Simple chiral chain dienes as ligands for Rh(I)-catalyzed conjugated additions

Article abstract of DOI:10.1021/ol901949n

This paper describes that a simple and readily available chain diene (3R,4R)-hexa-1,5-diene-3,4-dlol (L1) was successfully utilized as a novel steering ligand for Rh(I)-catalyzed asymmetric conjugated additions. Encouraging yields and ee's have been achieved, which may provide a new and practical direction for designing chiral diene ligands In the future.

Full text of DOI:10.1021/ol901949n

ORGANIC
LETTERS
2009
Vol. 11, No. 20
4744-4747
Simple Chiral Chain Dienes as Ligands
for Rh(I)-Catalyzed Conjugated Additions
Xichao Hu, Minyang Zhuang, Ziping Cao, and Haifeng Du*
Beijing National Laboratory of Molecular Sciences, CAS Key Laboratory of Molecular
Recognition and Function, Institute of Chemistry, Chinese Academy of Sciences,
Beijing 100190, China
haifengdu@iccas.ac.cn
Received August 21, 2009
ABSTRACT
This paper describes that a simple and readily available chain diene (3R,4R)-hexa-1,5-diene-3,4-diol (L1) was successfully utilized as a novel
steering ligand for Rh(I)-catalyzed asymmetric conjugated additions. Encouraging yields and ee’s have been achieved, which may provide a
new and practical direction for designing chiral diene ligands in the future.
The development of structurally new, effective, and acces-
sible chiral ligands represents one of the most important
subjects in asymmetric catalysis.1 Recently, since the seminal
contributions by Hayashi and Carreira,2 several chiral
chelating dienes have been successfully exploited as novel
and highly efficient steering ligands for metal-catalyzed
asymmetric reactions. Especially, in some cases, chiral dienes
exhibit an obvious advantage over other types of ligands.3
Figure 1. Representative diene ligands for asymmetric catalysis.
Some representatives (1-5) are listed in Figure 1, and it can
be found that these types of ligands all bear rigidly bicyclic
frameworks, which partially account for both high reactivity
and enantioselectivity.4-7 However, bicyclic structures also
lead to synthetic problems to some extent. As stated by
Carreira: “To ensure wide acceptance of these ligand systems,
an easy and straightforward synthetic access to chiral dienes
is of prime importance”.3b Compared with bicyclic ones,
chain dienes are more easily obtained. Although some chiral
chain dienes are well-known compounds, to the best of our
(1) (a) Noyori, R. Asymmetric Catalysis in Organic Synthesis; Wiley:
New York, 1994. (b) Jacobsen, E. N.; Pfaltz, A.; Yamamoto, H. Compre-
hensiVe Asymmetric Catalysis; Springer: Berlin, 1999; Vols. 1-3. (c) Ojima,
I. Catalytic Asymmetric Synthesis; Wiley-VSH: New York, 2000.
(2) (a) Hayashi, T.; Ueyama, K.; Tokunaga, N.; Yoshida, K. J. Am.
Chem. Soc. 2003, 125, 11508. (b) Fisher, C.; Defieber, C.; Suzuki, T.;
Carreira, E. M. J. Am. Chem. Soc. 2004, 126, 1628.
(4) For leading references on ligands 1-3, see: (a) Ref 2a. (b) Shintani,
R.; Ueyama, K.; Yamada, I.; Hayashi, T. Org. Lett. 2004, 6, 3425. (c)
Tokunaga, N.; Otomaru, Y.; Okamoto, K.; Ueyama, K.; Shintani, R.;
Hayashi, T. J. Am. Chem. Soc. 2004, 126, 13584. (d) Shintani, R.; Okamoto,
K.; Otomaru, Y.; Ueyama, K.; Hayashi, T. J. Am. Chem. Soc. 2005, 127,
54. (e) Otomaru, Y.; Tokunaga, N.; Shintani, R.; Hayashi, T. Org. Lett.
2005, 7, 307. (f) Shintani, R.; Sannohe, Y.; Tsuji, T.; Hayashi, T. Angew.
Chem., Int. Ed. 2007, 46, 7277. (g) Shintani, R.; Ichikawa, Y.; Takatsu,
K.; Chen, F.-X.; Hayashi, T. J. Org. Chem. 2009, 74, 869.
(3) For reviews on chiral diene ligands, see: (a) Glorius, F. Angew.
Chem., Int. Ed. 2004, 43, 3364. (b) Defieber, C.; Gru¨tzmacher, H.; Carreira,
E. M. Angew. Chem., Int. Ed. 2008, 47, 4482.
10.1021/ol901949n CCC: $40.75
Published on Web 09/17/2009
 2009 American Chemical Society

knowledge, successfully utilizing them as ligands for asym-
metric reactions has never been reported.8 The challenge may
consist in the flexibility character of chain dienes. Herein,
we wish to report our efforts on the development of chiral
chain dienes as effective ligands for Rh(I)-catalyzed conju-
gated additions.9
To test the feasibility of using chain dienes as ligands, an
initial study was conducted with Rh(I)-catalyzed conjugated
addition as a model reaction. As shown in Scheme 1, the
61% ee (Scheme 1). To prove that L1 was not a diol but a
diene ligand, (3R,4R)-hexane-3,4-diol (9) was subjected to
this conjugated addition. Only a trace amount of product was
observed, which strongly supports that olefin moieties of L1
played the key role for this asymmetric process. As a flexible
diene, the coordination mode and asymmetric induction
pathway remain unknown and need further investigation.
Although the enantioselectivity is still not satisfactory, it
represents a successful example for application of a chiral
chain diene as a novel type of diene ligand for metal-
catalyzed asymmetric reactions.
Encouraged by this promising result, a variety of chiral
chain dienes12,13 were prepared and subjected to the Rh(I)-
catalyzed asymmetric conjugated additions between 2-cy-
clohexenone (6) and phenylboronic acid (7) to search for
more effective ligands. Some selected results are summarized
in Figure 2. It was found that most of the ligand modified
Scheme 1. Initial Studies Using Chain Dienes As Ligands
reaction between 2-cyclohexenone (6) and phenylboronic
acid (7) employing [RhCl(C2H4)2]2 (5 mol % Rh) as a catalyst
precursor and 1,5-hexadiene (6 mol %) as a chain diene
ligand in dioxane/MeOH (v/v ) 10:1) at 50 °C proceeded
smoothly to give the corresponding product 8 in quantitative
conversion in 3 h,10 while a control experiment without
addition of 1,5-hexadiene gave no desired product. These
results suggested that chain dienes could no doubt be utilized
as efficient ligands and encouraged us to investigate the
possibility of using chiral chain dienes as ligands. Hence,
(3R,4R)-hexa-1,5-diene-3,4-diol (L1) was prepared and
subjected as a chiral ligand to this reaction (Scheme 1).11
To our surprise, with such a simple chiral diene bearing two
terminal double bonds, the reaction went efficiently to afford
the desired product 8 in >99% conversion and an encouraging
Figure 2.
Selected diene ligands for asymmetric 1,4-additions.14
Rh(I) catalysts can promote this reaction efficiently to afford
the desired product 8 in 43->99% conversions and 25-67%
ee’s. Studies showed that the steric bulkiness of oxygen
substituents for ligands (L1-L4) has a large impact on
enantioselectivity. Monobenzoyl ester L8 gave 67% ee but
(5) For leading references on ligand 4, see: (a) Ref 2b. (b) Defieber, C.;
Paquin, J.-F.; Serna, S.; Carreira, E. M. Org. Lett. 2004, 6, 3873. (c) Paquin,
J.-F.; Steptenson, C. R. J.; Defieber, C.; Carreira, E. M. Org. Lett. 2005, 7,
3821.
(6) For leading references on ligand 5, see: (a) Wang, Z.-Q.; Feng, C.-
G.; Xu, M.-H.; Lin, G.-Q. J. Am. Chem. Soc. 2007, 129, 5336. (b) Feng,
C.-G.; Wang, Z.-Q.; Shao, C.; Xu, M.-H.; Lin, G.-Q. Org. Lett. 2008, 10,
4101. (c) Feng, C.-G.; Wang, Z.-Q.; Tian, P.; Xu, M.-H.; Lin, G.-Q. Chem.
Asian J. 2008, 3, 1511.
(11) For leading references on the preparation and application of L1 in
organic synthesis, see: (a) Ramo Rao, A. V.; Mysorekar, S. V.; Gurjar,
M. K.; Yadav, J. S. Tetrahedron Lett. 1987, 28, 2183. (b) Yadav, J. S.;
Mysoreka, S. V.; Pawar, S. M.; Gurjar, M. K. J. Carbohydr. Chem. 1990,
9, 307. (c) Burke, S. D.; Sametz, G. M. Org. Lett. 1999, 1, 71. (d) Michaelis,
S.; Blechert, S. Org. Lett. 2005, 7, 5513. (e) Marvin, C. C.; Clemens,
A. J. L.; Burke, S. D. Org. Lett. 2007, 9, 5353. (f) Purser, S.; Timothy,
T. D. W.; Odell, B.; Moore, P. R.; Gouverneur, V. Org. Lett. 2008, 10,
(7) For other selected examples of chiral diene ligands, see: (a) Helbig,
S.; Sauer, S.; Cramer, N.; Laschat, S.; Baro, A.; Frey, W. AdV. Synth. Catal.
2007, 349, 2331. (b) Gendrineau, T.; Chuzel, O.; Eijsberg, H.; Genet, J.-
P.; Darses, S. Angew. Chem., Int. Ed. 2008, 47, 7669. (c) Gendrineau, T.;
Genet, J.-P.; Darses, S. Org. Lett. 2009, 11, 3486.
(8) For references on formation of metal complexes with natural chiral
dienes (one terminal double bond involved), see: (a) Johnson, B. D. G.;
Lewis, J.; Yarrow, D. J. J. Chem. Soc., Dalton. Trans. 1974, 1054. (b)
Winter, W.; Koppenho¨fer, B.; Schurig, V. J. Organomet. Chem. 1978, 150,
145. (c) Oro, L. A. J. Less-Common Met. 1977, 53, 289.
4263
.
(12) For leading references on L2-L4, see: (a) Brown, H. C.; Jadhav,
P. K.; Bhat, K. S. J. Am. Chem. Soc. 1988, 110, 1535. (b) Gurjar, M. K.;
Pawar, S. M. Indian J. Chem., Sect. B 1987, 26B, 55. (c) Abdelhedi, R.;
Bouguerra, M. L.; Pommelet, J. C.; Chuche, J. J. Soc. Chim. Tunis 1986,
(9) For leading reviews on Rh-catalyzed asymmetric conjugated addi-
tions, see: (a) Hayashi, T.; Yamashaki, K. Chem. ReV. 2003, 103, 2829.
(b) Gennari, C.; Monti, C.; Piarulli, U. Pure Appl. Chem. 2006, 78, 303.
(c) Christoffers, J.; Koripelly, G.; Rosoak, A.; Ro¨ssle, M. Synthesis 2007,
1279.
2, 7
.
(13) For leading references on L5-L7, L10, and L12, see: (a) Ref 11c.
Ref 11b. (c) Ref 11a. (d) Kang, S. H.; Ryu, D. H. Chem. Commun. 1996,
355. (e) Trost, B. M.; Aponick, A.; Stanzl, B. N. Chem.sEur. J. 2007, 13,
(10) Complex [RhCl(1,5-hexadiene)]2 is commercially available.
9547.
Org. Lett., Vol. 11, No. 20, 2009
4745

with a low conversion. Ligands bearing cyclic backbones
(L10-L12) were also effective for catalyzing this reaction
to give good conversions and moderate ee’s. Overall, L1
proved to be the best ligand to give both the highest
conversion and enantioselectivity.
Under the optimized conditions, the substrate scope was
investigated, and some of the results are summarized in Table
2. It was found that the chiral chain diene L1 modified Rh-
With the best ligand L1 in hand, to further improve the
enantioselectivity, the reaction conditions, including base,
solvent, and temperature, were investigated. It was found
that base has a significant effect on both reactivity and
enantioselectivity (Table 1, entries 1-4), and KOH proved
Table 2. Rh(I)/L1-Catalyzed Asymmetric Conjugated
Additionsa
Table 1. Optimizing Reaction Conditions for Rh(I)/
L1-Catalyzed Conjugated Addition of Phenylboronic Acid (7) to
2-Cyclohexenone (6)a
temp convn
(°C)
ee
(%)e
entry
solventc
base
(%)d
1
2
3
4
5
6
7
8
dioxane/MeOH (10/1) KOH
dioxane/MeOH (10/1) K2CO3
dioxane/MeOH (10/1) KOAc
dioxane/MeOH (10/1) Et3N
50
50
50
50
50
50
50
50
50
50
50
50
20
10
0
>99
96
14
65
59
61
50
64
55
80
73
72
49
58
68
68
75
82
85
85
dioxane/H2O (10/1)
dioxane/H2O (5/1)
dioxane/H2O (2/1)
H2O
KOH
KOH
KOH
KOH
KOH
KOH
KOH
KOH
KOH
KOH
KOH
81
>99
>99
98
78
>99
82
>99
91
43
9
toluene/H2O (2/1)
DCE/H2O (2/1)
THF/H2O (2/1)
10
11
12
13
14b
15
CH2Cl2/H2O (2/1)
dioxane/H2O (2/1)
dioxane/H2O (2/1)
dioxane/H2O (2/1)
a All the reactions were carried out with 2-cyclohexenone (6) (0.20
mmol), phenylboronic acid (7) (0.30 mmol), base (0.015 mmol),
[RhCl(C2H4)2]2 (0.005 mmol), and L1 (0.012 mmol) in solvent (0.60 mL)
under argon for 3 h unless otherwise stated. b The reaction was carried out
for 12 h. c The ratio was in volume. d The conversion was determined by
crude 1H NMR. e The ee was determined by chiral HPLC (Chiralpak AD-H
column).
to be the best one. Water was found to play a crucial role in
this reaction which awaits further studies: up to 80% ee was
obtained when changing MeOH with H2O (Table 1, entry 1
vs 5), but the conversion only reached 59%. Studies showed
that the reaction using water as a solvent was very fast but
only gave a quite low enantioselectivity (Table 1, entry 8).
By tuning the ratio of dioxane and water to 2:1, >99%
conversion and 72% ee were obtained (Table 1, entry 7).
Other organic solvents were also studied (Table 1, entries
9-12), and CH2Cl2 could give 75% ee with 82% conversion.
When the temperature was lowered to 20 °C, up to 82% ee
was afforded without losing any activity (Table 1, entry 13).
Further reduction of the temperature to 10 °C could improve
the enantioselectivity to 85%, but the reaction needs longer
time (Table 1, entry 14). Overall, the best reaction conditions
(Table 1, entry 13) involved 5 mol % of Rh(I) and 6 mol %
of L1 in dioxane/H2O (v/v 2:1) at 20 °C for 3 h.
a All the reactions were carried out with an organoboron reagent (0.30
mmol), unsaturated carbonyl compound (0.20 mmol), KOH (0.015 mmol),
[RhCl(C2H4)2]2 (0.005 mmol), and L1 (0.012 mmol) in dioxane/H2O (2/1, v/v,
0.60 mL) under argon for 3 h unless otherwise noted. For entry 2, the reaction
was carried out with organoboron reagent (0.10 mmol), and for entries 9 and
14-17, the reaction scale was doubled. b The reaction was carried out for
12 h. c The reaction was carried out at 50 °C for 5 h. d The absolute
configuration was deterimined by comparing the optical rotation with the
reported one. e Isolated yield. f The ee was determined by chiral HPLC
(Chiralpak AD-H column) unless otherwise stated, Chiralcel OD-H column
for entries 8 and 14, Chiralcel OJ-H column for entries 11 and 16, Chiralcel
OB-H column for entry 15, and Chiralcel AS-H column for entry 17.
catalyst can promote these reactions with moderate to
excellent reactivities (50-99% yields) and moderate to good
enantioselectivities (61-83% ee’s). Addition of meta- or
para-substituted arylboronic acids to 2-cyclohexenone (6)
(14) All the reactions were carried out with 2-cyclohexenone (6) (0.20
mmol), phenylboronic acid (7) (0.30 mmol), KOH (0.015 mmol),
[RhCl(C2H4)2]2 (0.005 mmol), diene ligand (0.012 mmol) in dioxane/MeOH
(10/1, v/v, 0.60 mL) at 50 °C under argon for 3 h.
4746
Org. Lett., Vol. 11, No. 20, 2009

under the catalysis of Rh(I)/L1 gave excellent yields and
good ee’s, and boronic acids with electron-donating groups
displayed higher activities (Table 2, entries 4, 6, and 9).
Ortho-substituted arylboronic acids are also effective sub-
strates for this reaction but only resulted in relatively lower
ee’s (Table 2, entries 11-13). The reactions between other
types of organoboron reagents, such as boronate ester and
potassium trifluoroborates, and 2-cyclohexenone (6) went
smoothly to afford desired products in good yields and ee’s
(Table 2, entries 3, 5, and 14). Rh(I)/L1 can also promote
the asymmetric conjugated addition of phenylboronic acid
(7) to other unsaturated carbonyl compounds, giving the
corresponding adducts in 56-87% yields with 61-73% ee’s
(Table 2, entries 15-17).
are able to be used as steering ligands for metal-catalyzed
asymmetric reactions, which will probably provide a practical
approach to design novel chiral diene ligands in the future.
Searching for more effective chiral chain dienes, understand-
ing the detailed coordination mode and asymmetric induction
pathway, and expanding the applications of chiral chain diene
ligands in other types of metal-catalyzed asymmetric reac-
tions are currently underway in our laboratory.
Acknowledgment. We are grateful to the generous
financial support from the National Science Foundation of
China (20802079), Ministry of Science and Technology
(2009ZX09501-018), and start foundation from Institute of
Chemistry, CAS.
In summary, a simple chiral chain diene L1 bearing two
terminal double bonds was successfully employed as a novel
type and effective chelating ligand for Rh(I)-catalyzed
asymmetric conjugated additions, and encouraging results
(up to 85% ee) have been achieved. Although the efficiency,
enantioselectivity, and substrate scope still await further
improvement, it demonstrates that flexible chiral chain dienes
Supporting Information Available: The procedure for
Rh(I)-catalyzed conjugated addition and the characterization
and data for the determination of enantiomeric excess of
addition products along with the NMR spectra. This material
is available free of charge via the Internet at http://pubs.acs.org.
OL901949N
Org. Lett., Vol. 11, No. 20, 2009
4747