addition of phenylboronic acid to an α,β-unsaturated ketone catalyzed by a rhodium-binap complex was established by use of RhPh(PPh₃)(binap) as a key intermediate. The reaction proceeds through three intermediates, phenylrhodium, oxa-φ,β-allylrhodium, and hydroxorhodium complexes, all of which were observed in NMR spectroscopic studies. The transformations between the three intermediates, that is, insertion, hydrolysis, and transmetalation, were also observed. On the basis of the catalytic cycle, a more active chiral catalyst, [Rh(OH)(binap)]₂, was found and used successfully for the asymmetric 1,4-addition reactions.

Full text of DOI:10.1021/ja012711i

Published on Web 04/11/2002
Catalytic Cycle of Rhodium-Catalyzed Asymmetric
1,4-Addition of Organoboronic Acids. Arylrhodium,
Oxa-π-allylrhodium, and Hydroxorhodium Intermediates
Tamio Hayashi,* Makoto Takahashi, Yoshiaki Takaya, and Masamichi Ogasawara
Contribution from the Department of Chemistry, Graduate School of Science, Kyoto UniVersity,
Sakyo, Kyoto 606-8502, Japan
Received December 14, 2001
Abstract: The catalytic cycle of asymmetric 1,4-addition of phenylboronic acid to an R,â-unsaturated ketone
catalyzed by a rhodium-binap complex was established by use of RhPh(PPh3)(binap) as a key intermediate.
The reaction proceeds through three intermediates, phenylrhodium, oxa-π-allylrhodium, and hydroxorhodium
complexes, all of which were observed in NMR spectroscopic studies. The transformations between the
three intermediates, that is, insertion, hydrolysis, and transmetalation, were also observed. On the basis of
the catalytic cycle, a more active chiral catalyst, [Rh(OH)(binap)]2, was found and used successfully for
the asymmetric 1,4-addition reactions.
tages over other asymmetric 1,4-addition reactions13 in that (1)
the enantioselectivity is very high, usually over 95%, (2) the
Introduction
Growing attention is currently devoted to development of new
reactions by using a combination of a rhodium catalyst and
organoboron reagents. The rhodium-catalyzed reaction has
realized the addition of arylboronic acids and their analogues
to the carbon-carbon double bond,1-3 carbon-carbon triple
bond,4 and carbon-heteroatom double bonds.5,6 One of the most
exciting applications of the rhodium-catalyzed addition reactions
is an extension to catalytic asymmetric carbon-carbon bond-
forming reactions.7 The rhodium-catalyzed asymmetric 1,4-
addition of organoboronic acids8-12 has several unique advan-
reaction is carried out in an aqueous solvent, (3) the reaction
temperature is not very low, usually between 60 and 100 °C,
(4) a variety of sp2 carbon groups (aryl and alkenyl groups)
can be introduced, and (5) the asymmetric addition takes place
on various types of electron-deficient olefins including R,â-
unsaturated ketones, esters, amides, phosphonates, and nitroalk-
enes.12 A typical example is the reaction of 2-cyclohexenone
(1a) with phenylboronic acid (2m) in the presence of 3 mol %
of Rh(acac)(binap) as a catalyst in dioxane/H2O (10/1) at 100
°C, which gives the phenylation product 3am of 97% ee8
(Scheme 1). The catalytic cycle of the rhodium-catalyzed 1,4-
addition of arylboronic acid has been proposed to involve (a)
transmetalation of an aryl group from boron to rhodium, (b)
insertion of enone into the aryl-rhodium bond forming a
rhodium enolate, and (c) its hydrolysis giving the 1,4-addition
product and hydroxorhodium species.1,8-10 However, there have
been no reports to date on isolation of any intermediates or
observation of transformation from one intermediate to another
in the catalytic cycle. Here we report our successful studies on
the mechanism which clearly establish the catalytic cycle of
the rhodium-catalyzed 1,4-addition. The reaction proceeds
through three intermediates, phenylrhodium, oxa-π-allylrhodi-
um, and hydroxorhodium species (Scheme 2), all of which have
been observed in NMR spectroscopic studies. The mechanistic
* Corresponding author. E-mail: thayashi@kuchem.kyoto-u.ac.jp.
(1) R,â-Unsaturated ketones: Sakai, M.; Hayashi, H.; Miyaura, N. Organo-
metallics 1997, 16, 4229. For the asymmetric version, see refs 8-12.
(2) Norbornene: Oguma, K.; Miura, M.; Satoh, T.; Nomura, M. J. Am. Chem.
Soc. 2000, 122, 10464.
(3) Styrenes: Lautens, M.; Roy, A.; Fukuoka, K.; Fagnou, K.; Mart´ın-Mature,
B. J. Am. Chem. Soc. 2001, 123, 5358.
(4) Hayashi, T.; Inoue, K.; Taniguchi, N.; Ogasawara, M. J. Am. Chem. Soc.
2001, 123, 9918.
(5) Aldehydes: (a) Sakai, M.; Ueda, M.; Miyaura, N. Angew. Chem., Int. Ed.
Engl. 1998, 37, 3279. (b) Ueda, M.; Miyaura, N. J. Org. Chem. 2000, 65,
4450. (c) Fu¨rstner, A.; Krause, H. AdV. Synth. Catal. 2001, 343, 543.
(6) Imines: (a) Ueda, M.; Miyaura, N. J. Organomet. Chem. 2000, 595, 31.
(b) Ueda, M.; Saito, A.; Miyaura, N. Synlett 2000, 1637.
(7) For recent reviews on asymmetric 1,4-addition see: (a) Krause, N.;
Hoffmann-Ro¨der, A. Synthesis 2001, 171. (b) Sibi, M. P.; Manyem, S.
Tetrahedron 2000, 56, 8033. (c) Tomioka, K.; Nagaoka, Y. In Compre-
hensiVe Asymmetric Catalysis; Jacobsen, E. N., Pfaltz, A., Yamamoto, H.,
Eds.; Springer: Berlin, 1999; Vol. 3, Chapter 31.1. (d) Kanai, M.; Shibasaki,
M. In Catalytic Asymmetric Synthesis, 2nd ed.; Ojima, I., Ed.; Wiley: New
York, 2000; pp 569-592. (e) Noyori, R. Asymmetric Catalysis in Organic
Synthesis; Wiley: New York, 1994; pp 207-212.
(8) Takaya, Y.; Ogasawara, M.; Hayashi, T.; Sakai, M.; Miyaura, N. J. Am.
Chem. Soc. 1998, 120, 5579.
(9) (a) Takaya, Y.; Ogasawara, M.; Hayashi, T. Tetrahedron Lett. 1998, 39,
8479. (b) Takaya, Y.; Senda, T.; Kurushima, H.; Ogasawara, M.; Hayashi,
T. Tetrahedron: Asymmetry 1999, 10, 4047. (c) Takaya, Y.; Ogasawara,
M.; Hayashi, T. Tetrahedron Lett. 1999, 40, 6957. (d) Hayashi, T.; Senda,
T.; Takaya, Y.; Ogasawara, M. J. Am. Chem. Soc. 1999, 121, 11591. (e)
Takaya, Y.; Ogasawara, M.; Hayashi, T. Chirality 2000, 12, 469. (f)
Hayashi, T.; Senda, T.; Ogasawara, M. J. Am. Chem. Soc. 2000, 122, 10716.
(g) Senda, T.; Ogasawara, M.; Hayashi, T. J. Org. Chem. 2001, 66, 6852.
(10) Sakuma, S.; Sakai, M.; Itooka, R.; Miyaura, N. J. Org. Chem. 2000, 65,
5951.
(11) Kuriyama, M.; Tomioka, K. Tetrahedron Lett. 2001, 42, 921.
(12) For a review: Hayashi, T. Synlett 2001, 879.
(13) As recent examples of copper-catalyzed asymmetric 1,4-addition of
organozinc reagents with high enantioselectivity see: (a) Arnold, L. A.;
Naasz, R.; Minnaard, A. J.; Feringa, B. L. J. Am. Chem. Soc. 2001, 123,
5841. (b) Degrado, S. J.; Mizutani, H.; Hoveyda, A. H. J. Am. Chem. Soc.
2001, 123, 755. (c) Escher, I. H.; Pfaltz, A. Tetrahedron 2000, 56, 2879.
(d) Yan, M.; Chan, A. S. C. Tetrahedron Lett. 1999, 40, 6645. (e) Alexakis,
A.; Benha¨ım, C.; Fournioux, X.; van den Heuvel, A.; Leveˆque, J. M.;
March, S.; Rosset, S. Synlett 1999, 1811.
9
5052
J. AM. CHEM. SOC. 2002, 124, 5052-5058
10.1021/ja012711i CCC: $22.00 © 2002 American Chemical Society

Rh-Catalyzed Asymmetric 1,4-Addition of Organoboronic Acids
A R T I C L E S
Scheme 1
The phenylrhodium complex 6 was allowed to react with an
excess (4 equiv to 6) of 2-cyclohexenone (1a) in dioxane/H2O
(10/1) at 100 °C for 1 h. This stoichiometric reaction gave a
64% yield of 3-phenylcyclohexanone (3am), which is an (S)
isomer of 98.8% ee (Scheme 4). The high enantioselectivity
and the same absolute configuration as that observed in the
catalytic reaction8 (Scheme 1) may indicate that the catalytic
cycle involves the phenylrhodium species as a key intermediate.
The phenylrhodium complex 6 was found to be active as a
catalyst for the reaction of 1a with phenylboronic acid (2m).
The catalytic activity and enantioselectivity of 6 are essentially
the same as those of the acetylacetonato rhodium complex, Rh-
(acac)((S)-binap), or that generated in situ from Rh(acac)(C2H4)2
and (S)-binap,8 the yield (94%) and the enantiomeric purity
(98.6% ee) of 3am being a little higher than those observed
with the rhodium acetylacetonato catalyst.
Scheme 2
NMR spectroscopic studies on a sequence of reactions starting
with the phenylrhodium complex 6 established the catalytic
cycle shown in Scheme 2. Thus, in an NMR sample tube, a
solution of 6 (0.05 M) in THF was prepared, whose 31P NMR
is shown as spectrum A in Figure 1. To the solution was added
5 equiv of tert-butyl vinyl ketone at 25 °C. The three ddd
resonances assigned to the phenyl complex 6 were gradually
replaced by new signals. The 31P NMR after 1 h, which is shown
as spectrum B in Figure 1, demonstrates the formation of two
species in a ratio of 2 to 1. Both isomers have two dd’s, 37.9
(JP-Rh ) 186 Hz, JP-Pcis ) 45 Hz) and 48.4 ppm (JP-Rh ) 222
Scheme 3
Hz, JP-Pcis ) 45 Hz) for the major isomer and 40.8 (JP-Rh
)
182 Hz, JP-Pcis ) 45 Hz) and 49.5 ppm (JP-Rh ) 228 Hz, JP-Pcis
) 45 Hz) for the minor isomer. A singlet assignable to
triphenylphosphine free from rhodium was also observed at -4.5
ppm. The new resonances, two sets of two dd’s, can be assigned
to two diastereomeric oxa-π-allylrhodium complexes 7 and 7′
(Scheme 5). The structure of the oxa-π-allylrhodium complexes
was confirmed by comparison of the 31P NMR spectra with
those of the authentic samples prepared by the reaction of [RhCl-
(binap)]2 with potassium enolate of tert-butyl 2-phenylethyl
ketone according to the procedures reported for the preparation
of oxa-π-allylrhodium complexes from [RhCl(PR3)2]2 and
potassium enolates.16 It should be noted that complex 7 adopts
the oxa-π-allyl structure, not that of rhodium enolate17 or
R-rhodioketone, even in the presence of triphenylphosphine.
Addition of water (10 equiv to Rh) to the THF solution
containing the oxa-π-allylrhodium complexes 7 and 7′ at 25
°C immediately generated a new rhodium species (spectrum C
in Figure 1), which is assigned to be hydroxorhodium complex
8 (Scheme 6). A singlet for free triphenylphosphine stayed at
the same high field. The doublet of 31P NMR appearing at a
low field, 55.0 ppm (JP-Rh ) 186 Hz) and a singlet in a high
studies have led to the discovery of a rhodium catalyst that is
more catalytically active than Rh(acac)(binap).
Results and Discussion
As a key intermediate in the catalytic cycle, a square-planar
rhodium(I) complex RhPh(PPh3)((S)-binap) (6), which contains
a phenyl-rhodium bond and (S)-binap as a chelating bispho-
sphine ligand, was prepared by phenylation of chloro-rhodium
bond in RhCl(PPh3)((S)-binap) (5) with phenyllithium in ether14
(Scheme 3). Triphenylphosphine ligand was used as the third
ligand, which stabilizes the phenylrhodium(I) complex. In the
absence of triphenylphosphine, monomeric phenylrhodium
species were hardly obtained. The phenylrhodium complex 6
was fully characterized by 31P NMR. Three phosphorus atoms
appear as three ddd’s (see A in Figure 1), the coupling constants,
JP-P,trans ) 324 Hz, JP-P,cis ) 39 and 30 Hz, and JP-Rh ) 178,
170, and 121 Hz, being characteristic of square-planar rhodium
complexes coordinated with three unequivalent phosphorus
atoms. The coupling constant, 185 Hz, between rhodium and
the central phosphorus atom in the chloride complex 5 was
decreased to 121 Hz by conversion into phenyl complex 6,
indicating that the chloride was replaced by a phenyl group that
has a greater trans influence than chloride.15
1
field (-1.90 ppm) observed in its H NMR are characteristic
of hydroxo-bridged rhodium dimer complexes.18 The identical
hydroxorhodium complex coordinated with binap 8 can be
readily obtained by treatment of 1,5-cyclooctadiene complex
[Rh(OH)(cod)]219 with (S)-binap in benzene or by the reaction
(16) Slough, G. A.; Hayashi, R.; Ashbaugh, J. R.; Shamblin, S. L.; Aukamp,
A. M. Organometallics 1994, 13, 890.
(17) Bergman and Heathcock reported some oxygen-bound rhodium enolates:
Slough, G. A.; Bergman, R. G.; Heathcock, C. H. J. Am. Chem. Soc. 1989,
111, 938.
(18) Grushin, V. V.; Kuznetsov, V. F.; Bensimon, C.; Alper, H. Organometallics
1995, 14, 3927.
(19) Uson, R.; Oro, L. A.; Cabeza, J. A. Inorg. Synth. 1985, 23, 129.
(14) The preparation of a phenylrhodium complex by the reaction of a chloro-
(trialkylphosphine)rhodium(I) complex with phenyllithium or phenylmag-
nesium bromide has been reported: (a) Darensbourg, D. J.; Gro¨tsch, G.;
Wiegreffe, P.; Rheingold, A. L. Inorg. Chem. 1987, 26, 3827. (b) Keim,
W. J. Organomet. Chem. 1968, 14, 179.
(15) Yamamoto, A. Organotransition Metal Chemistry; John Wiley & Sons:
New York, 1986; pp 179-182.
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J. AM. CHEM. SOC. VOL. 124, NO. 18, 2002 5053

A R T I C L E S
Hayashi et al.
Figure 1. 31P NMR spectra (at 202 MHz in THF at 25 °C) of rhodium complexes observed in the reactions starting from phenylrhodium 6. (A) Phenylrhodium
complex 6. (B) Addition of tert-butyl vinyl ketone to A giving oxa-π-allylrhodium complexes 7 and 7′. (C) Addition of water to B giving hydroxorhodium
8. (D) Addition of phenylboronic acid to C giving phenylrhodium 6.
Scheme 4
Scheme 6
7 and 7′. The transmetalation is fast at 25 °C, the doublet
ascribed to the hydroxorhodium complex 8 being completely
replaced by the phenylrhodium complex 6 within 30 min, which
is shown as spectrum D in Figure 1. The triphenylphosphine,
which was free from rhodium in the oxa-π-allyl complexes 7
and the hydroxo complex 8, came back to the rhodium at the
transmetalation. In a separate experiment with an isolated
hydroxo complex 8 and 2 equiv of phenylboronic acid (2m) in
THF, it was confirmed that the transmetalation is completed in
30 min at 25 °C (Scheme 7).20
Scheme 5
of [RhCl((S)-binap)]2 (4) with potassium hydroxide in aqueous
THF. The pure sample of 8 is obtained by recrystallization from
benzene and ethanol.
As described above in the reactions shown in Figure 1 and
Schemes 5-7, which were carried out in one NMR sample tube,
(20) Miyaura and Suzuki reported the transmetalation of an alkenyl group from
boron to palladium(II) complexes containing Pd-O bonds in their
mechanistic studies on palladium-catalyzed cross-coupling: (a) Miyaura,
N.; Yamada, K.; Suginome, H.; Suzuki, A. J. Am. Chem. Soc. 1985, 107,
972. (b) Miyaura, N.; Suzuki, A. Chem. ReV. 1995, 95, 2457. (c) Suzuki,
A. Acc. Chem. Res. 1982, 15, 178.
Transmetalation of a phenyl group from boron to rhodium
was observed on addition of an excess of phenylboronic acid
(2m) to the THF solution of the hydroxorhodium complex 8
obtained by the hydrolysis of the oxa-π-allylrhodium complexes
9
5054 J. AM. CHEM. SOC. VOL. 124, NO. 18, 2002

Rh-Catalyzed Asymmetric 1,4-Addition of Organoboronic Acids
A R T I C L E S
Scheme 7
Scheme 8
Figure 2. 31P NMR spectra (at 202 MHz in THF at 25 °C) of oxa-π-
allylrhodium complexes. (E) Reaction of phenylrhodium 6 with 2-cyclo-
hexenone (1a) giving 9. (F) A mixture of oxa-π-allylrhodium complexes 9
and 10 obtained by the reaction of [RhCl(binap)]2 (4) with potassium
enolates generated from (S)-3am and potassium hydride.
we have succeeded in observing all three intermediates and all
three reaction steps in the catalytic cycle (Scheme 2), namely,
(a) insertion of an R,â-unsaturated ketone into the phenyl-
rhodium bond forming oxa-π-allylrhodium, (b) hydrolysis of
oxa-π-allylrhodium with water giving hydroxorhodium, and (c)
transmetalation of a phenyl group from phenylboronic acid to
hydroxorhodium to regenerate the starting phenylrhodium
complex. All reactions proceeded at 25 °C.
Scheme 9
The addition of 2-cyclohexenone (1a) to a THF solution of
phenylrhodium complex 6 gave oxa-π-allylrhodium complex
9 as a single isomer (Scheme 8), whose 31P NMR spectrum is
shown as spectrum E in Figure 2. Two phosphorus atoms
appeared as two dd’s at 44.2 (JP-Rh ) 205 Hz, JP-P,cis ) 51
Hz) and 54.8 ppm (JP-Rh ) 215 Hz, JP-P,cis ) 51 Hz).
Hydrolysis of oxa-π-allyl complex 9 with water produced (S)-
3-phenylcyclohexanone (3am) of 99% ee together with hydroxo
complex 8, indicating that the addition of the phenyl-rhodium
bond to the R,â-unsaturated ketone took place with nearly
perfect enantioselectivity (99% ee). It follows that the stereo-
chemical outcome in the catalytic reaction is determined at the
enantioselective insertion step. It would be possible for the oxa-
π-allyl complex to exist as a mixture of diastereoisomers (9
and 9′), which results from the coordination of diastereotopic
faces of oxa-π-allyl, but actually only one species was observed
in solution. It is probably due to the big difference in their
thermodynamic stability,21 isomer 9, where rhodium is coordi-
nated to oxa-π-allyl on the other side of phenyl, being much
more stable than the other isomer. The reaction of [RhCl((S)-
binap)]2 (4) with 2 equiv of potassium enolates generated from
(S)-3-phenylcyclohexanone (3am) (99% ee) and potassium
hydride gave a mixture of three oxa-π-allylrhodium isomers
(spectrum F in Figure 2), one of which is identical with that
obtained from phenylrhodium complex 6 by the phenylrhodation
of 2-cyclohexenone (2m). The other two isomers are considered
to be regioisomeric oxa-π-allylrhodium complexes 10 and 10′
resulting from potassium enolate where the double bond is
located at the other side of the phenyl group.
In the NMR experiments, it has been shown that each of the
three steps in the catalytic cycle takes place at 25 °C. However,
the catalytic reaction shown in Scheme 1 does not take place at
60 °C or lower. We found an answer to why the high
temperature is required for the catalytic reaction. The trans-
metalation of the phenyl group from boronic acid 2m is very
slow at 25 °C for Rh(acac)(binap), which is the rhodium
complex thus far used for the catalytic reaction (Scheme 9),
while the transmetalation is fast at 25 °C for [Rh(OH)(binap)]2
(cf. Scheme 7). For the transmetalation to Rh(acac)(binap) to
proceed at a reasonable rate, a reaction temperature as high as
80 °C is required. It was also observed that the hydroxorhodium
complex 8 is immediately converted into the Rh(acac)(binap)
by addition of 1 equiv of acetylacetone. Thus, in the catalytic
reaction starting with Rh complex whose anionic ligand is
acetylacetonate, the transmetalation step is very slow and the
hydroxorhodium species generated by hydrolysis of the oxa-
(21) The diastereomeric isomers 9 and 9′ should exist in an equilibrium takes
place by way of a rhodium enolate.
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J. AM. CHEM. SOC. VOL. 124, NO. 18, 2002 5055

A R T I C L E S
Hayashi et al.
Scheme 10
of 1,4-addition product is higher, especially for the addition of
arylboronic acids whose hydrolysis is fast at the high temper-
ature. A typical example is the addition of 4-methoxyphenyl-
boron reagents. The reaction with [Rh(OH)(binap)]2 (8) at 35
°C gave 96% yield of the 1,4-addition product, while no 1,4-
addition is observed with the Rh(acac)(binap) catalyst at 100
°C (entries 10 and 11). For the introduction of the 4-fluorophenyl
group, the yield is twice as high as that with the new hydroxo
catalyst (entries 8 and 9). (3) Most importantly, the enantiose-
lectivity is always higher in the reaction catalyzed by [Rh(OH)-
(binap)]2 (8) than that catalyzed by the Rh(acac)(binap) catalyst,
which results from the lower reaction temperature realized by
use of the new catalyst system. All the reactions shown in Table
1 proceeded with higher enantioselectivity in the presence of
[Rh(OH)(binap)]2 (8) as a catalyst. It should be noted that the
enantioselectivity is significantly lower with the rhodium catalyst
generated in situ by mixing [Rh(OH)(cod)]2 with binap ligand,
because the exchange between cod and binap is not fast enough
and [Rh(OH)(cod)]2 possesses catalytic activity toward the 1,4-
addition reaction.
Scheme 11
Conclusions
We have succeeded in establishing the catalytic cycle of the
rhodium-catalyzed asymmetric 1,4-addition reaction. All the
intermediates and their transformations were observed in the
NMR experiments using an actual catalyst system. This is a
rare example of successful mechanistic studies where all the
key steps were followed one by one and the catalytic cycle is
completed. The catalytic cycle shown here, which involves
insertion of an unsaturated compound into the aryl-rhodium
bond followed by hydrolysis giving hydroarylation product and
hydroxorhodium species, is also expected to be working in the
rhodium-catalyzed addition reactions to some other multiple
bonds such as the carbon-oxygen double bond5 or the carbon-
carbon triple bond,4 which are carried out in an aqueous solvent.
The study of the transmetalation step brought us a more
catalytically active rhodium complex, [Rh(OH)(binap)]2 (8),
which catalyzes the asymmetric 1,4-addition reaction at a low
temperature leading to higher yield of 1,4-addition product with
higher enantioselectivity.
π-allyl complex is immediately converted into the acetylaceto-
nate complex by reaction with acetylacetone generated at the
transmetalation step (path a in Scheme 10).
The results obtained above during the studies on the catalytic
cycle gave us an idea that the catalyst system which does not
contain acetylacetonate should catalyze the asymmetric 1,4-
addition at a lower temperature (path b in Scheme 10). It was
actually successful. By use of the hydroxo complex [Rh(OH)-
(binap)]2 (8) as a catalyst,22 the catalytic 1,4-addition reaction
proceeded even at 35 °C (Scheme 11). The results are sum-
marized in Table 1, which also contains the data obtained with
Rh(acac)(binap) as a catalyst for comparison. In the presence
of 3 mol % of the hydroxorhodium catalyst 8 the 1,4-addition
of phenylboronic acid (2m) or phenylboroxine23 (11m) to
2-cyclohexenone (1a) took place at 35 °C to give a 96-98%
yield of 1,4-addition product 3am (entries 4, 5), while with the
Rh(acac)(binap) catalyst the 1,4-addition is very slow at 60 °C
or lower, almost no reaction taking place (entries 2 and 3). A
hydroxorhodium complex generated in situ from [RhCl(binap)]2
and potassium hydroxide24 also catalyzed the 1,4-addition at
35 °C (entry 6). In addition to the lower reaction temperature,
the new catalyst system has the following advantages over the
rhodium acetylacetonate catalyst8-10 thus far used. (1) The
amount of boron reagent can be reduced while keeping the yield
of 1,4-addition product high (entry 7). This is because hydrolysis
of phenylboronic acid giving benzene, which is the main side
reaction of the rhodium-catalyzed reaction,8 is retarded by
carrying out the reaction at a lower temperature. (2) The yield
Experimental Section
General. All manipulations were carried out under a nitrogen
atmosphere. Nitrogen gas was dried by passage through P2O5. NMR
spectra were recorded on a JEOL JNM LA-500 spectrometer (500 MHz
1
for H, 125 MHz for 13C, and 202 MHz for 31P). Chemical shifts are
reported in δ ppm referenced to an internal tetramethylsilane standard
1
for H NMR, chloroform-d (δ 77.0) for 13C NMR, and external 85%
H3PO4 standard for 31P NMR.
Materials. Rhodium complexes [RhCl(C2H4)2]2 and [Rh(OH)-
25
(cod)]219 were prepared according to the reported procedures. Phenyl-
boronic acid (2m) was purchased from Tokyo Kasei Kogyo Co., Ltd.
Other arylboronic acids26 were prepared according to the reported
procedures.
Preparation of [RhCl((S)-binap)]2 (4). A solution of [RhCl(C2H4)2]2
(1.02 g, 2.62 mmol) and (S)-BINAP (3.42 g, 5.49 mmol) in CH2Cl2
(10 mL) was stirred at room temperture for 2 h. After concentration in
vacuo the red-orange residue was tritulated in Et2O (30 mL) and then
the supernatant was removed by cannulation at 0 °C. The precipitate
(22) A hydroxorhodium complex, [Rh(OH)(cod)]2 included in a cyclodextrin,
has been reported to be an effective catalyst for the 1,4-addition in water:
Itooka, R.; Iguchi, Y.; Miyaura, N. Chem. Lett. 2001, 722.
(23) Concerning the use of arylboroxine in place of arylboronic acid for the
rhodium-catalyzed 1,4-addition, see refs 9d and 9g.
(24) It has been reported that addition of KOH to a rhodium complex generates
an active catalyst: Ramnauth, J.; Poulin, O.; Bratovanov, S. S.; Rakhit,
S.; Maddafird, S. P. Org. Lett. 2001, 3, 2571.
(25) Cramer, R. Inorg. Synth. 1974, 15, 16.
(26) (a) Brown, H. C.; Cole, T. E. Organometallics 1983, 2, 1316. (b) Hawthorne,
M. F. J. Am. Chem. Soc. 1958, 80, 4291.
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5056 J. AM. CHEM. SOC. VOL. 124, NO. 18, 2002

Rh-Catalyzed Asymmetric 1,4-Addition of Organoboronic Acids
A R T I C L E S
Table 1. Asymmetric 1,4-Addition of Organoboron Reagents RB(OH)2 (2) or (RBO)3 (11) to R,â-Unsaturated Ketones and Esters 1
Catalyzed by [Rh(OH)((S)-binap)]2 (8)a
c
entry
1
2or 11 (equivd to 1)
catalystb
temp (°C)
time (h)
yield (%) of 3
%eee
1f
2f
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1b
1b
1c
1c
1d
1d
1e
1e
1f
2m (2.5)
2m (2.5)
2m (2.5)
2m (2.5)
11m (2.5)
2m (2.5)
11m (1.4)
2n (2.5)
A
A
A
8
8
B
8
A
8
A
8
A
8
A
8
100
60
40
35
35
35
35
100
35
100
35
100
35
100
35
100
35
100
35
5
5
5
3
3
3
3
5
3
5
3
5
3
5
3
5
3
5
3
5
3
93 (3am)
3 (3am)
97 (S)
97 (S)
3f
<2 (3am)
96 (3am)
98 (3am)
94 (3am)
94 (3am)
44 (3an)
96 (3an)
0 (3ao)
96 (3ao)
93 (3bm)
95 (3bm)
51 (3 cm)
94 (3 cm)
82 (3dm)
89 (3dm)
88 (3em)
92 (3em)
75 (3fp)
4
5
6
7
8
9
99.3 (S)
99.3 (S)
99.1 (S)
99.2 (S)
97.6
11n (2.5)
2o (2.5)
99.1
10g
11
12f
13
14f
15
16f
17
18f
19
20h
21
11o (2.5)
2m (1.4)
11m (2.5)
2m (1.4)
11m (2.5)
2m (5.0)
11m (2.5)
2m (2.5)
11m (2.5)
2p (5.0)
99.1
97 (S)
98 (S)
93 (S)
96.3 (S)
97 (S)
97.9 (S)
92 (R)
97.8 (R)
97 (S)
99.1 (S)
A
8
A
8
A
8
100
35
1f
11p (2.5)
85 (3fp)
a The reaction was carried out with substrate 1 (0.40 mmol) in dioxane/H2O (10/1, 2.2 mL) in the presence of 3 mol % of rhodium catalyst. b A: Rh(acac)((S)-
binap) or the in situ generated catalyst from Rh(acac)(C2H4)2 and (S)-binap. B: Catalyst generated in situ from [RhCl((S)-binap)]2 and KOH. c Isolated yield
by silica gel chromatography. d Equivalents of Ph-B unit to 1. e Determined by HPLC analysis with chiral stationary phase columns: Daicel Chiralcel OD-H
(hexane/2-propanol ) 98/2) for 3am, 3cm, 3dm, and 3em; OB-H (hexane/2-propanol ) 98/2) for 3bm; AD (hexane/2-propanol ) 9/1) for 3an and 3ao;
and OG (hexane/2-propanol ) 98/2) for 3fp. f Reported in ref 8. g Reported in ref 9c. h Reported in ref 9b.
was washed five times with Et2O at 0 °C and dried under vacuum.
The yield of 4 was 3.92 g (98%). 1H NMR (C6D6, 50 °C): δ 6.49 (br
t, J ) 7.3 Hz, 8H), 6.57 (t, J ) 7.3 Hz, 4H), 6.66 (ddd, J ) 8.6, 6.2
and 1.2 Hz, 4H), 6.69 (br d, J ) 8.6 Hz, 4H), 6.97 (t, J ) 7.3 Hz, 4H),
6.99 (ddd, J ) 8.2, 6.2 and 1.6 Hz, 4H), 7.05 (t, J ) 7.6 Hz, 8H), 7.20
(d, J ) 8.7 Hz, 4H), 7.26 (d, J ) 8.2 Hz, 4H), 7.60 (quint, J ) 4.2 Hz,
A Sequence of Reactions Starting with Phenylrhodium Complex
6 in an NMR Sample Tube. Conversion into Oxa-π-allylrhodium
Complexes 7 and 7′, Hydroxorhodium Complex 8, and Phenyl-
rhodium Complex 6. The 31P NMR charts obtained are shown in
Figure 1. In an NMR sample tube a solution of 6 (26.6 mg, 25.0 µmol)
in THF (0.5 mL) was charged and 4,4-dimethyl-1-penten-3-one (14.0
mg, 125 µmol) was added at 25 °C. After 1 h, the 31P NMR spectrum
of the solution showed generation of free PPh3 (-4.5 ppm) and two
diastereomeric isomers of oxa-π-allylrhodium species 7 and 7′ in a
4H), 8.01 (br, 8H), 8.28 (br, 8H); 31P NMR (C6D6) δ 49.7 (d, JRh-P
)
197 Hz). Anal. Calcd for C88H64Cl2P4Rh2: C, 69.44; H, 4.24. Found:
C, 69.16; H, 4.33.
Preparation of RhCl(PPh3)((S)-binap) (5). A solution of 4 (846
mg, 0.556 mmol) and PPh3 (350 mg, 1.33 mmol) in toluene (5 mL)
was stirred at room temperature for 3 h. After concentration in vacuo
the red residue was tritulated in Et2O (10 mL) and then the supernatant
was removed by cannulation at 0 °C. The precipitate was washed five
times with Et2O at 0 °C and dried under vacuum. The yield of 5 was
1.13 g (99%). 1H NMR (C6D6, 50 °C) δ 6.21 (br, 2H), 6.35 (t, J ) 6.9
Hz, 1H), 6.43-6.58 (m, 7H), 6.77-6.93 (m, 14H), 6.97 (t, J ) 7.5
Hz, 1H), 7.19-7.31 (m, 7H), 7.67 (t, J ) 7.3 Hz, 1H), 7.76 (m, 8H),
8.04 (br, 2H), 8.22-8.30 (m, 4H); 31P NMR (C6D6) δ 29.6 (ddd, JP-P,trans
ratio of 2:1. 7: 31P NMR (THF) δ 37.9 (dd, JRh-P ) 186 Hz, JP-P
)
45 Hz), 48.4 (dd, JRh-P ) 222 Hz, JP-P ) 45 Hz). 7′: 31P NMR (THF)
δ 40.8 (dd, JRh-P ) 182 Hz, JP-P ) 45 Hz), 49.5 (dd, JRh-P ) 228 Hz,
JP-P ) 45 Hz). To the solution containing oxa-π-allylrhodium 7 and
7′ was added water (5 µL). In 10 min all the rhodium complexes were
completely converted into [Rh(OH)((S)-binap)]2 (8). Free PPh3 remained
at -4.5 ppm. 8: 31P NMR (THF) δ 55.0 (d, JRh-P ) 186 Hz). To the
reaction mixture was added a solution of phenylboronic acid (30.5 mg,
250 µmol) in THF (0.1 mL). In 1 h, most of the 8 was replaced by the
phenylrhodium complex 6.
) 375 Hz, JRh-P ) 143 Hz, JP-P,cis ) 36 Hz), 31.9 (ddd, JP-P,trans
)
Reaction of [RhCl((S)-binap)]2 (4) with Potassium Enolate of 4,4-
Dimethyl-1-phenylpenten-3-one Forming Oxa-π-allylrhodium Com-
plexes 7 and 7′. In an NMR sample tube, 4 (22.8 mg, 15.0 µmol) and
a powdery potassium enolate (6.9 mg, 30.0 µmol) prepared from 4,4-
dimethyl-1-phenylpentan-3-one and potassium hydride were charged
and THF (0.5 mL) was added at 25 °C. Within 40 min, 4 was
completely converted into a 2:1 mixture of 7 and 7′. 7: 1H NMR (C6D6)
δ 1.30 (s, 9H), 3.40 (br d, J ) 12.7 Hz, 1H), 3.49 (br d, J ) 11.3 Hz,
1H), 4.02 (dd, J ) 12.7 and 11.3 Hz, 1H); 31P NMR (THF) δ 37.9 (dd,
JRh-P ) 185 Hz, JP-P ) 44 Hz), 48.3 (dd, JRh-P ) 222 Hz, JP-P ) 44
Hz). 7′: 1H NMR (C6D6) δ 1.32 (s, 9H), 2.48 (br d, J ) 12.5 Hz, 1H),
3.63 (br d, J ) 10.6 Hz, 1H), 3.69 (br dd, J ) 12.5 and 10.6 Hz, 1H);
31P NMR (THF) δ 40.8 (dd, JRh-P ) 182 Hz, JP-P ) 44 Hz), 49.4 (dd,
JRh-P ) 222 Hz, JP-P ) 44 Hz).
Reaction of Phenylrhodium Complex 6 with 2-Cyclohexen-1-one
(1a) Forming Oxa-π-allylrhodium Complex 9. In an NMR sample
tube, 2-cyclohexen-1-one (19.2 mg, 200 µmol) was added to a solution
of 6 (21.3 mg, 20.0 µmol) in THF (0.5 mL). The 31P NMR spectrum
of the solution showed generation of free PPh3 (-4.5 ppm) and oxa-
π-allylrhodium complex 9. After 2 h, 17% of 6 was converted into 9.
375 Hz, JRh-P ) 144 Hz, JP-P,cis ) 43 Hz), 50.6 (ddd, JRh-P ) 185 Hz,
JP-P,cis ) 44 Hz, JP-P,cis ) 36 Hz). Anal. Calcd for C62H47ClP3Rh: C,
72.77; H, 4.63. Found: C, 72.95; H, 4.78.
Preparation of RhPh(PPh3)((S)-binap) (6). The solid 5 (1.24 g,
1.12 mmol) was suspended in Et2O (80 mL), and PhLi (2.2 mL, 0.88
M) was added at 0 °C. The mixture was stirred at room temperature
for 72 h. After filtation of the insoluble LiCl, the solvent was removed
in vacuo to yield dark-red powders. The powdery complex was
dissolved in Et2O (40 mL) and passed through a short alumina column
1
(Et2O) to give 946 mg (73%) of 6. H NMR (C6D6) δ 6.26-6.41 (m,
9H), 6.49-6.57 (m, 4H), 6.86-6.90 (m, 10H), 6.97-7.05 (m, 6H),
7.12 (t, J ) 7.3 Hz, 1H), 7.19 (t, J ) 7.3 Hz, 2H), 7.26 (d, J ) 8.3 Hz,
1H), 7.31 (t, J ) 7.8 Hz, 1H), 7.40-7.52 (m, 12H), 7.81-7.87 (m,
3H), 8.22 (t, J ) 8.1 Hz, 2H), 8.43 (dd, J ) 8.8 and 6.8 Hz, 1H); 31P
NMR (C6D6) δ 29.5 (ddd, JP-P,trans ) 324 Hz, JRh-P ) 178 Hz, JP-P,cis
) 39 Hz), 32.8 (ddd, JP-P,trans ) 324 Hz, JRh-P ) 170 Hz, JP-P,cis ) 30
Hz), 35.4 (ddd, JRh-P ) 121 Hz, JP-P,cis ) 39 Hz, JP-P,cis ) 30 Hz).
Anal. Calcd for C68H52P3Rh: C, 76.69; H, 4.92. Found: C, 76.55; H,
5.22.
9
J. AM. CHEM. SOC. VOL. 124, NO. 18, 2002 5057

A R T I C L E S
Hayashi et al.
9: 31P NMR (THF) δ 44.2 (dd, JRh-P ) 205 Hz, JP-P ) 51 Hz), 54.8
(dd, JRh-P ) 215 Hz, JP-P ) 51 Hz).
temperature for 30 min and then concentrated in vacuo. The crude
mixture was dissolved in benzene (5 mL), and the organic layer was
washed with water (2 × 5 mL). The organic layer was dried over
anhydrous Na2SO4 and concentrated. The residual solid was dried under
vacuum. The yield of 8 was 132 mg (60%). Complex 8 thus obtained
was used as a catalyst without further purification for the asymmetric
1,4-addition reaction.
Reaction of [RhCl((S)-binap)]2 (4) with Potassium Enolate of (S)-
3-Phenylcyclohexan-1-one Forming Oxa-π-allylrhodium Complexes
9 and 10. A mixture of 4 (304 mg, 0.200 mmol) and a powdery
potassium enolate (85 mg, 0.40 mmol) generated from (S)-3-phenyl-
cyclohexan-1-one and potassium hydride in THF (3 mL) was stirred
at 25 °C for 1 h. 31P NMR of the mixture showed that 4 was completely
converted into oxa-π-allylrhodium complexes which can be assigned
to regio- and diastereoisomers 9, 10, and 10′ in a ratio of 2:8:1. 9: 31P
NMR (THF) δ 44.3 (dd, JRh-P ) 205 Hz, JP-P ) 51 Hz), 54.8 (dd,
JRh-P ) 215 Hz, JP-P ) 51 Hz). 10: 31P NMR (THF) δ 43.8 (dd, JRh-P
) 202 Hz, JP-P ) 50 Hz), 55.0 (dd, JRh-P ) 216 Hz, JP-P ) 50 Hz).
10′: 31P NMR (THF) δ 45.0 (dd, JRh-P ) 205 Hz, JP-P ) 51 Hz), 53.9
(dd, JRh-P ) 212 Hz, JP-P ) 51 Hz).
Rhodium-Catalyzed 1,4-Addition. The reaction conditions and
results are summarized in Table 1. A typical procedure is given for
the reaction of 2-cyclohexen-1-one (1a) with phenylboroxine (11m)
giving (S)-3-phenylcyclohexan-1-one (3am) (entry 5): To a mixture
of [Rh(OH)((S)-binap)]2 (8) (8.9 mg, 6 µmol) and phenylboroxine (104
mg, 0.33 mmol) were added 1,4-dioxane (2 mL), water (0.2 mL), and
2-cyclohexen-1-one (39 mg, 0.40 mmol). The mixture was stirred at
35 °C for 3 h. After evaporation of the solvent, the residue was dissolved
in ethyl acetate. The solution was washed twice with saturated aqueous
sodium bicarbonate and dried over anhydrous magnesium sulfate.
Chromatography on silica gel (hexane:EtOAc 4:1) gave (S)-3-phenyl-
cyclohexan-1-one (68 mg, 98%) as a colorless oil.
Reaction of [Rh(OH)(cod)]2 with (S)-binap Forming [Rh(OH)-
((S)-binap)]2 (8). A solution of [Rh(OH)(cod)]2 (68.4 mg, 0.150
mmol) and (S)-binap (187 mg, 0.300 mmol) in benzene (3 mL)
was stirred at 50 °C for 2 h. The dark-red solution was filtered
through Celite using 10 mL of benzene, and the filtrate was concen-
trated in volume into ca. 3 mL. EtOH (10 mL) was added, and the
mixture was left for 6 h until a considerable amount of dark-red
crystals were precipitated. The crystals were separated, washed with
EtOH (4 × 5 mL), and dried under vacuum. The yield of 8 was 152
1
3an: H NMR (CDCl3) δ 1.73-1.86 (m, 2H), 2.07 (dm, J ) 11.6
Hz, 1H), 2.12-2.17 (m, 1H), 2.38 (td, J ) 12.7 and 6.3 Hz, 1H), 2.45-
2.51 (m, 2H), 2.58 (ddt, J ) 13.9, 4.1, and 2.1 Hz, 1H), 3.00 (tt, J )
11.8 and 3.9 Hz, 1H), 7.01 (t, J ) 8.6 Hz, 2H), 7.18 (dd, J ) 8.6 and
5.5 Hz, 2H); 13C NMR (CDCl3) δ 25.37, 32.85, 41.08, 43.96, 49.05,
1
mg (68%). Mp 212-214 °C dec. H NMR (C6D6) δ -1.90 (s, 2H),
2
3
115.40 (d, JC-F ) 21.0 Hz), 127.95 (d, JC-F ) 8.3 Hz), 140.00 (d,
4JC-F ) 3.1 Hz), 161.49 (d, 1JC-F ) 244 Hz), 210.69. Anal. Calcd for
C12H13OF: C, 74.98; H, 6.82. Found: C, 74.88; H, 6.87. [R]20D -18.7
(c 1.00, CHCl3) for (S)-3an of 99.1% ee.
6.57 (br, 8H), 6.59 (t, J ) 6.7 Hz, 4H), 6.63 (d, J ) 3.4 Hz, 8H),
6.70 (t, J ) 7.2 Hz, 4H), 6.76 (t, J ) 7.3 Hz, 8H), 6.98 (ddd, J )
8.1, 4.2, and 3.1 Hz, 4H), 7.14 (d, J ) 8.8 Hz, 4H), 7.23 (d, J ) 8.3
Hz, 4H), 7.44 (quint, J ) 4.2 Hz, 4H), 8.14 (br, 8H), 8.30 (very br,
8H); 31P NMR (C6D6) δ 55.2 (d, JRh-P ) 185 Hz). This complex is
extremely air sensitive, and satisfactory elemental analysis could not
be achieved.
Preparation of [Rh(OH)((S)-binap)]2 (8) from [RhCl((S)-binap)]2
(4). Aqueous KOH (0.6 mL, 5 M) was added to a solution of 4 (228.3
mg, 0.150 mmol) in THF (6 mL). The solution was stirred at room
Acknowledgment. This work was supported by “Research
for the Future” Program, the Japan Society for the Promotion
of Science, and a Grant-in-Aid for Scientific Research, the
Ministry of Education, Japan.
JA012711I
9
5058 J. AM. CHEM. SOC. VOL. 124, NO. 18, 2002