Vicinal-diamine-based chiral chain dienes as ligands for rhodium(i)-catalyzed highly enantioselective conjugated additions

Article abstract of DOI:10.1021/ol1023536

A variety of readily accessible vicinal-diamine-based chiral chain dienes were successfully synthesized and utilized as steering ligands for rhodium-catalyzed conjugated additions of organoboronic acids to α,β-unsaturated carbonyl compounds to afford the desired adducts in good to excellent yields and ee's.

Full text of DOI:10.1021/ol1023536

ORGANIC
LETTERS
2010
Vol. 12, No. 23
5482-5485
Vicinal-Diamine-Based Chiral Chain
Dienes as Ligands for
Rhodium(I)-Catalyzed Highly
Enantioselective Conjugated Additions
Yazhou Wang, Xichao Hu, 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 September 30, 2010
ABSTRACT
A variety of readily accessible vicinal-diamine-based chiral chain dienes were successfully synthesized and utilized as steering ligands for
rhodium-catalyzed conjugated additions of organoboronic acids to r,ꢀ-unsaturated carbonyl compounds to afford the desired adducts in
good to excellent yields and ee’s.
Chiral dienes as highly effective steering ligands for transi-
tion-metal-catalyzed enantioselective reactions have attracted
extensive attention since the pioneering studies by the groups
of Hayashi and Carreira in 2003 and 2004, respectively.1-5
Especially, in recent years, there has been rapid progress for
both exploring novel diene ligands6 and utilizing chiral diene
ligands to achieve challenging asymmetric reactions,7 which
stand for the most important two subjects in this field.
However, the types of chiral diene ligands are still very
limited, and almost all of these ligands are bicyclic dienes.2
The rigid bicyclic structures are important to produce high
reactivities and enantioselectivities in catalytic asymmetric
reactions, but the synthetic problems may partially restrict
the wide application of these ligand systems. The develop-
ment of novel, effective, easily synthesized and modified
chiral diene ligands is still of prime importance. As part of
our general interest in exploring acyclic chiral diene ligands
which was inspired by the experimental result that flexible
(3) For leading references on chiral diene ligands, see: (a) Tokunaga,
N.; Otomaru, Y.; Okamoto, K.; Ueyama, K.; Shintani, R.; Hayashi, T. J. Am.
Chem. Soc. 2004, 126, 13584. (b) Defieber, C.; Paquin, J.-F.; Serna, S.;
Carreira, E. M. Org. Lett. 2004, 6, 3873. (c) Shintani, R.; Okamoto, K.;
Otomaru, Y.; Ueyama, K.; Hayashi, T. J. Am. Chem. Soc. 2005, 127, 54.
(d) Paquin, J.-F.; Stephenson, C. R. J.; Defieber, C.; Carreira, E. M. Org.
Lett. 2005, 7, 3821. (e) Paquin, J.-F.; Defieber, C.; Stephenson, C. R. J.;
Carreira, E. M. J. Am. Chem. Soc. 2005, 127, 10850. (f) Shintani, R.; Duan,
W.-L.; Hayashi, T. J. Am. Chem. Soc. 2006, 128, 5628. (g) Aikawa, K.;
Akutagawa, S.; Mikami, K. J. Am. Chem. Soc. 2006, 128, 12648. (h)
Shintani, R.; Sannohe, Y.; Tsuji, T.; Hayashi, T. Angew. Chem., Int. Ed.
2007, 46, 7277. (i) Helbig, S.; Sauer, S.; Cramer, N.; Laschat, S.; Baro, A.;
Frey, W. AdV. Synth. Catal. 2007, 349, 2331. (j) Wang, Z.-Q.; Feng, C.-
G.; Xu, M.-H.; Lin, G.-Q. J. Am. Chem. Soc. 2007, 129, 5336.
(1) (a) Hayashi, T.; Ueyama, K.; Tokunaga, N.; Yoshida, K. J. Am.
Chem. Soc. 2003, 125, 11508. (b) Fischer, C.; Defieber, C.; Suzuki, T.;
Carreira, E. M. J. Am. Chem. Soc. 2004, 126, 1628
.
(2) For reviews on chiral olefin ligands, see: (a) Glorius, F. Angew.
Chem., Int. Ed. 2004, 43, 3364. (b) Johnson, J. B.; Rovis, T. Angew. Chem.,
Int. Ed. 2008, 47, 840. (c) Defieber, C.; Gru¨tzmacher, H.; Carreira, E. M.
Angew. Chem., Int. Ed. 2008, 47, 4482. (d) Shintani, R.; Hayashi, T.
Aldrichimica Acta 2009, 42, 31
.
10.1021/ol1023536  2010 American Chemical Society
Published on Web 11/01/2010

1,5-hexadiene can act as an efficient ligand for rhodium(I)-
catalyzed asymmetric additions, we have successfully de-
veloped chiral ligands 1-3 (Figure 1) from readily available
tory. To achieve excellent enantioselectivity using flexible
acyclic diene ligands is therefore a great interest.
In our previous study, we found that more flexible chiral
diene 1 exhibited an obvious advantage over ligand 7 bearing
a cyclic framework in both reactivity (>99% vs 60%) and
enantioselectivity (61% vs 50%) for the Rh(I)-catalyzed con-
jugated addition of phenylboronic acid (5) to 2-cyclohexenone
(4) under the same reaction conditions (Scheme 1),8a while
Scheme 1
.
Rh(I)/Diene Complex Catalyzed Asymmetric
Conjugated Additions
Figure 1. Development of acyclic chiral diene ligands for asym-
metric catalysis.
starting materials.8 Although encouraging results were
obtained when employing these ligands in the catalytic
asymmetric conjugated additions8a,b,9 or arylations,8c the
enantioselectivity (no more than 85% ee) is still not satisfac-
(4) For leading references on phosphine-alkene hybrid ligands, see:
(a) Maire, P.; Deblon, S.; Breher, F.; Geier, J.; Bo¨hler, C.; Ru¨egger, H.;
Scho¨nberg, H.; Gru¨tzmacher, H. Chem.sEur. J. 2004, 10, 4198. (b) Shintani,
R.; Duan, W.-L.; Nagano, T.; Okada, A.; Hayashi, T. Angew. Chem., Int.
Ed. 2005, 44, 4611. (c) Duan, W.-L.; Iwamura, H.; Shintani, R.; Hayashi,
T. J. Am. Chem. Soc. 2007, 129, 2130. (d) Defieber, C.; Ariger, M. A.;
Moriel, P.; Carreira, E. M. Angew. Chem., Int. Ed. 2007, 46, 3139. (e)
Stemmler, R. T.; Bolm, C. Synlett 2007, 9, 1365. (f) Minuth, T.; Boysen,
M. M. K. Org. Lett. 2009, 11, 4212.
chiral diene 2 bearing an imidazolin-2-one framework prepared
from 1,5-hexadiene in only one step via Pd(0)-catalyzed
asymmetric diamination10,11 using di-tert-butyldiaziridinone12
as the nitrogen source was found to promote the Rh(I)-catalyzed
reactions of 4 and 5 efficiently to afford the corresponding adduct
6 in 99% yield and 85% ee (Scheme 1).8b We envisioned that
deprotection of tert-butyl and carbonyl groups of 2 followed by
introduction of different groups on the nitrogen atoms may provide
a good opportunity to discover highly effective vicinal-diamine-
based chiral chain diene ligands 8 (Scheme 1). Herein, we report
our efforts on this subject.
Initially, the enantiopure compound (S,S)-9 was prepared
using diene (S,S)-2 as a starting material according to the
reported methods.8b,11 After removal of the carbonyl group
in concentrated hydrochloric acid and neutralization with
aqueous sodium hydroxide solution, (3S,4S)-hexa-1,5-diene-
3,4-diamine (8a) was obtained in 95% yield (Scheme 2).
(5) For leading references on amine-alkene hybrid ligands, see: (a)
Maire, P.; Breher, F.; Scho¨nberg, H.; Gru¨tzmacher, H. Organometallics
2005, 24, 3207. (b) Hahn, B. T.; Tewes, F.; Fro¨hlich, R.; Glorius, F. Angew.
Chem., Int. Ed. 2010, 49, 1143.
(6) For leading references, see: (a) Feng, C.-G.; Wang, Z.-Q.; Shao, C.;
Xu, M.-H.; Lin, G.-Q. Org. Lett. 2008, 10, 4101. (b) Gendrineau, T.; Chuzel,
O.; Eijsberg, H.; Genet, J.-P.; Darses, S. Angew. Chem., Int. Ed. 2008, 47,
7669. (c) Nishimura, T.; Yasuhara, Y.; Nagaosa, M.; Hayashi, T. Tetra-
hedron: Asymmetry 2008, 19, 1778. (d) Okamoto, K.; Hayashi, T.; Rawal,
V. H. Org. Lett. 2008, 10, 4387. (e) Okamoto, K.; Hayashi, T.; Rawal,
V. H. Chem. Commun. 2009, 4815. (f) Brown, M. K.; Corey, E. J. Org.
Lett. 2010, 12, 172. (g) Luo, Y.; Carnell, A. J. Angew. Chem., Int. Ed.
2010, 49, 2750. (h) Shao, C.; Yu, H.-J.; Wu, N.-Y.; Feng, C.-Q.; Lin, G.-
Q. Org. Lett. 2010, 12, 3820.
(7) For leading references on expanding the application of chiral olefin
ligands in asymmetric catalysis, see: (a) Nishimura, T.; Kumamoto, H.;
Nagaosa, N.; Hayashi, T. Chem. Commun. 2009, 5713. (b) Shintani, R.;
Tsutsumi, Y.; Nagaosa, M.; Nishimura, T.; Hayashi, T. J. Am. Chem. Soc.
2009, 131, 13588. (c) Gendrineau, T.; Genet, J.-P.; Darses, S. Org. Lett.
2010, 12, 308. (d) Nishimura, T.; Wang, J.; Nagaosa, M.; Okamoto, K.;
Shintani, R.; Kwong, F.; Yu, W.; Chan, A. S. C.; Hayashi, T. J. Am. Chem.
Soc. 2010, 132, 464. (e) Nishimura, T.; Kawamoto, T.; Nagaosa, M.;
Kumanmoto, H.; Hayashi, T. Angew. Chem., Int. Ed. 2010, 49, 1638. (f)
Shintani, R.; Isobe, S.; Takeda, M.; Hayashi, T. Angew. Chem., Int. Ed.
2010, 49, 3795. (g) Shintani, R.; Takeda, M.; Nishimura, T.; Hayashi, T.
Angew. Chem., Int. Ed. 2010, 49, 3969. (h) Wang, Z.-Q.; Feng, C.-G.;
Zhang, S.-S.; Xu, M.-H.; Lin, G.-Q. Angew. Chem., Int. Ed. 2010, 49, 5780.
(i) Nishimura, T.; Maeda, Y.; Hayashi, T. Angew. Chem., Int. Ed. 2010,
49, 7324. (j) Nishimura, T.; Yasuhara, Y.; Sawano, T.; Hayashi, T. J. Am.
Chem. Soc. 2010, 132, 7872. (k) Nishimura, T.; Makino, H.; Nagaosa, M.;
Hayashi, T. J. Am. Chem. Soc. 2010, 132, 12865. (l) Shintani, R.; Takeda,
M.; Tsuji, T.; Hayashi, T. J. Am. Chem. Soc. 2010, 132, 13168. (m) Pattison,
G.; Piraux, G.; Lam, H. W. J. Am. Chem. Soc. 2010, 132, 14373.
(8) (a) Hu, X.; Zhuang, M.; Cao, Z.; Du, H. Org. Lett. 2009, 11, 4744.
(b) Hu, X.; Cao, Z.; Liu, Z.; Wang, Y.; Du, H. AdV. Synth. Catal. 2010,
352, 651. (c) Cao, Z.; Du, H. Org. Lett. 2010, 12, 2602. For a reference on
terminal-alkene phosphine hybrid ligand, see: (d) Liu, Z.; Du, H. Org.
Lett. 2010, 12, 3054.
Scheme 2. Synthesis of Vicinal-Diamine-Based Chiral Dienes
(9) For leading reviews on Rh-catalyzed asymmetric conjugated addi-
tions, see: (a) Hayashi, T.; Yamasaki, K. Chem. ReV. 2003, 103, 2829. (b)
Gennari, C.; Monti, C.; Piarulli, U. Pure Appl. Chem. 2006, 78, 303. (c)
Christoffers, J.; Koripelly, G.; Rosiak, A.; Ro¨ssle, M. Synthesis 2007, 1279.
(d) Edwards, H. J.; Hargrave, J. D.; Penrose, S. D.; Frost, C. G. Chem.
However, when subjecting 8a to the Rh(I)-catalyzed reaction
of 2-cyclohexenone (4) and phenylboronic acid (5), no
desired product was observed (Table 1, entry 1) which may
Soc. ReV. 2010, 39, 2093
.
Org. Lett., Vol. 12, No. 23, 2010
5483

highest conversion and ee for this reaction (Table 1, entry
8). Further studies on the solvent effects showed that all these
solvents gave the same ee’s (Table 1, entries 8 vs 12-14),
and benzene/methanol was found to be an alternative solvent
for this reaction. Decreasing the loading amount of the Rh/
8h complex from 5 to 1 mol %, the reaction still went
Table 1. Evaluation of Chiral Diene Ligands and Optimization
of Reaction Conditionsa
temp conv
(°C)
ee
(%)d
entry ligand
solventb
(%)c
1
2
3
4
5
6
7
8
8a
8b
8c
8d
8e
8f
8g
8h
8i
dioxane/MeOH (2/1)
dioxane/MeOH (2/1)
dioxane/MeOH (2/1)
dioxane/MeOH (2/1)
dioxane/MeOH (2/1)
dioxane/MeOH (2/1)
dioxane/MeOH (2/1)
dioxane/MeOH (2/1)
dioxane/MeOH (2/1)
dioxane/MeOH (2/1)
dioxane/MeOH (2/1)
dioxane/H2O (2/1)
10
10
10
10
10
10
10
10
50
50
10
10
10
10
50
NRe
67
-
92
89
89
90
89
90
95
78
78
-
>99
>99
>99
>99
>99
>99
>99
16
Table 2. Enantioslective Conjugated Additions Catalyzed by the
Rh(I)/8h Complexa
9
10
11
12
13
14
15f
8j
8k
8h
8h
8h
8h
NRe
93
73
>99
>99
95
95
95
89
THF/MeOH (2/1)
benzene/MeOH (2/1)
dioxane/MeOH (2/1)
a All the reactions were carried out with 2-cyclohexenone (4) (0.20
mmol), phenylboronic acid (5) (0.30 mmol), KOH (0.015 mmol),
[RhCl(C2H4)2]2 (0.005 mmol), and ligand 8 (0.012 mmol) at the indicated
temperature in solvent (0.6 mL) under argon for 5 h unless otherwise stated.
c
b The ratio was in volume. The conversion was determined by crude H
NMR. d The ee was determined by chiral HPLC (Chiralpak AD-H column).
e No reaction. f The catalyst loading was 1 mol %.
1
be due to the relatively stronger coordination ability of vicinal
diamine moieties than that of diene moieties. Hence, acyl
and sulfonyl groups were introduced to the nitrogen atoms
to decrease the coordination ability of diamine groups, and
a variety of diene ligands 8b-k were afforded in 49-87%
yields (Scheme 2).
Ligands 8b-k (6.0 mol %) were then subjected to the
reactions of 2-cyclohexenone (4) and phenylboronic acid (5)
with [RhCl(C2H4)2]2 (2.5 mol %) in dioxane/methanol (2/1,
v/v) using KOH (7.5 mol %) as base for 5 h. As shown in
Table 1, we were pleased to find that the majority of Rh/
diene complexes can promote this reaction efficiently to
afford the desired product (R)-6 in quantitative conversions
and 89-95% ee’s (Table 1, entries 2-8). Ligand 8i gave
78% ee with a quantitative conversion at 50 °C (Table 1,
entry 9), while ligand 8k bearing only one 4-toluenesulfonyl
(Ts) group on the nitrogen atom was not effective for this
reaction (Table 1, entry 11). Overall, ligand 8h gave the
a All the reactions were carried out with R,ꢀ-unsaturated carbonyl
compound (0.40 mmol), organoboronic acid (0.60 mmol), [RhCl(C2H4)2]2
(0.01 mmol), KOH (0.030 mmol), and ligand 8h (0.024 mmol) in dioxane/
MeOH (2/1, v/v) (1.2 mL) at 10 °C under argon for 2 h. b The absolute
configuration was determined by comparing the optical rotation with the
reported one. c Isolated yield. d The ee was determined by chiral HPLC
(Chiralpak AD-H column) unless otherwise stated. Chiralcel OD-H column
for entries 8 and 11, Chiralcel OJ-H column for entries 10 and 13, Chiralcel
OB-H column for entry 14, and Chiralcel AS-H column for entry 12.
Figure 2. X-ray structure of chiral diene ligand 8h.
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Org. Lett., Vol. 12, No. 23, 2010

smoothly at 50 °C to give the corresponding adduct (R)-6
in >99% conversion but with a slightly lower ee (Table 1,
entry 15). One single crystal of ligand 8h was obtained, and
its X-ray structure is shown in Figure 2. To clarify the
binding mode between 8h and rhodium, ligand 8h was
hydrogenated and then subjected to the reaction, but no
desired product was observed, which indicates that ligand
8h is likely binding to rhodium through the olefins rather
than the sulfonamides. To have a better insight into the
coordination mode between 8h and rhodium, NMR studies
were carried out by using C6D6/CD3OD as solvent. However,
to our surprise, only slight changes were observed for all
the proton signals of ligand 8h (see Supporting Information)
which suggests that the complex formed between Rh and
8h has the possibility to be less stable, and a very fast
coordination/dissociation process may be involved, even
though the Rh/8h complex still displays enough activity to
promote this reaction to afford up to 95% ee with excellent
yields which is interesting and awaits further study.
aryboronic acids and 2-cyclohexenone (4) afforded excellent
yields and ee’s (Table 2, entries 2-5, 8, and 9), while using
ortho-substituted arylboronic acids as substrates gave high
yields but with lower ee’s (Table 2, entries 6, 7, and 10).
(E)-Styrylboronic acid was also an effective substrate for
this reaction to give 90% ee with 54% yield (Table 2, entry
11). The Rh/8h complex was found to be an efficient catalyst
for the reactions of other R,ꢀ-unsaturated carbonyl com-
pounds and phenylboronic acid (5) to give 81-95% yields
with 76-90% ee’s (Table 2, entries 12-14).
In summary, a variety of novel vicinal-diamine-based
chiral chain diene ligands were easily prepared in reasonable
yields through a straightforward synthetic route. Ligand 8h
was found to be a highly effective steering ligand for
rhodium-catalyzed asymmetric conjugated additions to give
promising results (up to 95% ee). It is encouraging that such
a simple and flexible diene can be utilized as a ligand in
asymmetric reactions to achieve excellent reactivities and
enantioselectivities which will benefit the development of
accessible diene ligands in the future. Searching for more
effective acyclic diene ligands, exploring their application
in other asymmetric reactions, and understanding the detailed
coordination mode are currently underway in our laboratory.
With the best ligand 8h, the substrate scope was then
investigated. Some of the results are summarized in Table
2. We were pleased to find that the asymmetric conjugated
additions under the catalysis of Rh/8h (5 mol %) in dioxane/
methanol (2/1, v/v) at 10 °C for 2 h proceeded smoothly to
give the corresponding adducts in 54-99% yields with
76-95% ee’s. The reactions of meta- or para-substituted
Acknowledgment. We are grateful to the generous
financial support from the National Science Foundation of
China (20802079, 21072194), the National Basic Research
Program of China (973 program, 2010CB833300), and the
Ministry of Science and Technology (2009ZX09501-018).
(10) For leading reviews on diamination, see: (a) Lucet, D.; Gall, T. L.;
Mioskowski, C. Angew. Chem., Int. Ed. 1998, 37, 2580. (b) Mortensen,
M. S.; O’Doherty, G. A. Chemtracts: Org. Chem. 2005, 18, 555. (c) Kotti,
S. R. S. S.; Timmons, C.; Li, G. Chem. Biol. Drug Des. 2006, 67, 101. (d)
de Figueiredo, R. M. Angew. Chem., Int. Ed. 2009, 48, 1190. (e) Cardona,
F.; Goti, A. Nature Chem. 2009, 1, 269.
Supporting Information Available: The procedure for
the synthesis of chiral dienes, rhodium-catalyzed conjugated
additions, characterization of diene ligands and adducts,
NMR study for the Rh/8h complex, and data for the
determination of enantiomeric excesses of adducts along with
NMR spectra. This material is available free of charge via
the Internet at http://pubs.acs.org.
(11) For leading references on Pd(0)-catalyzed diamination, see: (a) Du,
H.; Zhao, B.; Shi, Y. J. Am. Chem. Soc. 2007, 129, 762. (b) Du, H.; Yuan,
W.; Zhao, B.; Shi, Y. J. Am. Chem. Soc. 2007, 129, 7496. (c) Du, H.; Yuan,
W.; Zhao, B.; Shi, Y. J. Am. Chem. Soc. 2007, 129, 11688. (d) Du, H.;
Zhao, B.; Shi, Y. J. Am. Chem. Soc. 2008, 130, 8590. (e) Wang, B.; Du,
H.; Shi, Y. Angew. Chem., Int. Ed. 2008, 47, 8224. (f) Zhao, B.; Du, H.;
Cui, S.; Shi, Y. J. Am. Chem. Soc. 2010, 132, 3523.
(12) (a) Greene, F. D.; Stowell, J. C.; Bergmark, W. R. J. Org. Chem.
1969, 34, 2254. (b) Du, H.; Zhao, B.; Shi, Y. Org. Synth. 2009, 86, 315.
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