Electronic tuning of chiral diene ligands in iridium-catalyzed asymmetric 1,6-addition of arylboroxines to δ-aryl-α,β,γ,δ- unsaturated ketones

Article abstract of DOI:10.1039/c2cc16973h

Asymmetric addition of arylboroxines to δ-aryl-α,β, γ,δ-unsaturated ketones proceeded in the presence of an iridium catalyst coordinated with a chiral diene ligand to give high yields of δ-diaryl ketones with very high enantioselectivity.

Full text of DOI:10.1039/c2cc16973h

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COMMUNICATION
Electronic tuning of chiral diene ligands in iridium-catalyzed asymmetric
1,6-addition of arylboroxines to d-aryl-a,b,c,d-unsaturated ketonesw
Takahiro Nishimura,* Akira Noishiki and Tamio Hayashi*
Received 10th November 2011, Accepted 25th November 2011
DOI: 10.1039/c2cc16973h
Asymmetric addition of arylboroxines to d-aryl-a,b,c,d-unsaturated
ketones proceeded in the presence of an iridium catalyst coordinated
with a chiral diene ligand to give high yields of d-diaryl ketones with
very high enantioselectivity.
The transition metal-catalyzed asymmetric addition of organo-
metallic reagents to a,b-unsaturated carbonyl compounds offers
a practical access to a variety of chiral carbonyl compounds,
where diverse aryl, alkenyl, and alkyl groups are introduced
Scheme 1 Iridium-catalyzed enantioselective 1,6-addition to a,b,g,
d-unsaturated carbonyl compounds.
with high regioselectivity and enantioselectivity.1 On the other
hand, the addition to extended conjugated systems such as
a,b,g,d-unsaturated ketones has been a challenging objective in
the asymmetric 1,6-addition of arylboroxines to d-aryl dienyl
ketones giving the 1,6-addition products in high yields with
high enantioselectivity.
organic synthesis because of the difficulty of controlling the
regioselectivity (e.g., 1,2-, 1,4-, and 1,6-addition).2 Copper
reagents and catalysts have been reported to display high
1,6-selectivity3,4 and, recently, successful examples of copper-
catalyzed enantioselective 1,6-addition to dienones and dienoates
have been reported by Feringa,5 Alexakis,6 and Fillion7 et al.
Asymmetric rhodium catalysis has also been reported in the
1,6-addition of arylzinc reagents to dienones having b-substituents
to suppress the competing 1,4-addition.8 Iron-catalyzed diastereo-
selective addition of arylmagnesium reagents to dienoates having a
chiral auxiliary has been reported by Urabe et al.9–11 In this
context, we recently reported that the enantioselective conjugate
addition of arylboroxines to linear a,b,g,d-unsaturated carbonyl
compounds with perfect 1,6-selectivity is realized by the use of a
chiral iridium complex as a catalyst (Scheme 1).12 The iridium
complex coordinated with the chiral tetrafluorobenzobarrelene
(tfb) ligand L1,13 which is substituted with methyl groups,
displayed a high catalytic activity and enantioselectivity in the
addition of arylboroxines to dienyl ketones that have alkyl
groups at the d-position. Unfortunately, however, the catalyst
displayed no catalytic activity toward the reaction of d-aryl
dienyl ketones, which would provide diarylmethine stereogenic
centers. Here we report that the electronic tuning of chiral diene
ligands develops a catalytic activity of the iridium complex in
We found that the electronic nature of the diene ligands has
a significant influence on the catalytic activity of the iridium
complexes in the reaction of d-aryl dienyl ketones (Table 1).
Treatment of (2E,4E)-1,5-diphenyl-2,4-pentadien-1-one (1a)
with p-tolylboroxine (2s) (1.5 equiv. of B) in the presence of
[IrCl((S,S)-L1)]2 (2 mol% of Ir) and K2CO3 (5 mol%) in
MeOH/CH2Cl2 (4 : 1) at 30 1C for 24 h, which is one of
the best catalytic conditions for the asymmetric addition to
d-alkyl-substituted dienyl carbonyl compounds, did not give
any of the addition products (entry 1). The reaction using
ligand L2 substituted with benzyl groups also resulted in no
formation of the 1,6-adducts (entry 2). On the other hand,
the use of ligand L3 substituted with phenyl groups gave
1,6-addition products as a mixture of non-conjugated (Z)-enone
3as and its (E)-isomer 4as in 21% yield (entry 3). The
enantioselectivity was determined to be 99.5% ee by HPLC
analysis of conjugated enone 5as formed by isomerization with
DBU. The catalytic activity was greatly improved by the use of
ligand L4, which is substituted with 4-(trifluoromethyl)phenyl
groups, giving the addition products in 64% yield (entry 4).
Electron-deficient chiral dienes L5 and L6 bearing ester groups
at the alkene moieties, which are prepared from ditriflate L013b
as shown in Scheme 2, also displayed high performance in the
present reaction (entries 5 and 6), and the reaction using
2-naphthyl ester L6 gave 93% yield of the addition products,
which were transformed into conjugated enone 5as in 81%
yield (entry 6). The ee of 5as was over 99.5% ee.14 The
tetrafluorobenzo (tfb) moiety of the diene ligands is important
for the catalytic activity of the iridium complex. Thus, the ligand
Department of Chemistry, Graduate School of Science,
Kyoto University, Sakyo, Kyoto 606-8502, Japan.
E-mail: tnishi@kuchem.kyoto-u.ac.jp, thayashi@kuchem.kyoto-u.ac.jp;
Fax: +81 75 753 3988; Tel: +81 75 753 3983
w Electronic supplementary information (ESI) available: Experimental
procedures and compound characterization data. See DOI: 10.1039/
c2cc16973h
c
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Chem. Commun., 2012, 48, 973–975 973

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Table 1 Iridium-catalyzed 1,6-addition of 2s to dienone 1aa
Table 2 Scope of arylboroxines 2a
Entry
Ar
Yieldb (%)
eec (%)
1
2
4-MeC6H4 (2s)
3-MeC6H4 (2t)
4-MeOC6H4 (2u)
3,4-(OCH2O)C6H3 (2v)
4-ClC6H4 (2w)
93 (6as)
90 (6at)
87 (6au)
86 (6av)
82 (6aw)
79 (6ax)
91 (6ay)
>99.5
99.5
99.0
99.4
99.3
3d
4d
5
6d,e
7
3,4-Cl2C6H3 (2x)
4-FC6H4 (2y)
>99.5
>99.5
a
Reaction conditions: 1a (0.20 mmol), arylboroxine 2 (0.10 mmol,
1.5 equiv. of B), [IrCl((S,S)-L5)]2 (2 mol% of Ir), K2CO3 (5 mol%),
MeOH/CH2Cl2 (4 : 1, 1.0 mL) at 30 1C. Hydrogenation was carried out in
the presence of RhCl(PPh3)3 (5 mol%) in MeOH under H2 (1 atm).
Entry
Ligand
Yieldb (%)
Yield of 5asc (%)
eed (%)
b
c
d
Isolated yield of 6. Determined by chiral HPLC analysis. Performed
e
with 0.20 mmol of arylboroxine 2. For 48 h.
1
2
3
4
5
6
7
L1
L2
L3
L4
L5
L6
L7
0
0
—
—
14
49
46
81e
—
—
99.5
21 (71 : 29 : 0)
64 (39 : 58 : 3)
62 (30 : 65 : 5)
93 (33 : 64 : 3)
6 (50 : 50 : 0)
>99.5
>99.5
>99.5
the corresponding d-diaryl ketones in high yields with over
99.0% ee (Table 2). Aryl groups having a variety of substituents
at the meta and para position of phenyl (2s–2y) were successfully
introduced into the d-position of the dienone 1a with high
enantioselectivity (entries 1–7), but the reaction with o-tolylboroxine
f
f
—
—
a
Reaction conditions: 1a (0.20 mmol), p-tolylboroxine (2s) (0.10 mmol,
1.5 equiv. of B), [IrCl(diene*)]2 (2 mol% of Ir), K2CO3 (5 mol%),
b
MeOH/CH2Cl2 (4:1, 1.0 mL) at 30 1C for 24 h. Combined yield of
Table 3 Iridium-catalyzed 1,6-addition of 2s to dienone 1a
3as–5as determined by 1H NMR. The values in parenthesis are the ratios
of 3as, 4as, and 5as. Yield of 5as determined by 1H NMR after
c
d
e
treatment with DBU. Determined by chiral HPLC analysis. Isolated
f
yield. Not determined. DBU: 1,8-diazabicyclo[5.4.0]undec-7-ene.
Entry
R1
R2
Yieldb (%)
eec (%)
1
2
3
4
Ph
Ph (1a)
Ph (1b)
Ph (1c)
Ph (1d)
Ph (1e)
Ph (1f)
Ph (1g)
Ph (1h)
Ph (1i)
Ph (1j)
2-BrC6H4 (1k)
2-MeOC6H4 (1l)
Ph (1m)
Ph (1n)
93 (6as)
93 (6bs)
84 (6cs)
96 (6ds)
95 (6es)
91 (6fs)
91 (6gs)
91 (6hs)
95 (6is)
95 (6js)
92 (6ks)
90 (6ls)
79 (6ms)
76 (6ns)
82 (6os)
96 (6ps)
87 (6qs)
93 (6rs)
>99.5
>99.5
>99.5
>99.5
>99.5
99.0
>99.5
>99.5
>99.5
99.0
>99.5
99.1
>99.5
99.5
98
4-CF3C6H4
4-FC6H4
4-ClC6H4
3-ClC6H4
4-MeC6H4
4-MeOC6H4
2-MeOC6H4
2-Furyl
2-Thienyl
Ph
Ph
Me
Et
Bu
Ph
Ph
Ph
5
6d
7d
8d
9d
10d
11
12
13d
14d
15d
16
17
18
Ph (1o)
Scheme 2 Preparation of ligands L5 and L6.
Me (1p)
Pr (1q)
i-Pr (1r)
98
99.0
>99.5
L7, which lacks the tfb moiety but has a bicyclo[2.2.2]octadiene
skeleton and 2-naphthyl ester groups at the diene moieties, gave
only 6% yield of the addition products (entry 7) in contrast to the
high catalytic activity of L6 based on the tfb moiety (entry 6).
The present catalytic system can be applied to the asym-
metric addition of several arylboroxines 2 to dienone 1a to
give, after hydrogenation of the initially formed 1,6-adducts,
a
Reaction conditions: 1a (0.20 mmol), arylboroxine 2 (0.10 mmol,
1.5 equiv. of B), [IrCl((S,S)-L6)]2 (2 mol% of Ir), K2CO3 (5 mol%),
MeOH/CH2Cl2 (4 : 1, 1.0 mL) at 30 1C. Hydrogenation was carried out in
the presence of RhCl(PPh3)3 (5 mol%) in MeOH under H2 (1 atm).
b
c
d
Isolated yield of 6. Determined by chiral HPLC analysis. Performed
with [IrCl((S,S)-L6)]2 (5 mol% of Ir).
c
974 Chem. Commun., 2012, 48, 973–975
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Asymmetric Conjugate Reactions, ed. A. Cordova, Wiley-VCH,
Weinheim, 2010, p. 1.
2 A. G. Csaky, G. de la Herran and M. C. Murcia, Chem. Soc. Rev.,
2010, 39, 4080.
3 For reviews, see: (a) Y. Yamamoto, Angew. Chem., Int. Ed. Engl.,
1986, 25, 947; (b) N. Krause and A. Gerold, Angew. Chem., Int. Ed.
Engl., 1997, 36, 186; (c) N. Krause and S. Thorand, Inorg. Chim.
Acta, 1999, 296, 1.
4 For recent examples of non-asymmetric 1,6-selective conjugate
addition, see: (a) K. Fukuhara and H. Urabe, Tetrahedron Lett.,
2005, 46, 603; (b) G. de la Herran, C. Murcia and A. G. Csaky,
Org. Lett., 2005, 7, 5629; (c) G. de la Herran and A. G. Csaky,
Synlett, 2009, 585.
Scheme 3 Iridium-catalyzed asymmetric 1,6-addition to dienone 7.
gave only 3% yield of the addition products (the result is not
shown).
5 T. den Hartog, S. R. Harutyunyan, D. Font, A. J. Minnaard and
B. L. Feringa, Angew. Chem., Int. Ed., 2008, 47, 398.
6 (a) H. Henon, M. Mauduit and A. Alexakis, Angew. Chem., Int.
Ed., 2008, 47, 9122; (b) J. Wencel-Delord, A. Alexakis, C. Crevisy
and M. Mauduit, Org. Lett., 2010, 12, 4335.
7 E. Fillion, A. Wilsily and E.-T. Liao, Tetrahedron: Asymmetry,
2006, 17, 2957.
8 T. Hayashi, S. Yamamoto and N. Tokunaga, Angew. Chem., Int.
Ed., 2005, 44, 4224.
9 S. Okada, K. Arayama, R. Murayama, T. Ishizuka, K. Hara,
N. Hirone, T. Hata and H. Urabe, Angew. Chem., Int. Ed., 2008,
47, 6860.
10 For enantioselective silyl 1,6-addition to a b-substituted cyclic
dienone, see: K. Lee and A. H. Hoveyda, J. Am. Chem. Soc.,
2010, 132, 2898.
11 For selected examples of organocatalytic asymmetric 1,6-addition
of carbon nucleophiles, see: (a) L. Bernardi, J. Lopez-Cantarero,
B. Niess and K. A. Jørgensen, J. Am. Chem. Soc., 2007, 129, 5772;
(b) J. J. Murphy, A. Quintard, P. McArdle, A. Alexakis and
J. C. Stephens, Angew. Chem., Int. Ed., 2011, 50, 5095.
12 (a) T. Nishimura, Y. Yasuhara, T. Sawano and T. Hayashi, J. Am.
Chem. Soc., 2010, 132, 7872. For a non-asymmetric variant, see:
(b) T. Nishimura, Y. Yasuhara and T. Hayashi, Angew. Chem., Int.
Ed., 2006, 45, 5164.
The results obtained for the 1,6-addition of p-tolylboroxine
(2s) to several dienones are summarized in Table 3, where the
initial 1,6-adducts were subjected to hydrogenation. The addition
of the p-tolyl group to dienones having substituted phenyls
(1b–1h) and heteroaromatic groups (2-furyl (1i) and 2-thienyl
(1j)) at carbonyl (R1) gave after hydrogenation the corresponding
ketones 6bs–6js in high yields with over 99.0% ee (entries 2–10).
The addition to dienones 1k and 1l substituted with o-bromo- and
o-methoxyphenyl at d-position (R2) gave high yields of the
corresponding 1,6-adducts 6ks and 6ls (entries 11 and 12).
Dienones substituted with alkyl groups at carbonyl (1m–1o,
entries 13–15) or at d-position (1p–1r, entries 16–18) are also
good substrates to give the corresponding ketones 6ms–6rs in high
yields with high enantioselectivity.
The reaction of non-linear dienone (E)-3-styryl-2-cyclohexenone
(7) with p-tolylboroxine (2s) in the presence of the Ir/(S,S)-L6
(5 mol% of Ir) catalytic system also proceeded with perfect
1,6-selectivity and enantioselectivity to give the conjugated
enone 8 in 93% yield (Scheme 3).
13 (a) T. Nishimura, Y. Yasuhara, M. Nagaosa and T. Hayashi, Tetra-
hedron: Asymmetry, 2008, 19, 1778; (b) T. Nishimura, H. Kumamoto,
M. Nagaosa and T. Hayashi, Chem. Commun., 2009, 5713;
(c) T. Nishimura, Y. Ichikawa, T. Hayashi, N. Onishi, M. Shiotsuki
and T. Masuda, Organometallics, 2009, 28, 4890; (d) T. Nishimura,
J. Wang, M. Nagaosa, K. Okamoto, R. Shintani, F. Kwong, W. Yu,
A. S. C. Chan and T. Hayashi, J. Am. Chem. Soc., 2009, 132, 464;
(e) T. Nishimura, T. Kawamoto, M. Nagaosa, H. Kumamoto and
T. Hayashi, Angew. Chem., Int. Ed., 2010, 49, 1638; (f) R. Shintani,
M. Takeda, T. Nishimura and T. Hayashi, Angew. Chem., Int. Ed.,
2010, 49, 3969; (g) T. Nishimura, Y. Maeda and T. Hayashi, Angew.
Chem., Int. Ed., 2010, 49, 7324; (h) T. Nishimura, H. Makino,
M. Nagaosa and T. Hayashi, J. Am. Chem. Soc., 2010, 132, 12865;
(i) Y. Ichikawa, T. Nishimura and T. Hayashi, Organometallics, 2011,
30, 2342; (j) T. Nishimura, A. Kasai, M. Nagaosa and T. Hayashi,
Chem. Commun., 2011, 47, 10488.
In summary, we have developed an iridium-catalyzed asymmetric
1,6-addition of arylboroxines to dienones bearing an aryl
group at the d-position, which was realized by the use of an
iridium/electron-deficient chiral diene catalyst. The reaction
gave 1,6-adducts, which have a diarylmethine stereogenic
center, in high yields with very high enantioselectivity.
Notes and references
1 For reviews, see (a) M. P. Sibi and S. Manyem, Tetrahedron, 2000,
56, 8033; (b) N. Krause and A. Hoffmann-Roder, Synthesis, 2001,
171; (c) K. Fagnou and M. Lautens, Chem. Rev., 2003, 103, 169;
(d) T. Hayashi and K. Yamasaki, Chem. Rev., 2003, 103, 2829;
(e) S. Darses and J.-P. Genet, Eur. J. Org. Chem., 2003,
4313; (f) J. Christoffers, G. Koripelly, A. Rosiak and M. Rossle,
Synthesis, 2007, 1279; (g) G. Berthon and T. Hayashi, in Catalytic
14 The absolute configuration of 5as was determined to be R by
analogy with (R)-5au. See ESIw for details.
c
This journal is The Royal Society of Chemistry 2012
Chem. Commun., 2012, 48, 973–975 975