Practical method for asymmetric addition of arylboronic acids to α,β-unsaturated carbonyl compounds utilizing an in situ prepared rhodium catalyst

Article abstract of DOI:10.1021/jo802136j

A new practical method for the asymmetric Michael addition of arylboronic acids to α,β-unsaturated carbonyl compounds utilizing in situ generated chiral rhodium-binap-based catalyst has been developed to address the unavailability of the preformed catalys

Full text of DOI:10.1021/jo802136j

generation Hayashi catalyst (2) could be obtained commercially
in gram quantities, while Miyaura catalyst (3) is not available
at all. The older, first generation Hayashi catalyst (4) could be
conveniently prepared in situ from the available starting
materials, but its practical applications are limited due to
insufficient reactivity.
Practical Method for Asymmetric Addition of
Arylboronic Acids to r,ꢀ-Unsaturated Carbonyl
Compounds Utilizing an In Situ Prepared
Rhodium Catalyst
Kirill Lukin,* Qunying Zhang, and M. Robert Leanna
{Rh[(S)-binap]OH}2 {Rh(nbd)[(R)-binap]}BF4
GPRD Process Research and DeVelopment, Abbott
2
3
Laboratories, North Chicago, Illinois 60064
Rh(acac)[(S)-binap]
4
Alternative “in house” preparation of large quantities of
catalysts 2 or 3 was deemed not feasible due to their particular
air sensitivity requiring specialized equipment. Although a
number of newer, more efficient catalysts have been introduced
in recent years, these new entities typically employ “designer”
ligands, which need to be independently synthesized, thus further
limiting their utility.4
kirill.lukin@abbott.com
ReceiVed September 24, 2008
Another undesirable characteristic of the reaction outlined
in eq 1 is the requirement to use 1.5-3 equiv of the corre-
sponding arylboronic acid, which is needed to compensate for
the protodeborylation (hydrolysis) side reaction.3 The excess
reagent and the side product formation complicate the product
isolation and reduce the overall cost efficiency of the process.
In this note, we describe a new practical method for the
asymmetric Michael addition of arylboronic acids to R,ꢀ-
unsaturated carbonyl compounds, which utilizes in situ prepared
Miyaura type catalyst 3. This methodology provides convenient
access to either enantiomer, utilizing commercially available
starting materials, while maintaining the high enantioselectivity
reported for the preformed catalysts. Additionally, our conditions
allow reduction of the catalyst load from 3 to 1.5 mol % while
decreasing the required excess of arylboronic acids from 1.5-3
to just 1.05-1.1 equiv.5a
A new practical method for the asymmetric Michael addition
of arylboronic acids to R,ꢀ-unsaturated carbonyl compounds
utilizing in situ generated chiral rhodium-binap-based catalyst
has been developed to address the unavailability of the
preformed catalysts. While maintaining high levels of
enantioselectivity reported for the preformed catalysts, the
new method provides a convenient access to either enantio-
meric form of the product and allows for a substantial
reductions in both the boronic acid and the catalyst loads.
To address the catalyst availability issue, we thought that its
in situ generation from commercially available precursors could
be a valuable solution. Additional advantages of this approach
include the elimination of the special handling requirements for
the highly air-sensitive active catalyst and convenient access
to either desired enantiomer of the product by simply switching
to a ligand with the opposite stereochemistry.
Rhodium-catalyzed asymmetric addition of arylboronic acids
to R,ꢀ-unsaturated carbonyl compounds, which was originally
developed by Hayashi1 and Miyaura,2 has become an important
synthetic method for the preparation of chiral ꢀ-aryl-substituted
ketones and esters 1 (eq 1). High levels of asymmetric induction
Unfortunately, we soon learned that in situ preparation of
the most widely used Hayashi catalyst 2 was a difficult problem.
Although, combining the available [Rh(cod)OH]2 starting mate-
rial with (S)-binap ligand liberates cyclooctadiene while provid-
ing the desired highly reactive binap complex (eq 2), the
reactions utilizing the resulting catalyst displayed only modest
asymmetric inductions.
observed in these reactions make this approach particularly
valuable.3 However, when considering applications of this
methodology for large-scale preparations, the catalysts’ avail-
ability becomes a substantial obstacle. The standard reaction
protocol requires relatively high loads of the catalysts (typically
3 mol %);1-3 however, only the S-form of the desirable second
For example, the addition of bromophenylboronic acid 5 to
cyclopentenone (eq 3) gave product 6 with 55% ee (vs 96% ee
observed for the preformed catalyst 2). It was reported in the
literature that achiral rhodium-cyclooctadiene complexes were
highly active catalysts for the Michael-type addition of aryl-
boronic acids.2 We suggested that small amounts of such
complexes could be presented in the reaction mixture and were
(1) (a) The first generation catalyst: Takaya, Y.; Ogasawara, M.; Hayashi,
T.; Sakai, M.; Miyaura, N. J. Am. Chem. Soc. 1998, 120, 5579. (b) The second
generation catalyst: Hayashi, T.; Takahashi, M.; Takaya, Y.; Ogasawara, M.
J. Am. Chem. Soc. 2002, 124, 5052.
(2) Itooka, R.; Iguchi, Y.; Miyaura, N. J. Org. Chem. 2003, 68, 6000.
(3) For reviews, see: (a) Hayashi, T.; Yamasaki, K. Chem. ReV. 2003, 103,
2829. (b) Hayashi, T. Synlett 2001, 879.
10.1021/jo802136j CCC: $40.75
Published on Web 12/05/2008
2009 American Chemical Society
J. Org. Chem. 2009, 74, 929–931 929

responsible for the observed background reaction. Indeed,
attempted removal of cyclooctadiene from the in situ generated
catalyst under vacuum resulted in the improvement of the
product chiral purity to ∼90% ee but was not practical due to
its insufficient reproducibility.5
FIGURE 1. R,ꢀ-Unsaturated carbonyl components and products in
asymmetric Michael additions of arylboronic acids.
With these lessons learned, we thought that Miyaura catalyst
3 could be a better fit for the in situ preparation method because
it could be synthesized from commercially available rhodium-
norbornadiene complex (eq 4), which has been previously found
poorly active in Michael additions of arylboronic acids.2
Indeed, we were pleased to find that the reaction outlined in
eq 3 utilizing the catalyst prepared by combining bis(norbor-
nadiene)rhodium tetrafluoroborate with (S)-binap (eq 4) in
dioxane gave the desired compound 6 in 85% isolated yield
and 97% ee purity versus 87% yield and 96.5% ee obtained
with preformed catalyst 3.
TABLE 1. Asymmetric Additions of Arylboronic Acids to
r,ꢀ-Unsaturated Carbonyl Compoundsa
reaction
isolated
chiral purity
(% ee for S-series)
entry
product
yield (%)b
yield (%)c
1
2
3
4
5
6
7
8
9
6
96
90
93
96
94
86
99
92
0
85
78
75
81
80
71
79
75
0
97.0
95.1
95.7
97.3
98.6
98.7
93.4
91.6
N/A
11a
11cd
11d
12a
12b
13
14e
15
a Reaction conditions: 1.05 equiv of arylboronic acid, 1.5 mol % of
catalyst, 23-27 °C. b As determined by HPLC method. c After column
chromatography. d 1.1 equiv of arylboronic acid was used. e In 12:1
dioxane/water.
Further reaction optimization allowed us to develop a very
robust protocol, where the catalyst was prepared in situ by
combining the phosphine and rhodium components directly in
a dioxane slurry of the desired boronic acid at room temperature
(see Experimental Section for details). Upon the formation of
the active catalyst, water cosolvent was added, followed by the
addition of R,ꢀ-unsaturated carbonyl compound and triethy-
lamine as a base. Under these optimized conditions, the reaction
proceeded at room temperature and required only 1.5 mol % of
the catalyst, versus previously reported 3%. Moreover, as we
observed very little protodeborylation in the reaction mixture
under these conditions, the possibility of reduction of the excess
boronic acid below the standard 1.5 equiv was investigated. We
found that only 1.05 equiv of the boronic acid was required to
achieve complete consumption of the carbonyl component. The
reduction in the arylboronic acid amount also allowed us to
simplify the reaction workup. Thus common chromatographic
isolation could be replaced with a simple extractive protocol,
which gave the products suitable for further utilization.
To demonstrate the generality of this practical method, we
conducted a series of asymmetric additions of arylboronic acids
to R,ꢀ-unsaturated carbonyl compounds using the standard set
of literature substrates 7-10, affording the formation of
compounds 6 and 11-14 (Figure 1). The results of these
experiments are summarized in Table 1.
We were pleased to find that the levels of asymmetric
induction and the assayed reaction yields observed in these
experiments matched the literature data.6 The isolated yields
of individual compounds in Table 1 have not been optimized
and in some cases were slightly lower than those reported. Most
of the reactions were also repeated with the R-form of binap
ligand in order to achieve accurate assessment of the chiral
purity of products.7
The following additional observations are noteworthy: (a) the
water content in dioxane for the reactions listed in Table 1 could
be reduced from typical 15 to 7%. Lower water content benefited
the reaction involving compounds with larger lypophilic groups
(entry 8), which resulted in better conversion and chiral purity;
(b) 1.1 equiv of 4-(methoxyphenyl)boronic acid was used due
to its faster hydrolysis under the reaction conditions (entry 3);
(c) no addition to trans-cinnamaldehyde8 was observed under
the current conditions.
In summary, we have developed a highly practical protocol
for asymmetric additions of arylboronic acids to conjugated
carbonyl compounds utilizing an in situ generated Miyaura-
type catalyst. Due to commercial availability of the catalyst
components, the overall simplicity, and convenient access to
either of the desired enantiomers, this method represents a
substantial improvement over the previously reported conditions.
In the current form, the methodology could be applied for the
(4) (a) Boiteau, J.-G.; Minnaard, A. J.; Feringa, B. J. Org. Chem. 2003, 68,
9481. (b) Otomaru, Y.; Okamoto, K.; Shintani, R.; Hayashi, T. J. Org. Chem.
2005, 70, 2503. (c) Paquin, J.-F.; Stephenson, C. R. J.; Defieber, G.; Carreira,
E. M. J. Am. Chem. Soc. 2005, 127, 10850. (d) Duan, W.-L.; Iwamura, H.;
Shintani, R.; Hayashi, T. J. Am. Chem. Soc. 2007, 129, 2130. (e) Mariz, R.;
Luan, X.; Gatti, M.; Linden, A.; Dorta, R. J. Am. Chem. Soc. 2008, 130, 2172.
(5) (a) A solvent switch from water to isopropyl alcohol was recently reported
to reduce the boronic acid loss due to protodeborylation: Brock, S.; Hose, D. R. J.;
Mosely, J. D.; Parker, A. J.; Patel, I.; Williams, A. J. Org. Process Res. DeV.
2008, 12, 496. (b) In situ generation of catalyst 2 from [RhCl(S)-binap)]2 and
KOH has been reported (ref 1b). However, the precursor complex is not available
commercially. Additionally, formation of a racemic product was reported when
utilizing the catalyst prepared in this way (ref 2).
(6) Literature data for rhodium-catalyzed asymmetric additions of arylboronic
acids to compounds 11-14: 11a, ref 1a; 11c,11d, ref 1b; 12b: Pucheault, M.;
Darses, S.; Genet, J.-P. Eur. J. Org. Chem. 2002, 21, 3552. 12a,14, ref 2.
(7) Experiments in R-series gave products with slightly lower chiral purities
probably due to the lower chiral purity of the ligand used (99.3 vs 99.9% ee for
S-series): 6, 96.1% ee; 11c, 93.2% ee; 11d, 96.6% ee; 12a, 98.8% ee; 12b, 99.1%
ee; 13, 91.2% ee.
(8) R,ꢀ-Unsaturated aldehydes have been reported to give poor yields/chiral
purities in rhodium-binap-catalyzed additions of arylboronic acids. See, for
example, ref 4c.
930 J. Org. Chem. Vol. 74, No. 2, 2009

General isolation procedure followed by column chromatography
gave compound 13 (1.01 g, 79% yield, 93% ee chiral purity).
Other compounds listed in Table 1 were prepared using the above
procedure in the specified yields and chiral purities.10 The reaction
yields were determined by HPLC method using isolated reference
material. The reference materials were obtained from the crude
isolated products by column chromatography (silica; ethyl
acetate-hexane).11 Crude isolated products typically had >90%
robust and scalable preparations of ꢀ-aryl-substituted carbonyl
compounds with high yields and enantiomeric purities.
Experimental Section
General Procedure for the Asymmetric Addition of Arylbo-
ronic Acids to r,ꢀ-Unsaturated Carbonyl Compounds. Synthesis
of 3-(S)-(4-Bromophenyl)cyclopentanone (6). Bis(norbornadiene)r-
hodium tetrafluoroborate (0.28 g, 0.75 mmol) and (S)-binap (0.5
g, 0.8 mmol) were added to a mixture of 4-bromophenylboronic
acid (10 g, 50 mmol) in nitrogen sparged dioxane (65 mL) under
nitrogen atmosphere. After 2 h of agitation at ambient temperature,
water was added (10 mL) followed by 2-cyclopenten-1-one (3.9 g,
47.5 mmol) and triethylamine (4.8 g, 47.5 mmol). The agitation
was continued for 15 h at 23-27 °C.9 The mixture was then diluted
with heptane (65 mL), MTBE (17.5 mL), and water (50 mL). The
organic layer was separated and washed with water (50 mL). The
aqueous layers were combined and extracted with MTBE/heptane
(1:2, 50 mL). Combined organic layers were filtered through filtrol
and concentrated in vacuo. The resulting solid was re-slurried in
heptane, filtered, and dried in vacuo to give 6 (9.65 g, 85% yield,
97% ee chiral purity).
1
purity (as determined by HPLC and H NMR) and were suitable
for further chemical transformations.
Supporting Information Available: HPLC methods for
chiral analysis and 1H spectra of compounds 6 and 11-14. This
material is available free of charge via the Internet at
http://pubs.acs.org.
JO802136J
(10) Literature refs for the isolated compounds. 6: Li, Z.; Chen, W.; Hale,
J. J.; Lynch, C. L.; Mills, S. G.; Hajdu, R.; Keohane, C. A.; Rosenbach, M. J.;
Milligan, J. A.; Shei, G.-J.; Chrebet, G.; Parent, S. A.; Bergstrom, J.; Card, D.;
Forrest, M.; Quackenbush, E. J.; Wickham, L. A.; Vargas, H.; Evans, R. M.;
Rosen, H.; Mandala, S. J. Med. Chem. 2005, 48, 6169. 11a: Paquette, L. A.;
Gilday, J. P.; Ra, C. S. J. Am. Chem. Soc. 1987, 109, 6858. 11c,11d: Takaya,
Y.; Ogasawara, M.; Hayashi, T. Tetrahedron Lett. 1999, 40, 6957. 12a: Barnhart,
R. W.; Wang, X.; Noheda, P.; Bergens, S. H.; Whelan, J.; Bosnich, B. J. Am.
Chem. Soc. 1994, 116, 1821. 12b: Zhang, Y.; Schuster, G. B. J. Org. Chem.
1994, 59, 1855. 13: Marugesan, N.; Barrish, J. C.; Lloyd, J. Jpn. Kokai Tokkyo
Koho; Patent JP 09124620 A 19970513, 1997. 14: Ref 1a.
Ethyl (S)-3-(4-Bromophenyl)butenoate (13) was prepared
according to a general procedure from ethyl crotonate (9, 0.51 g,
4.5 mmol) and 4-bromophenylboronic acid (0.95 g, 4.75 mmol).
(9) The reaction is exothermic with adiabatic heat of 40 °C. External cooling
was used to maintain 23-27 °C temperature.
(11) No further enhancement in the chiral purity of products was observed
during the isolation.
J. Org. Chem. Vol. 74, No. 2, 2009 931