High Efficiency and Enantioselectivity in the Rh-Catalyzed Conjugate Addition of Arylboronic Acids Using Monodentate Phosphoramidites

Article abstract of DOI:10.1021/jo035155e

A very fast reaction and enantioselectivities >98% have been reached in the rhodium-catalyzed arylboronic acid addition to enones using a monodentate phosphoramidite ligand. Temperature-dependent studies show that monodentate phosphoramidites form stable

Full text of DOI:10.1021/jo035155e

SCHEME 1. Rh od iu m -Ca ta lyzed Con ju ga te
Ad d ition of P h en ylbor on ic Acid to Cycloh exen on e
High Efficien cy a n d En a n tioselectivity in
th e Rh -Ca ta lyzed Con ju ga te Ad d ition of
Ar ylbor on ic Acid s Usin g Mon od en ta te
P h osp h or a m id ites
J ean-Guy Boiteau, Adriaan J . Minnaard,* and
Ben L. Feringa*
Department of Organic and Molecular Inorganic Chemistry,
Stratingh Institute, University of Groningen,
Nijenborgh 4, 9747 AG Groningen, The Netherlands
of substrates have been obtained. The chiral ligands em-
ployed in this reaction are bidentate in nature; most fre-
quently, BINAP is used although binol-based diphospho-
nites,7 and amidomonophosphines,8 are also successful.9
feringa@chem.rug.nl
Received August 6, 2003
Recently, we showed that simple monodentate phos-
phoramidites can be used as ligands in the rhodium-
catalyzed asymmetric conjugate addition of boronic ac-
ids.10 This was confirmed in a communication by Miyaura
and co-workers.11 Compared to bis-phosphines, phos-
phoramidites are simple, readily accessible, and easily
tunable ligands. The amine part as well as the diol part
can be extensively modified due to the molecular struc-
ture of these ligands. Despite the rather drastic condi-
tions (dioxane, water, 100 °C for 5 h), the rhodium-bound
phosphoramidite is remarkably stable.10 In an attempt
to improve the observed enantioselectivity, we examined
phosphoramidites L1-L4 in the rhodium-catalyzed con-
jugate addition of phenylboronic acid 1a to cyclohexenone
2 (Scheme 1 and Table 1, entries 1-4).
We were pleased to find that ligand L4 showed very
high enantioselectivity, and (S)-3-phenylcyclohexanone
(S)-2a was obtained quantitatively with an ee > 98%!
To extend the scope of this reaction, we tested phos-
phoramidite L4 using several substrates and arylboronic
acids (Table 1, Scheme 2, entries 5-11). In most cases,
full conversion was achieved within 5 h at 100 °C, and
high levels of enantioselectivity (85 to >98% ee) were
reached.12 These results clearly show that the catalyst
based on phosphoramidite L4 is more enantioselective
than the catalysts based on phosphoramidites L1-L3
used in the screening.13
Abstr a ct: A very fast reaction and enantioselectivities
>98% have been reached in the rhodium-catalyzed arylbor-
onic acid addition to enones using a monodentate phos-
phoramidite ligand. Temperature-dependent studies show
that monodentate phosphoramidites form stable complexes
with metals and can induce high enantioselectivities even
at high temperatures in polar solvents.
Enantioselective 1,4-additions of organometallic re-
agents to enones hold a prominent position in our reper-
toire to assemble carbon-carbon bonds in organic chem-
istry.1 Following the introduction of chiral phosphora-
midite ligands for the copper-catalyzed conjugate addition
of dialkylzinc reagents,2 which showed excellent enan-
tioselectivities, numerous chiral catalysts have been
introduced in recent years for this asymmetric reaction.3
These methods are, however, limited to aliphatic dial-
kylzinc reagents although a variety of functional groups
are tolerated. A prominent example is the copper-catal-
yzed conjugate addition of an ester-functionalized organ-
ozinc reagent to a cyclopentenone as applied in the short
asymmetric synthesis of prostaglandin PGE1.4 So far, the
use of aryl- or alkenylzinc reagents in the copper-cata-
lyzed conjugate addition has met with limited success.5
Hayashi and Miyaura have reported the rhodium-
catalyzed conjugate addition of boronic acids as the me-
thod of choice to introduce aryl or alkenyl moieties to
enones,6 and high enantioselectivities with a broad scope
(6) (a) Sakai, M.; Hayashi, H.; Miyaura, N. Organometallics 1997,
16, 4229. (b) Hayashi, T. Synlett 2001, 879. (c) Takaya, Y.; Ogasawara,
M.; Hayashi, T.; Sakai, M.; Miyaura, M. J . Am. Chem. Soc. 1998, 120,
5579. (d) Hayashi, T.; Senda, T.; Takaya, Y.; Ogasawara, M. J . Am.
Chem. Soc. 1999, 121, 11591. (e) Takaya, Y.; Senda, T.; Kurushima,
H.; Ogasawara, M.; Hayashi, T. Tetrahedron: Asymmetry 1999, 10,
4047. (f) Sakuma, S.; Sakai, M.; Itooka, R.; Hayashi, T. J . Org. Chem.
2000, 65, 5951. (g) Senda, T.; Ogasawara, M.; Hayashi, T. J . Org.
Chem. 2001, 66, 6852. (h) Hayashi, T.; Senda, T.; Ogasawara, M. J .
Am. Chem. Soc. 2000, 122, 10716. (i) Hayashi, T.; Takahashi, M.;
Takaya, Y.; Ogasawara, M. J . Am. Chem. Soc. 2002, 124, 5052. (J )
Sakuma, S.; Miyaura, N. J . Org. Chem. 2001, 66, 8944-8946.
(7) Reetz, M. T.; Moulin, D.; Gosberg, A. Org. Lett. 2001, 3, 4083.
(8) (a) Kuriyama, M.; Tomioka, K. Tetrahedron Lett. 2001, 42, 921.
(b) Kuriyama, M.; Nagai, K.; Yamada, K.-I.; Miwa, Y.; Taga, T.;
Tomioka, K. J . Am. Chem. Soc. 2002, 124, 8932.
* Corresponding author.
(1) Tomioka, K. Nagaoka, Y. In Comprehensive Asymmetric Cataly-
sis; J acobsen, E. N., Pfalz, A., Yamamoto, H., Eds.; Springer-Verlag:
Berlin, Heidelberg, 1999; Vol. 3; Chapter 31.1.
(2) (a) de Vries, A. H. M.; Meetsma, A.; Feringa, B. L. Angew. Chem.,
Int. Ed. Engl. 1996, 35, 2374. (b) Naasz, R.; Arnold, L. A.; Minnaard,
A. J .; Feringa B. L. Angew. Chem., Int. Ed. 2001, 40, 927. (c) Naasz,
R.; Arnold, L. A.; Pineschi, M.; Keller, E.; Feringa, B. L. J . Am. Chem.
Soc. 1999, 121, 1104. (d) Naasz, R.; Arnold, L. A.; Minnaard, A. J .;
Feringa, B. L. Chem. Commun. 2001, 735. (e) Bertozzi, F.; Crotti, P.;
Macchia, F.; Pineschi, M.; Feringa, B. L. Angew. Chem., Int. Ed. 2001,
40, 930.
(3) For reviews, see: (a) Krause N.; Gerold, A. Angew. Chem., Int.
Ed. Engl. 1997, 36, 186. (b) Krause N. Angew. Chem., Int. Ed. 1998,
37, 283. (c) Feringa, B. L.; Naasz, R.; Imbos, R.; Leggy, A. L. In Modern
Organocopper Chemistry; Krause, N., Ed.; Wiley-VCH: Weinheim,
2002; Chapter 7, p 224. (d) Alexakis, A.; Benhaim, C. Eur. J . Org.
Chem. 2002, 3221.
(9) For a review on rhodium-catalyzed carbon-carbon bond-forming
reactions of organometallic compounds, see: Fagnou, K.; Lautens, M.
Chem. Rev. 2003, 103, 169.
(4) (a) Arnold, L. A.; Naasz, R.; Minnaard, A. J .; Feringa, B. L. J .
Am. Chem. Soc. 2001, 123, 5841. (b) Arnold, L. A.; Naasz, R.; Minnaard,
A. J .; Feringa, B. L. J . Org. Chem. 2002, 67, 7244.
(5) Schinnerl, M.; Seitz, M.; Kaiser, A.; Reiser, O. Org. Lett. 2001,
3, 4259.
(10) Boiteau, J . G.; Imbos, R.; Minnaard, A. J .; Feringa, B. L. Org.
Lett. 2003, 5, 681 and 1385.
(11) Iguchi, Y.; Itooka, R.; Miyaura N. Synlett 2003, 7, 1040.
(12) The reaction time of 5 h as well as the use of 3 equiv of boronic
acid was chosen as a standard protocol.
10.1021/jo035155e CCC: $25.00 © 2003 American Chemical Society
Published on Web 11/05/2003
J . Org. Chem. 2003, 68, 9481-9484
9481

TABLE 1. Asym m etr ic Con ju ga te Ad d ition of Bor on ic
Acid s to En on esa
entry
enone
R(BOH)2
L
convb (%)
eec (%)
1
2
3
4
5
6
7
8
9
2
2
2
2
3
4
5
2
2
2
2
1a
1a
1a
1a
1a
1a
1a
1b
1c
1d
1e
L1
L2
L3
L4
L4
L4
L4
L4
L4
L4
L4
100
100
100
100
100
95
100
60
100
100
100
84
94
89
>98
85
96
87
95
98
10
11
96
98
F IGURE 1. Comparison of ligands L4 and BINAP. Reactions
performed in 1,4-dioxane/water ) 10/1 at 100 °C, on 2 mmol
scale with a loading of 1 mol % of catalyst.
a
Reactions performed in dioxane/water at 100 °C, with 3 equiv
of boronic acid on 0.4 mmol scale and a loading of 3 mol % catalyst.
Ratio Rh/L: 1/2.5. b Conversions are determined by 1H NMR. c Ee’s
are determined by chiral HPLC, on a DAICEL AD column.
TABLE 2. Effect of th e Tem p er a tu r e on th e Asym m etr ic
Ad d ition of P h en ylbor on ic Acid to Cycloh exen on e 2
Usin g L4 a s liga n d a
SCHEME 2. Str u ctu r e of th e Su bstr a tes, Liga n d s,
a n d Bor on ic Acid s Used in th e Rh -Ca ta lyzed
Con ju ga te Ad d ition
entry
T (°C)
convb (%)
eec (%)
ln kS/ kR
1
2
3
4
5
6
7
8
9
45
60
70
100
100
100
100
100
100
100
100
100
99.1
98.7
98.8
98.5
98.3
98.2
98.4
96.1
94.2
5.39
5.04
5.17
4.93
4.71
4.68
4.81
3.93
3.51
80
100
110
120
130
140
a
All reactions were performed on 0.4 mmol scale, using 3 mol
b
% of rhodium catalyst and 1,4-dioxane as a solvent. Conversions
are determined by 1H NMR. c Ee’s are determined by chiral HPLC
on a DAICEL AD column. Ee’s and ln kS/kR values are the average
of two runs. See the Supporting Information.
These exciting results showing fast catalytic conversion
at 100 °C initiated several experiments at lower temper-
atures. Surprisingly, the ee found for (S)-2a was only
improved marginally when the reaction was performed
at 45 °C (Table 2).
To investigate the activity and robustness of our new
catalytic system, the addition of phenylboronic acid 1a
to cyclohexenone 2 was performed with a loading of 0.05
mol % of rhodium (ratio Rh/L: 1/2.5), which resulted in
full conversion and ee of >98% within 2 h at 80 °C. This
means a turnover number (TON) for this catalyst of 2000
which is remarkable for an asymmetric carbon-carbon
bond-forming reaction. In addition, a comparison of
phosphoramidite L4 versus BINAP under the same
conditions was made. With L4 as a ligand using 1 mol %
of catalyst, >99% conversion was reached within 5 min
at 100 °C which corresponds to an initial turnover
frequency (TOF) of 2500 h-1 (initial TOF ) 110 h-1 for
BINAP).14 The conversion against time for the two
ligands is depicted in Figure 1. In both cases, high levels
of enantioselectivity (97-98%) are obtained but the rate
of the reaction using phosphoramidite L4 as a ligand is
dramatically larger.
This intriguing insensitivity of the ee toward the
temperature incited us to run some reactions at higher
temperatures.15 Much to our surprise, the ee of (S)-2a
was still exceeding 94% at 140 °C, which is remarkable
in an asymmetric catalytic reaction using monodentate
ligands. A similar trend with a BINAP-based catalyst has
also been observed by Hayashi,6i as the same enantiose-
lectivity at 120 °C and at 40 °C was reported, although
the conversion obtained at 40 °C was less than 2%.16
In asymmetric catalysis, the observed enantioselectiv-
ity for a reaction is usually temperature dependent.
Therefore, reactions are often performed at low temper-
ature to allow an enhanced stereocontrol, though at the
expence of reaction rate. In our particular case, we
observed that the stereocontrol was hardly temperature-
dependent, although obviously the conversion was slower
at 45 °C than at 100 °C (16 h vs 5 min).17
It is also interesting to note that the enantioselectivity
of this reaction was found to be largely solvent-indepen-
dent. When toluene and 2-propanol were used as solvent,
(13) Using different reaction conditions, Miyaura et al. obtained the
highest ee using L2 as the ligand; see ref 11.
(14) With BINAP, the rhodium-catalyzed conjugate addition requires
5 h to achieve complete conversion under these conditions. After
completion of this study, it was published that using modified condi-
tions, the reaction can be performed using the BINAP-based Rh
catalyst in 6 h at 25 °C; see: Itooka, R.; Iguchi, Y.; Miyaura, N. J .
Org. Chem. 2003, 68, 6000.
(15) Reactions were performed in a pressure-resistant flask on 0.4
mmol scale with 3 mol % of catalyst.
(16) For the BINAP-based catalyst, the rate of the transmetalation
from phenylboronic acid to the hydroxorhodium species is very slow
at temperatures lower than 80 °C; see ref 6i.
(17) Reactions at room temperature were difficult to reproduce.
9482 J . Org. Chem., Vol. 68, No. 24, 2003

SCHEME 3. P r op osed Mech a n ism for th e
Rh -Ca ta lyzed Con ju ga te Ad d ition of
P h en ylbor on ic Acid to Cycloh exen on e
F IGURE 2. Eyring plots of ln(kS/ kR) as a function of 1/T for
the catalytic asymmetric addition of phenylboronic acid to
cyclohexenone: (O) MonoPhos L1, (b) phosphoramidite L4. For
L1 at 373 K, ∆∆Hq ) - 0.83 ( 0.06 kcal‚mol-1 (45%), T∆∆Sq
) 0.96 ( 0.07 kcal‚mol-1 (55%); for L4 at 373 K, ∆∆Hq ) -
2.1 ( 0.2 kcal‚mol-1 (60%), T∆∆Sq ) 1.4 ( 0.2 kcal‚mol-1
(40%).
the ee for (S)-2a remained >98%, although complete
conversion required 3 h at 80 °C compared to 20 min in
dioxane. In addition, the small amount of water (10%)
present in these reactions could be replaced by methanol
without a change in ee, although the rate of the reaction
again decreased.
The catalytic cycle of the rhodium catalyzed conjugate
addition of boronic acids has been studied by Hayashi
and several of the intermediates have been characterized
by NMR6i (Scheme 3). The enantiodiscrimination is
attributed to the addition of the phenyl bound to rhodium
to one of the π-faces of the R,â-unsaturated ketone (step
B f C).
Encouraged by the high enantioselectivities obtained,
we were interested in determining the contributions of
enthalpy and entropy to the ee of this reaction. The
temperature independence allowed us to consider an
entropy-driven or largely entropy-driven enantioselec-
tion.18 In asymmetric catalysis, the effect of temperature
on enantioselectivity has been studied in the asymmetric
hydrosilylation by Scharf et al.19 A partially entropy-
controlled enantioselectivity has been reported for a Mn-
catalyzed oxidation by Katsuki et al.20
In a chemical reaction, when enantiomers or diaster-
eoisomers are produced, the ee or de is determined by
the difference in ∆Gq between the two transition states
(∆∆Gq). To determine the terms ∆∆Hq and ∆∆Sq, and
their contribution to the enantioselectivity, a modified
Eyring equation21 is usually employed (eq 1).
sentially irreversible and the products do not racemize,
kS/kR is identical to the enantiomeric product ratio.
The Eyring plots for the rhodium-catalyzed addition
of boronic acid to cyclohexenone show a straight curve
with a small slope whereas a fully entropy controlled
enantioselection should give a horizontal curve. Calcula-
tions of ∆∆Hq, derived from the slope, and ∆∆Sq, derived
from the intercept (eq 1), reveals that in both cases the
entropy contribution to the ee roughly equals the en-
thalpy contribution. Both ∆∆Hq (<0) and ∆∆Sq (>0) favor
the major enantiomer, which gives a kind of rationale
for the high ee’s observed. This large entropy contribution
to the enantioselectivity probably originates from the
catalytic complex and is not due to differences in solva-
tion between the two diastereomeric complexes as various
solvents give the same ee.23
The interpretation of the large entropy contribution to
the enantioselectivity is not straightforward, and cannot
be related directly to a characteristic of monodentate
ligands, since temperature independence of the ee has
also been reported using the bidentate ligand BINAP.6b
It is usually accepted that rigid and bulky bidentate
ligands, like BINAP, create a well-defined chiral environ-
ment around the metal center where the substrate can
access the metal almost exclusively in one orientation.1
For this reason, the bidentate nature of ligands is
generally assumed to be very important in order to obtain
a high enantioselectivity. Here, we show that small
monodentate phosphoramidite ligands, like L4, create
probably a similar well defined asymmetric surrounding
around the rhodium even at high temperatures. Com-
pared to BINAP where the two phosphorus atoms are
linked by covalent bonds, the preferred orientation of the
phosphoramidites is probably only maintained by strong
steric interactions. The similar performance of BINAP
and L4, in terms of enantioselectivity, can be explained
by a pseudo-bidentate behavior of two phosphoramidites
-∆∆Hq
RT
∆∆Sq
R
kS
ln
)
+
(1)
kR
Figure 2 shows the values of ln(kS/ kR) with ligand L1
and L4 plotted against 1/T.22 As the reaction is es-
(18) (a) Sugimura, T.; Tei, T.; Mori, A.; Okuyama, T.; Tai, A. J . Am.
Chem. Soc. 2000, 122, 2128. (b) Sugimura, T.; Hagiya, K.; Sato, Y.;
Tei, T.; Tai, A.; Okuyama, T. Org. Lett. 2001, 3, 37. (c) Tei, T.; Sato,
Y.; Hagiya, K.; Tai, A.; Okuyama, T.; Sugimura, T. J . Org. Chem. 2002,
67, 6593.
(19) Haag, D.; Runsink, J .; Scharf, H-D. Organometallics 1998, 17,
(22) The same behavior was observed for the two phosphoramidites
although the ee values are lower in the case of L1. In the case of L4,
the ln kS/kR values at 130 °C and 140 °C were not included in the curve
because in this range, a decrease of 4% ee induces an important drop
in the ratio value.
398.
(20) Nishida, T.; Miyafuji, A.; Ito, Y. N.; Katsuki, T. Tetrahedron
Lett. 2000, 41, 7053.
(21) (a) Eyring, H. J . Chem. Phys. 1935, 3, 107. (b) Bushmann, H.;
Scharf, H-D.; Hoffmann, N.; Esser, P. Angew. Chem., Int. Ed. Engl.
1991, 30, 477. See also ref 18a.
(23) Strictly spoken, the difference in ∆Sq
between both
solvation
diastereomeric complexes is the same in various solvents.
J . Org. Chem, Vol. 68, No. 24, 2003 9483

contains two ligands L1 at the Rh in a cis coordination).
Based on this crystal structure, a computational simu-
lated rotation of the phosphoramidites around the rhod-
ium-phosphorus bond using molecular mechanics showed
that such a rotation is strongly disfavored by the steric
hindrance of the bis-â-naphthol moieties. The concept
that monodentate ligands can act in a similar way as
bidentate ligands is of great interest in the search for
new catalysts using simple monodentate chiral ligands.25
In conclusion, monodentate phosphoramidites are ex-
tremely effective ligands in the rhodium-catalyzed con-
jugate addition of boronic acids to enones. A very fast
reaction and enantioselectivities >98% have been reached,
which clearly confirms that monodentate ligands and
especially monodentate phosphoramidites can be as
efficient as the bidentate diphosphines used so far.
Temperature-dependent studies show that in contrast to
the common notion, monodentate ligands can form stable
complexes with metals and can induce high enantiose-
lectivities even at high temperatures in polar solvents.
F IGURE 3. Crystal structure of Rh(L1)4BF4.
at the metal center as these ligands might bind to the
rhodium in a locked configuration, thereby mimicking a
bidentate ligand. The high enantioselectivity obtained at
140 °C (entry 9, Table 2) indicates that the rotation of
the ligands around the P-Rh bond should be difficult.
An equilibrium of the rhodium-phosphoramidite com-
plex with the free ligand has to be excluded because free
L1 rapidly hydrolyses in dioxane/H2O ) 10/1 at 100 °C.10
Additional support for the hypothesis that the two
monodentate ligands restrict each other in their confor-
mational flexibility is obtained from the crystal structure
of Rh(L1)4BF4 depicted in Figure 3,24 although the
complex differs from the actual catalytic species (which
Ack n ow led gm en t. This work was supported by the
European Combicat network. Prof. Dr. J . B. F. N.
Engberts is acknowledged for helpful discussions. T.
Tiemersma is gratefully acknowledged for the assistance
with HPLC separations.
Su p p or tin g In for m a tion Ava ila ble: Experimental de-
tails describing the synthesis, characterization, and analysis
of the products. This material is available free of charge via
the Internet at http://pubs.acs.org.
(24) Van den Berg, M.; Minnaard, A. J .; Haak, R. M.; Leeman, M.;
Schudde, E. P.; Meetsma, A.; Feringa, B. L.; de Vries, A. H. M.;
Maljaars, C. E. P.; Willans, C. E.; Hyett, D.; Boogers, J . A. F.;
Henderickx, H. J . W.; de Vries, J . G. Adv. Synth. Catal. 2003, 345,
308.
J O035155E
(25) Komarov, I. V.; Bo¨rner, A. Angew. Chem., Int. Ed. 2001, 40,
1197.
9484 J . Org. Chem., Vol. 68, No. 24, 2003