Rhodium-catalyzed 1,4-addition of arylboronic acids to α,β-unsaturated carbonyl compounds: Large accelerating effects of bases and ligands

Article abstract of DOI:10.1021/jo0207067

The effects of ligands and bases in the rhodium(I)-catalyzed 1,4-addition of arylboronic acids to α,β-unsaturated carbonyl compounds were reinvestigated to carry out the reaction under mild conditions. Rhodium(I) complexes possessing a 1,5-cyclooctadiene (cod) and a hydroxo ligand such as [RhOH(cod)]₂ exhibited excellent catalyst activities compared to those of the corresponding rhodium-acac or -chloro complexes and their phosphine derivatives. The reaction was further accelerated in the presence of KOH, thus allowing the 1,4-addition even at 0 °C. A cationic rhodium-(I)-(R)-binap complex, [Rh(R-binap)(nbd)]BF₄, catalyzed the reaction at 25-50 °C in the presence of Et₃N with high enantioselectivities of up to 99% ee for α,β-unsaturated ketones, 92% for aldehydes, 94% for esters, and 92% for amides.

Full text of DOI:10.1021/jo0207067

Rh od iu m -Ca ta lyzed 1,4-Ad d ition of Ar ylbor on ic Acid s to
r,â-Un sa tu r a ted Ca r bon yl Com p ou n d s: La r ge Acceler a tin g Effects
of Ba ses a n d Liga n d s
Ryoh Itooka, Yuki Iguchi, and Norio Miyaura*
Division of Molecular Chemistry, Graduate School of Engineering, Hokkaido University,
Sapporo 060-8628, J apan
miyaura@org-mc.eng.hokudai.ac.jp
Received November 19, 2002
The effects of ligands and bases in the rhodium(I)-catalyzed 1,4-addition of arylboronic acids to
R,â-unsaturated carbonyl compounds were reinvestigated to carry out the reaction under mild
conditions. Rhodium(I) complexes possessing a 1,5-cyclooctadiene (cod) and a hydroxo ligand such
as [RhOH(cod)]2 exhibited excellent catalyst activities compared to those of the corresponding
rhodium-acac or -chloro complexes and their phosphine derivatives. The reaction was further
accelerated in the presence of KOH, thus allowing the 1,4-addition even at 0 °C. A cationic rhodium-
(I)-(R)-binap complex, [Rh(R-binap)(nbd)]BF4, catalyzed the reaction at 25-50 °C in the presence
of Et3N with high enantioselectivities of up to 99% ee for R,â-unsaturated ketones, 92% for aldehydes,
94% for esters, and 92% for amides.
The conjugate addition of nucleophiles to activated
alkenes is a widely used process in organic chemistry.
Since the reaction often yields a stereogenic center at the
â-carbon, considerable efforts have been devoted to the
development of its asymmetric versions.1 Perhaps the
most commonly used metal catalyst is copper in combi-
nation with organolithium,2 -magnesium,3 or -zinc4
reagents,1a,d but rhodium-catalyzed reactions of organo-
boranes,5-8 -silicones,9,10 and -stannanes11,12 are an at-
tractive alternative because of their insensitivity to
functional groups and the availability of various chiral
phosphine ligands for rhodium catalysts. It was recently
demonstrated that rhodium(I) complexes are excellent
(6) Addition of B to aldehydes and imines: (a) Fu¨rstner, A.; Krause,
H. Adv. Synth. Catal. 2001, 343. (b) Ueda, M.; Saito, A.; Miyaura, N.
Synlett 2000, 1637. (c) Ueda, M.; Miyaura, N. J . Org. Chem. 2000, 65,
4450. (d) Ueda, M.; Miyaura, N. J . Organomet. Chem. 2000, 595, 31.
(e) Sakai, M.; Ueda, M.; Miyaura, N. Angew. Chem., Int. Ed. 1998, 37,
3279.
(7) Asymmetric 1,4-addition of
B to enones: (a) Hayashi, T.;
Takahashi, M.; Takaya, Y.; Ogasawara, M. J . Am. Chem. Soc. 2002,
124, 5052. (b) Kuriyama, M.; Nagai, K.; Yamada, K.; Miwa, Y.; Taga,
T.; Tomioka, K. J . Am. Chem. Soc. 2002, 124, 8932. (c) Sakuma, S.;
Miyaura, N. J . Org. Chem. 2001, 66, 8944. (d) Reetz, M. T.; Moulin,
D.; Gosberg, A. Org. Lett. 2001, 3, 4083. (e) Kuriyama, M.; Tomioka,
K. Tetrahedron Lett. 2001, 42, 921. (f) Senda, T.; Ogasawara, M.;
Hayashi, T. J . Org. Chem. 2001, 66, 6852. (g) Sakuma, S.; Sakai, M.;
Itooka, R.; Miyaura, N. J . Org. Chem. 2000, 65, 5951. (h) Hayashi, T.;
Senda, T.; Ogasawara, M. J . Am. Chem. Soc. 2000, 122, 10716. (i)
Hayashi, T.; Senda, T.; Takaya, Y.; Ogasawara, M. J . Am. Chem. Soc.
1999, 121, 11591. (j) Takaya, Y.; Senda, T.; Kurushima, H.; Ogasawara,
M.; Hayashi, T. Tetrahedron: Asymmetry 1999, 10, 4047. (k) Takaya,
Y.; Ogasawara, M.; Hayashi, T. Tetrahedron Lett. 1999, 40, 6957. (l)
Takaya, Y.; Ogasawara, M.; Hayashi, T. Tetrahedron Lett. 1998, 39,
8479. (m) Takaya, Y.; Ogasawara, M.; Hayashi, T.; Sakai, M.; Miyaura,
N. J . Am. Chem. Soc. 1998, 120, 5579. For reviews, see: (n) Hayashi,
T. Synlett 2001, 879. (o) Miyaura, N. In Organoboranes for Synthses;
ACS Symp. Ser. 783; Ramachandran, P. V., Brown, H. C., Eds.;
American Chemical Society: Washington, DC, 2000; pp 94-107.
(8) Addition of B to alkenes and alkynes: (a) Lautenes, M.; Dock-
endorff, C.; Fagnou, K.; Malicki, A. Org. Lett. 2002, 4, 1311. (b)
Murakami, M.; Igawa, H. J . Chem. Soc., Chem. Commun. 2002, 390.
(c) Lautens, M.; Yoshida, M. Org. Lett. 2002, 4, 123. (d) Hayashi, T.;
Inoue, K.; Taniguchi, N.; Ogasawara, M. J . Am. Chem. Soc. 2001, 123,
9918. (e) Lautens, M.; Roy, A.; Fukuoka, K.; Fagnou, K.; Martin-
Matute, B. J . Am. Chem. Soc. 2001, 123, 5358. (f) Oguma, K.; Miura,
M.; Satoh, T.; Nomura, M. J . Am. Chem. Soc. 2000, 122, 10464.
(9) Addition of Si to enones and alkynes: (a) Murata, M.; Shimazaki,
R.; Ishikura, M.; Watanabe, S.; Masuda, Y. Synthesis 2002, 717. (b)
Fujii, T.; Koike, T.; Mori, A.; Osakada, K. Synlett 2002, 295. (c) Koike,
T.; Du, X.; Mori, A.; Osakada, K. Synlett 2002, 301. (d) Oi, S.; Honma,
Y.; Inoue, Y. Org. Lett. 2002, 667. (e) Huang, T.-S.; Li, C.-J . J . Chem.
Soc., Chem. Commun. 2001, 2348.
(1) For reviews, see: (a) Krause, N.; Hoffmann-Ro¨der, A. Synthesis
2001, 171. (b) Sibi, M. P.; Manyem, S. Tetrahedron 2000, 56, 8033. (c)
Shibasaki, M.; Gro¨ger, H. In Comprehensive Asymmetric Catalysis;
J acobsen, E. N., Pfaltz, A., Yamamoto, H., Eds.; Springer: Berlin,
Germany, 1999; Chapter 29.3. (d) Tomioka, K.; Nagaoka, Y. In
Comprehensive Asymmetric Catalysis; J acobsen, E. N., Pfaltz, A.,
Yamamoto, H., Eds.; Springer: Berlin, Germany, 1999; Chapter 31.1.
(e) Yamaguchi, M. In Comprehensive Asymmetric Catalysis; J acobsen,
E. N., Pfaltz, A., Yamamoto, H., Eds.; Springer: Berlin, Germany,
1999;, Chapter 31.2. (f) Noyori, R. Asymmetric Catalysis in Organic
Synthesis; Wiley: New York, 1994.
(2) (a) Villacorta, G. M.; Rao, C. P.; Lippard, S. J . J . Am. Chem.
Soc. 1988, 110, 3175. (b) Ahn, K.-H.; Klassen, R. B.; Lippard, S. J .
Organometallics 1990, 9, 3178.
(3) (a) Zhou, Q.-L.; Pfaltz, A. Tetrahedron 1994, 50, 4467. (b) Kanai,
M.; Tomioka, K. Tetrahedron Lett. 1995, 36, 4275. (c) Stangeland, E.
L.; Sammakia, T. Tetrahedron 1997, 53, 16503.
(4) (a) Shintani, R.; Fu, G. C. Org. Lett. 2002, 4, 3699. (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.
(5) Addition of B to enones: (a) Yamamoto, Y.; Fujita, M.; Miyaura,
N. Synlett 2002, 767. (b) Amengual, R.; Michelet, V.; Geneˆt, J .-P.
Tetrahedron Lett. 2002, 43, 5905. (c) Pucheault, M.; Darses, S.; Geneˆt,
J .-P. Tetrahedron Lett. 2002, 43, 6155. (d) Itooka, R.; Iguchi, Y.;
Miyaura, N. Chem. Lett. 2001, 722. (e) Ramnaulth, J .; Poulin, O.;
Bratovanov, S. S.; Rakhit, S.; Maddaford, S. P. Org. Lett. 2001, 3, 2571.
(f) Ogasawara, M.; Yoshida, K.; Hayashi, T. Organometallics 2000, 19,
1567. (g) Batey, R. A.; Thadani, A. N.; Smil, D. V. Org. Lett. 1999, 1,
1683. (h) Sakai, M.; Hayashi, H.; Miyaura, N. Organometallics 1997,
16, 4229.
(10) Addition of Si to aldehydes: (a) Fujii, T.; Koike, T.; Mori, A.;
Osakada, K. Synlett 2002, 298. (b) Oi, S.; Moro, M.; Inoue, Y.
Organometallics 2001, 20, 1036. (c) Nakamura, K.; Nakamura, H.;
Yamamoto, Y. J . Org. Chem. 1999, 64, 2614.
10.1021/jo0207067 CCC: $25.00 © 2003 American Chemical Society
Published on Web 07/02/2003
6000
J . Org. Chem. 2003, 68, 6000-6004

Addition of Arylboronic Acids to Carbonyl Compounds
SCHEME 1. 1,4-Ad d ition to r,â-Un sa tu r a ted
Ca r bon yl Com p ou n d s
SCHEME 2. Asym m etr ic 1,4-Ad d ition to
r,â-Un sa tu r a ted Ca r bon yl Com p ou n d s
TABLE 1. Effects of Rh od iu m Com p lexes a n d Liga n d sa
catalysts for the conjugate additions of aryl- and alk-
enylboronic acids to R,â-unsaturated ketones, esters, and
amides.5 The protocol was extended to the addition to
unactivated C-C multiple bonds such as norbornene,8f
oxanorbornene,8a,b vinylarenes,8e and internal alkynes.8c,d
Among these reactions, the additions to R,â-unsaturated
ketones,7a,b,d,e,k-m esters,7g,j amides,7c,f phosphonates,7i
nitroalkenes,7h and oxanorbornenes8a were carried out in
the presence of rhodium(I)-chiral phosphine catalysts.
These reactions, however, often required the use of large
excesses of organoboronic acids because of a competitive
hydrolytic B-C bond cleavage of organoboronic acids and
perhaps the Rh-C bond cleavage of the rhodium inter-
mediate due to a low catalyst efficiency requiring a
temperature of over 100 °C in an aqueous solvent. Very
recently, [RhOH-binap]2 was found to be an efficient
catalyst that completes the reaction within 3 h at 35 °C.7a
In connection with our interests in metal-catalyzed
reactions of organoboronic acids,13 we report here the
effects of catalysts and bases reinvestigated for the 1,4-
addition of arylboronic acids to R,â-unsaturated carbonyl
compounds (Scheme 1).14 The (hydroxo)rhodium(I)-cod
complex or the catalyst in situ generated from a (chloro)-
rhodium(I)-cod complex and a base was recognized to
be the most efficient system that allows the reaction at
a temperature lower than room temperature. The results
were easily extended to asymmetric addition at room
temperature, using a cationic rhodium-binap complex
and triethylamine (Scheme 2).
ligand/
equivb
yield/%c yield/%c
(50 °C) (90 °C)
entry
Rh(I) precursor
[Rh(cod)2]BF4
1
2
none
25
93
[Rh(cod)(MeCN)2]BF4 none
74
84
3
[RhCl(cod)]2
none
93
99
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
[RhCl(nbd)]2
[RhCl(nbd)]2
[RhCl(coe)2]2
[RhCl(coe)2]2
Rh(acac)(cod)
Rh(acac)(coe)2
Rh(acac)(coe)2
Rh(acac)(coe)2
Rh(acac)(coe)2
Rh(acac)(coe)2
Rh(acac)(coe)2
Rh(acac)(coe)2
Rh(acac)(coe)2
Rh(acac)(coe)2
Rh(acac)(coe)2
Rh(acac)(coe)2
Rh(acac)(coe)2
none
cod (1)
none
cod (3)
none
none
trace
trace
93
trace
91
86
trace
90
0-22
88
7
36
38
52
23
5
9
3
trace
83
trace
-
trace
trace
trace
3
6
17
6
cod (1)
R3Pd
dppm (1)
dppe (1)
dppp (1)
dppb (1)
binap (1)
dppf (1)
DPFphos (1)
Xantphos (1)
DBEphos (1)
trace
trace
trace
a
All reactions were carried out for 6 h at 50 °C or 90 °C in
aqueous dioxane (6/1, 3 mL) in the presence of 2-cyclohexenone
(1 mmol), p-tolylboronic acid (1.5 mmol), a rhodium complex (3
b
mol % of Rh), and a ligand (3-9 mol %). Equivalents to rhodium
d
metal. c GC yields. The representative monophosphines resulted
in the following yields at 90 °C: P(t-Bu)3P (trace), Cy3P (trace),
(i-Pr)3P (2%), (p-MeOPh)3P (13%), Ph3P (7%), (p-CF3Ph)3P (22%),
(C6F5)3P (11%).
Rea ction Con d ition s
The effects of rhodium(I) precursors and ligands in the
conjugate addition of p-tolylboronic acid to 2-cyclohex-
enone are summarized in Table 1. There was a large
difference between the catalyst activities of the rhodium-
cod complexes and those of other alkene complexes. Var-
ious cationic and neutral rhodium complexes possessing
a cod ligand commonly exhibited an excellent catalyst
efficiency (entries 1-3), whereas the rhodium(I)-nor-
bornadiene (nbd) (entry 4), -cyclooctene (coe) (entries 6
and 9), and -ethylene complexes did not catalyze the
reaction at all. On the other hand, the addition of 1,5-
cyclooctadiene (1-3 equiv) to the rhodium-nbd and -coe
complexes resulted in almost quantitative conversions
within 6 h at 90 °C (entries 5, 7, and 10). Although
rhodium-phosphine complexes have been investigated
extensively to extend the reactions to asymmetric syn-
thesis, a small and less-donating cod is the best ligand
for achieving high conversions under mild conditions.
(11) Addition of Sn to enones: (a) Oi, S.; Moro, M.; Ito, H.; Honma,
Y.; Miyano, S.; Inoue, Y. Tetrahedron 2002, 58, 91. (b) Huang, T.;
Meng, Y.; Venkatraman, S.; Wang, D.; Li, C.-J . J . Am. Chem. Soc. 2001,
123, 7451. (c) Oi, S.; Moro, M.; Ono, S.; Inoue, Y. Chem. Lett. 1998,
83.
(12) Addition of Sn to aldehydes and imines: (a) Li, C.-J .; Meng, Y.
J . Am. Chem. Soc. 2000, 122, 9538. (b) Hayashi, T.; Ishigedani, M. J .
Am. Chem. Soc. 2000, 122, 976. (c) Oi, S.; Moro, M.; Fukuhara, H.;
Kawanishi, T.; Inoue, Y. Tetrahedron Lett. 1999, 40, 9259. (d) Oi, S.;
Moro, M.; Inoue, Y. J . Chem. Soc., Chem. Commun. 1997, 1621.
(13) (a) Miyaura, N. In Cross-Coupling Reactions; Miyaura, N., Ed.;
Springer: Berlin, Germany, 2002. (b) Miyaura, N. In Catalytic Het-
erofunctionalization; Togni, A., Gru¨tzmacher, H., Eds.; Wiley-VCH:
Weinheim, Germany, 2001; pp 1-45. (c) Miyaura, N. In Advances in
Metal-Organic Chemistry; Liebeskind, L. S., Ed.; J AI Press: London,
UK, 1998; Vol. 6, pp 187-243. (d) Suzuki, A. In Metal-Catalyzed Cross-
Coupling Reactions; Diederich, F., Stang, P. J ., Eds.; Wiley-VCH:
Weinheim, Germany, 1998; pp 49-97. (e) Miyaura, N.; Suzuki, A.
Chem. Rev. 1995, 95, 2457.
(14) Preliminary results were discussed at the 79th Annual Meeting
of J apan Chemical Society, 2001, 1H4 08, and the first Meeting of the
J apanese Society for Process Chemistry, 2002, p 11.
J . Org. Chem, Vol. 68, No. 15, 2003 6001

Itooka et al.
TABLE 2. Tu r n over Nu m ber of Ca ta lyst (TON)a
temp (°C)/
time (h)
entry
mol %b
yield/%c
TON
1
2
3
4
5
6
0.01
90/16
90/24
90/36
100/36
100/36
100/36
98
67
97
97
96
75
9 800
13 400
18 400
97 000
192 000
375 000
0.005
0.005
0.001
0.0005
0.0002
a
A mixture of 2-cyclohexenone (1 mmol), p-tolylboronic acid (1.5
mmol), [RhCl(cod)]2 (0.0002-0.01 mol % of Rh), cod (3 mol % for
entries 1-3 and 9 mol % for entries 4-6), and NaHCO3 (1 mol %)
in aqueous dioxane (6/1, 3 mL) was stirred in a sealed tube for
16-36 h at the temperature and for the period shown in the table.
b
mol % of Rh. c Isolated yields.
rhodium(I) complex16 that is effective for transmetalation
with arylboronic acids.
The accelerating effect of bases is shown in Figure 1.
Five reactions of p-tolylboronic acid (1.5 equiv) with
2-cyclohexenone were carried out at 5 °C with [RhOH-
(cod)]2 or [RhCl(cod)]2 (1.5 mol %) in the presence or
absence of KOH or Et3N (1 equiv). Although the RhOH
complex (0) was indeed a better catalyst than the RhCl
complex (O), the RhOH-catalyzed reaction was found to
be further accelerated in the presence of KOH (b) and
was almost superimposable to a combination of the RhCl
complex and KOH (]). Both reactions resulted in 93-
98% yields after 1 h at 5 °C. The effect of Et3N is smaller
than that of KOH (2), but it was markedly faster than
that carried out in the absence of a base. Thus, there are
two roles of bases. The presence of base is critical in
generating an active species for transmetalation when
the RhCl or Rh(acac) complexes are used as the catalyst
precursors. There is no relevant information for the
additional effect that accelerated the RhOH(cod)-cata-
lyzed reaction; however, quarternization of arylboronic
acids with a base facilitates transmetalation to the RhOH
species as is demonstrated in palladium-catalyzed reac-
tions of organoboronic acids.13 Facilitation of hydrolysis
of a rhodium enolate intermediate is another probable
effect.17 Such an effect of bases has been reported for the
rhodium-catalyzed addition of organoboronic acids to
aldehydes6a and the conjugate addition to acetylated
enones derived from glycals.5e
F IGURE 1. Effect of bases. All reactions were carried out at
5 °C in aqueous DME (6/1, 3 mL) in the presence of 2-cyclo-
hexenone (1 mmol), p-tolylboronic acid (1.5 mmol), a rhodium
complex (3 mol % of Rh), and a base (1 mmol), if used.
The effects of phosphine ligands are shown in entries
11-20. All monophoshines were ineffective (entry 11).
On the other hand, dppm was recognized to be the best
ligand among the representative diphosphines (entries
12-20). The dppm complex ( P-Rh-P, 72°) gave an 88%
yield of product at 90 °C, which was a much higher yield
than that of the dppp, dppb, binap, or dppf complex
having a bite angle in a range of 90-99° (entries 12-
17).15 These phosphine complexes catalyzed the reaction
efficiently at 90 °C but very slowly at 50 °C.
The addition of an inorganic base, such as NaHCO3,
Na2CO3, K3PO4, or KOH, to a mixture of p-tolylboronic
acid, 2-cyclohexenone, and [RhCl(cod)]2 (1.5 mol %) in
aqueous 1,4-dioxane exerted a remarkable accelerating
effect, in contrast to a very sluggish reaction under
neutral conditions. The reaction at 0 °C for 6 h in the
presence of a base (1 equiv) showed an accelerating effect
depending on the basic strengths: e.g., KOH (83%) > K3-
PO4 (49%) > K2CO3 (34%) > none (trace). The accelerat-
ing effect of a base was also significant for other rhodium
complexes possessing a cod ligand, a cod complex in situ
prepared from an appropriate rhodium precursor and cod,
and a cationic rhodium complex such as [Rh(cod)(MeCN)2]-
BF4.
The reaction proceeds through a catalytic cycle7a,g,n,o
involving (a) transmetalation between ArB(OH)2 and an
Rh(OH) complex yielding an Ar-Rh species, (b) insertion
of an alkene into the Rh-C bond, and finally (c) hydroly-
sis of a rhodium enolate intermediate with simultaneous
regeneration of an Rh(OH) species. In good agreement
with this mechanism, a change in the rhodium catalyst
from [RhCl(cod)]2 or Rh(acac)(cod) to [Rh(OMe)(cod)]2 or
[Rh(OH)(cod)]2 allowed reaction at room temperature in
the absence of bases.5d Thus, the results strongly sug-
gested that bases play a role in generating a (hydroxo)-
[RhCl(cod)]2 achieved high turnover numbers of the
catalyst (TON) at 90-100 °C (Table 2). The reaction at
a temperature over 90 °C suffered from incomplete
conversions due to decomposition of the catalyst via
dissociation of the cod ligand from the rhodium metal.
The addition of 1,5-cyclooctadiene (3-9 mol %) and a
small amount of a base (NaHCO3, 1 mol %) was found to
be highly effective for maintaining catalyst efficiency. The
reaction employing [RhCl(cod)]2 (0.0002 mol % of Rh), cod
(9 mol %), and NaHCO3 (1 mol %) at 100 °C gave 75%
yield of 3-tolylcyclohexanone after 36 h, corresponding
to 375 000 TON (entry 6). At 90-100 °C, there was no
(16) Formation of RhOH from RhCl and KOH: (a) Grushin, V. V.;
Kuznetsov, V. F.; Bensimon, C.; Alper, H. Organometallics 1995, 14,
3927. (b) Uson, R.; Oro, L. A.; Cabeza, J . A. Inorg. Synth. 1985, 23,
129.
(15) A review for bite angles in metal-catalyzed reactions: Leeuwen,
P. W. N. M.; Kamer, P. C. J .; Reek, J . N. H.; Dierkes, P. Chem. Rev.
2000, 100, 2741.
(17) Formation of rhodium enolates and their hydrolysis: Slough,
G. A.; Bergman, R. G.; Heathcock, C. H. J . Am. Chem. Soc. 1989, 111,
938.
6002 J . Org. Chem., Vol. 68, No. 15, 2003

Addition of Arylboronic Acids to Carbonyl Compounds
TABLE 3. Ad d ition of p-Tolylbor on ic Acid to r,â-Un sa tu r a ted Ca r bon yl Com p ou n d sa
temp (°C)/
entry
carbonyl compounds
(E)-PhCHdCHCOCH3
(E)-PhCHdCHCOCH3
(E)-PhCHdCHCOPh
â-ionone
catalyst/base (equiv)/solvent
time (h) product no. yield/%b
1
2
3
4
[RhCl(cod)]2/NaHCO3 (0.1)/dioxane-H2O
[RhOH(cod)]2/KOH (1)/DME-H2O
[RhOH(cod)]2/KOH (1)/DME-H2O
[RhCl(cod)]2/NaHCO3 (0.1)/dioxane-H2O
[RhCl(cod)]2/LiOH (1.5)/dioxane-H2O
[RhOH(cod)]2/KOH (1)/DME-H2O
[RhCl(cod)]2/NaHCO3 (0.1)/dioxane-H2O
[RhOH(cod)]2/KOH (1)/DME-H2O
25/16
0/6
3a
3a
3b
3c
3c
3c
3d
3d
3e
3f
96
99
82
36
92
35
94
98
trace
93
81
97
72
85
0/6
50/16
50/16
0/6
5c â-ionone
6
7
8
â-ionone
2-cyclohexenone
2-cyclohexenone
25/16
0/6
9
5-isopropenyl-2-methyl-2-cyclohexenone (carvone) [RhCl(cod)]2/NaHCO3 (0.1)/dioxane-H2O
90/16
25/16
0/6
10
11
12
13
14
(E)-CH3CHdCHCO2Me
(E)-CH3CHdCHCO2Me
(E)-PhCHdCHCO2Me
CH3CHdC(CO2Et)2
[RhCl(cod)]2/NaHCO3 (0.1)/dioxane-H2O
[RhOH(cod)]2/KOH (1)/DME-H2O
[RhOH(cod)]2/KOH (1)/DME-H2O
[RhCl(cod)]2/NaHCO3 (0.1)/dioxane-H2O
[RhOH(cod)]2/KOH (1)/DME-H2O
3f
0/6
50/16
0/6
3g
3h
3h
CH3CHdC(CO2Et)2
a
A mixture of a carbonyl compound (1 mmol), p-tolylboronic acid (1.5 mmol), and a base (0.1-1.0 mmol) in an aqueous solvent (6/1. 3
mL) was stirred in the presence a catalyst, unless stated otherwise. Isolated yields by chromatography over silica gel. c LiOH (1.5 mmol)
b
and p-tolylboronic acid (2 mmol) were used.
TABLE 4. Asym m etr ic Ad d ition of P h en ylbor on ic Acid
great difference between the catalyst efficiency of [RhOH-
(cod)]2 and that of [RhCl(cod)]2.
a
to 2-Cycloh exen on e Ca ta lyzed by [Rh (R-bin a p )(n bd )]BF 4
entry
base (equiv)
none
solvent
yield/%b
% eec
1
2
3
4
5
dioxane/H2O
dioxane/H2O
dioxane/H2O
dioxane/H2O
dioxane/H2O
dioxane/H2O
DME/H2O
trace
64
88
47
46
Scop e a n d Lim ita tion
KOH (1.0)
78
99
99
98
98-99
97
K3PO4 (1.0)
K2CO3 (1.0)
KHCO3 (1.0)
Et3N (0.1-1.5)
Et3N (1)
The scope for representative R,â-unsaturated carbonyl
compounds is summarized in Table 3. Quantitative
conversions resulting in over 90% yields were easily
realized at room temperature in the presence of [RhCl-
(cod)]2 (1.5 mol %) and NaHCO3 (0.1 equiv) or in the
presence of [RhOH(cod)]2 (1.5 mol %) and KOH (1 equiv)
at 0 °C for R,â-unsaturated ketones and esters having
no large steric hindrance (entries 1-3, 7, 8, and 10-12).
J udging from the observed high yields, aldol condensation
of ketones or saponification of esters was not significant,
but the use of NaHCO3 at room temperature is recom-
mended for ester derivatives since KOH often resulted
in low yields due to competitive saponification (entry 10).
The reaction is highly sensitive to steric hindrance and
electron density of the double bond. For example, the
addition to â-ionone was very slow at room temperature
due to steric hindrance of the â-substituent, but the
reaction smoothly proceeded at 50 °C in the presence of
a strong base (entries 4 and 5). Although all attempts
failed for three-substituted ketones and esters such as
carvone (entry 9) and ethyl (E)-2-methyl-2-butenoate,
much electron-deficient diethyl 2-ethylidenemalonate
completed the reaction under analogous conditions ef-
fective for methyl crotonate (entries 13 and 14).
6
7
79-98
34
8
Et3N (1)
EtOH/H2O
16
43
9
10
11
i-Pr2NEt (1.0)
i-Pr2NH (1.0)
TMEDA (1.0)
dioxane/H2O
dioxane/H2O
dioxane/H2O
89
88
9
99
98
98
a
A mixture of 2-cyclohexenone (1 mmol), PhB(OH)2 (1.5 mmol),
base (0.1-1.5 mmol), and [Rh(R-binap)(nbd)]BF4 (3 mol %) was
b
stirred for 6 h at 25 °C. Isolated yields by chromatography.
c Enantiomer excess determined by a chiral stationary column
(Dicel Chiralcel AD).
(R-binap)]2, the use of inorganic bases still suffered from
low enantioselectivities that varied depending on the
basic strength (entries 2-5 in Table 4). The results may
suggest the generation of a free-phosphine rhodium
species by coordination of an inorganic base with the
rhodium metal center. Finally, triethylamine was recog-
nized to be the best base to achieve 98-99% ee at room
temperature (entry 6). Although a catalytic amount of
Et3N (10%) allowed room temperature reaction (79%
yield), the yield was almost quantitative when 1 equiv
of Et3N (98% yield) was used. In contrast, the reaction
was very slow in DME and resulted in a significantly low
yield and low enatioselectivity in ethanol (entries 7 and
8). Diisopropylethylamine and diisoprpylamine were also
effective (entries 9 and 10), but tetramethylethylenedi-
amine strongly retarded the catalyst (entry 11).
Asym m etr ic Ad d ition
Of particular importance is extension of the protocol
to asymmetric synthesis.7 Although inorganic bases
exhibited an excellent accelerating effect for the rhodium-
binap complexes, the use of inorganic bases suffered from
low enantioselectivity. For example, the addition of KOH
to [RhCl(R-binap)]2 at room temperature resulted in the
formation of racemic 3-phenylcyclohexanone in the ad-
The asymmetric additions of arylboronic acids to
representative R,â-unsaturated ketones, aldehydes, es-
(19) (a) Tani, K.; Yamagata, T.; Akutagawa, S.; Kumobayashi, H.;
Taketomi, T.; Takaya, H.; Miyashita, A.; Noyori, R.; Otsuka, S. J . Am.
Chem. Soc. 1984, 106, 5208. (b) Miyashita, A.; Yasuda, A.; Takaya,
H.; Toriumi, K.; Ito, T.; Souchi, T.; Noyori, R. J . Am. Chem. Soc. 1980,
102, 7932. Reviews for binap catalysts: (c) Ohkuma, T.; Noyori, R. In
Comprehensive Asymmetric Catalysis; J acobsen, E. N., Pfaltz, A.,
Yamamoto, H., Eds.; Springer: Berlin, Germany, 1999; Chapter 6.1.
(d) Kumobayashi, H.; Miura, T.; Sayo, N.; Saito, T.; Zhang, X. Synlett
2001, 1055. (e) Noyori, R. In Asymmetric Catalysis in Organic
Synthesis; Wiley: New York, 1994; Chapter 1. (f) Noyori, R.; Takaya,
H. Acc. Chem. Res. 1990, 23, 345.
dition of phenylboronic acid to 2-cyclohexenone in aque-
18,19
ous dioxane. Although [Rh(R-binap)(nbd)]BF4
was
found to be a much more selective catalyst than [RhCl-
(18) Cationic rhodium catalysts were used for 1,4-addition of Si and
Sn compounds, see: refs 9d,e and 11.
J . Org. Chem, Vol. 68, No. 15, 2003 6003

Itooka et al.
% eec
TABLE 5. Asym m etr ic Ad d ition to r,â-Un sa tu r a ted Ca r bon yl Com p ou n d sa
entry
carbonyl compound
ArB(OH)2 (2)
product no.
yield/%b
1
2
3
4
5
2-cyclohexenone
2-cyclohexenone
2-cyclohexenone
2-cyclohexenone
2a
2c
2b
2d
2b
2a
2c
2a
2c
2c
2a
2d
2a
5a
5b
5c
5d
5e
5f
5g
5h
5i
99
98
97
87
99
98
91
75
82
59
56
93
97
99
99
99
nd
2-cyclopentenone
97
6
7
(E)-C5H11CHdCHCOCH3
(E)-C5H11CHdCHCOCH3
(E)-i-C3H7CHdCHCOCH3
(E)-i-C3H7CHdCHCOCH3
(E)-CH3CHdCHCHO
(E)-C3H7CHdCHCHO
(E)-CH3CHdCHCO2i-Pr
(E)-CH3CHdCHCONHBn
83 (86)d
88 (90)e
97
8f
9f
10f
11f
12
13f
98
86
92
94
5j
5k
5l
5m
92
a
A mixture of a carbonyl compound (1 mmol), ArB(OH)2 (1.5 mmol), Et3N (1 mmol), and [Rh(R-binap)(nbd)]BF4 (3 mol %) in dioxane/
H2O (6/1, 3 mL) was stirred for 6 h at 25 °C, unless otherwise noted. Isolated yields by chromatography. c Enantiomer excess determined
b
by a chiral stationary column (Dicel Chiralcel OD-H, OB-H, or AD). The aldehydes in entries 10 and 11 were reduced to alcohols before
d
HPLC analyses. Additional (R)-binap (6 mol %) was added. e K3PO4 (1 mmol) was used in place of Et3N. f The reactions were conducted
at 50 °C for 6 h.
Syn th esis of [Rh ((R)-bin a p )(n bd )]BF 4.19a In a 25-mL
ters, and amides catalyzed by [Rh(R-binap)(nbd)]BF4/
flask containing a magnetic stirring bar were placed [Rh(nbd)2]-
BF4 (169 mg, 0.452 mmol) and (R)-BINAP (310 mg, 0.498
mmol) under argon. CH2Cl2 (10 mL) was added and the
mixture was then stirred at room temperature for 3 h. THF
(10 mL) was slowly added to the resulting orange-red solution.
The mixture was allowed to stand in a freezer for 1 day and
the solvent was then evaporated. The orange crystal was
collected by filtration, washed with THF and ether, and dried.
Yield 348 mg (85%); 31P NMR (CDCl3) δ 26.31 (d, J Rh-P ) 154.1
Et3N are summarized in Table 5. A variety of arylboronic
acids can be used for 2-cyclohexenone with excellent
isolated yields and perfect enantioselectivities (entries
1-4). All reactions were completed within 6 h at room
temperature. Analogously, the additions to 2-cyclopeten-
one (entry 5), 3-nonen-2-on (entries 6 and 7), and isopro-
pyl crotonate (entry 12) easily proceeded at room tem-
perature, whereas the reaction mixtures were heated to
50 °C for more sterically hindered ketones (entries 8 and
9), R,â-unsaturated aldehydes (entries 10 and 11), and
N-benzyl crotonamide (entry 13). There were no large
differences in selectivity for para and meta substituents
of arylboronic acids, but they were highly dependent on
substrates and functionalities therein. Aliphatic enones
including alicyclic compounds are desirable substrates
to achieve high enantioselectivities up to 99% ee (entries
1-9). Among them, the additions to 3-nonene-2-one
exceptionally resulted in significantly low enantioselec-
tivities for an unknown reason, though the addition of
an excess binap ligand or change of the base to K3PO4
slightly improved the selectivity (entries 6 and 7). The
effect of the â-substituent (R1) was significant for enals
such as crotonaldehyde and 2-hexenal (entries 10 and
11).20 These reactions at room temperature resulted in
higher isolated yields and higher enantioselectivities
than that of an Rh(acac)(binap) catalyst previously
employed at 100 °C.7
Hz). Anal. Calcd for
C51H40BF4P2Rh: C, 67.72; H, 4.46.
Found: C, 66.79; H, 4.66.
Gen er a l P r oced u r e for Ta ble 1. Rhodium complex (0.03
mmol for Rh), a ligand (0-0.09 mmol), and (4-methylphenyl)-
boronic acid (1.5 mmol) were added to a 25-mL flask containing
a magnetic stirring bar and a septum inlet. The flask was
flashed with argon and charged with aqueous 1,4-dioxane (6/
1, 3 mL). After being stirred for 30 min, 2-cyclohexenone (1.0
mmol) was added. The mixture was then stirred for 6 h at the
temperature shown in Table 1. Yields of products were
analyzed by GC, using pentadecane as an internal standard.
Gen er a l P r oced u r e for Ta ble 5. [Rh((R)-binap)(nbd)]BF4
(0.03 mmol) and arylboronic acid (1.5 mmol) were added to a
25-mL flask equipped with a magnetic stirring bar and a
septum inlet. The flask was flashed with argon and charged
with aqueous 1,4-dioxane (6/1, 3 mL). Triethylamine (1.0
mmol) and R,â-unsaturated carbonyl compound (1.0 mmol)
were then added. The mixture was stirred for 6 h at 25 °C.
The product was extracted with benzene, washed with brine,
and finally dried over MgSO4. Chromatography over silica gel
gave the desired product.
Exp er im en ta l Section
All reactions were carried out under nitrogen. HPLC
analyses were carried out with a chiral stationary phase
column, Chiralpak AD, Chiralcel OD-H or OB-H, purchased
from Dicel Co., Ltd.
Su p p or tin g In for m a tion Ava ila ble: Text describing
experimental details and spectral and/or analytical data of the
products. This material is available free of charge via the
Internet at http://pubs.acs.org.
(20) No addition to the CHO group was observed, see ref 6.
J O0207067
6004 J . Org. Chem., Vol. 68, No. 15, 2003