Nickel-catalyzed asymmetric addition of alkyne C-H bonds across 1,3-dienes using taddol-based chiral phosphoramidite ligands

Article abstract of DOI:10.1002/anie.201001188

(Figure Presented) Enantioenriched 3-methyl-1,4-enynes are the products of the title reaction. The terminal α-siloxy-sec-alkyl groups were then converted into γ-oxoalkyl groups by rhodium-catalyzed conjugate alkynyl addition to α,β-unsaturated ketones thr

Full text of DOI:10.1002/anie.201001188

Angewandte
Chemie
DOI: 10.1002/anie.201001188
À
Asymmetric C H Addition
À
Nickel-Catalyzed Asymmetric Addition of Alkyne C H Bonds across
1,3-Dienes Using Taddol-Based Chiral Phosphoramidite Ligands**
Masamichi Shirakura and Michinori Suginome*
Much interest has been focused on the catalytic, direct
The reaction of alkyne 1a with trans-1-phenyl-1,3-buta-
diene (2a) was carried out in the presence of [Ni(cod)2]
(cod = cycloocta-1,5-diene) with various chiral monodentate
phosphorus ligands (Table 1). The reactions afforded various
ratios of the desired diene–alkyne coupling product 3a along
with alkyne dimerization product 4a. Use of H-mop[11] and
binol (binol = 1,1’-binaphthol)-derived phosphoramidite
ligands[12] resulted in low to moderate enantiomeric excess
values (Table 1, entries 1–4). In particular, the binol-derived
phosphoramidite ligands that have a bulky amino group
showed significantly lower selectivities for the desired hydro-
alkynylation product 3a (Table 1, entries 3 and 4). We found
that the product selectivity (3a/4a) was highly sensitive to the
chiral ligand that was utilized in the reaction, with some
dependence upon bulkiness of the ligand. Taddol-derived
phosphorus ligands[13] afford higher product selectivity and
acceptably high enantioselectivity for the formation of 3.
Examination of a series of chiral ligands that were derived
from 3,5-xylyl-taddol showed that the enantioselectivities
increased on changing the N substituents from ethyl to benzyl,
and then to phenyl (Table 1, entries 5–8). The highest
enantioselectivity (91–92% ee) was obtained using NPh2
derivative (R,R)-9 with a phosphorus/nickel ratio of 2:1 to
1.2:1 (Table 1, entry 9). No further improvement in product
selectivity or enantioselectivity could be achieved using other
taddol-derived NPh2 phosphoramidite ligands 10–13 (Table 1,
entries 10–13).
In these reactions, the use of trans diene was found to be
crucial for obtaining high enantioselectivity and reactivity. In
contrast, the reaction of cis-1-phenyl-1,3-butadiene with
alkyne 1a under the optimized reaction conditions afforded
3a in only 8% yield with 18% ee, along with the alkyne
dimerization product 4a as the major product. Furthermore,
the structure of the terminal alkyne was also crucially
important. In contrast to alkyne 1a, dimethyl derivative 3-
trimethylsiloxy-3-methyl-1-butyne and triisopropylsilylacety-
lene completely failed to give the corresponding diene–
alkyne coupling product, but gave the corresponding alkyne
dimerization and oligomerization products. Alkyne 1b, which
carries a dimethylphenylsilyl group instead of a trimethylsilyl
group on the oxygen atom, gave comparable product
selectivity (57:31) with high enantioselectivity (92% ee).
Various trans-1-aryl-1,3-butadienes were subjected to the
asymmetric hydroalkynylation reaction (Table 2).[14] Impor-
tantly, in this investigation, the diene was used as the yield-
limiting component, and alkyne 1 was added slowly using a
syringe pump over 80–90 hours. The slow-addition method
minimized the formation of dimer 4, thus leading to higher
yields of hydroalkynylation products 3. Besides 1-phenyl- and
1-para-tolyl-1,3-butadiene (Table 2, entries 1–3), para-tri-
À
À
conversion of alkyne C H bonds through C C bond-forming
reactions without the stoichiometric generation of acety-
lides.[1] One of the most widely used procedures for such an
atom-economical process is the nucleophilic alkynylation of
carbonyl compounds, a,b-unsaturated carbonyl compounds,
or related electrophiles, in which catalytically generated
metal acetylides often play a key role.[2,3] Recent attention
has focused on the development of asymmetric variants of
these nucleophilic alkynylation reactions for the synthesis of
highly functionalized chiral alkyne derivatives.[4,5]
Besides these nucleophilic alkynylation reactions, hydro-
À
alkynylation, i.e. the addition of alkyne C H bonds, across
unactivated carbon–carbon multiple bonds has attracted
increasing attention.[1b] After extensive studies on the homo-
and cross-dimerization reactions of alkynes using rhodium,
palladium, and nickel catalysts,[6] hydroalkynylation has been
extended to carbon–carbon double bonds, such as those in
allenes and cyclopropenes.[7,8] However, the scope of the
hydroalkynylation reaction is still significantly limited.[9,10] As
a consequence, no successful catalytic asymmetric hydro-
alkynylation reactions have been established, except for the
rhodium-catalyzed hydroalkynylation of allenes.[10]
We recently showed that bulky triisopropylsilylacetylene
=
underwent addition to C C bonds in 1,3-dienes, norbornene,
styrenes, and methylenecyclopropanes in the presence of
nickel triorganophosphine catalysts.[9] The relatively narrow
scope for the choice of phosphine ligands in these reactions
could be a major difficulty in applying this system to
asymmetric synthesis. Herein, we report the nickel-catalyzed
asymmetric hydroalkynylation reactions of 1-aryl-1,3-buta-
dienes involving the essential use of taddol-derived phos-
phoramidite ligands (taddol = 2,2-dimethyl-a,a,a’,a’-tetra-
phenyldioxolane-4,5-dimethanol). In addition to the signifi-
cance of the chiral ligands, the use of a terminal alkyne that
contains an a-siloxy-sec-alkyl group on the alkynyl carbon is
important to achieve sufficient reaction efficiency.
[*] Dr. M. Shirakura, Prof. Dr. M. Suginome
Department of Synthetic Chemistry and Biological Chemistry
Graduate School of Engineering, Kyoto University
Katsura, Nishikyo-ku, Kyoto 615-8510 (Japan)
Fax: (+81)75-383-2722
E-mail: suginome@sbchem.kyoto-u.ac.jp
Homepage: http://www.sbchem.kyoto-u.ac.jp/suginome-lab/
[**] This work was supported by a Grant-in-Aid for Scientific Research on
Priority Areas “Advanced Molecular Transformations of Carbon
Resources” from MEXT. M. Shirakura acknowledges the JSPS for
fellowship support.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201001188.
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Table 1: Screening of chiral phosphine ligands in nickel-catalyzed
asymmetric hydroalkynylation of 2a with 1a.[a]
Table 2: Nickel-catalyzed asymmetric hydroalkynylation of 1-aryl-1,3-
butadienes.[a]
Entry
1
2 (Ar)
Prod.
Yield [%][b]
ee [%][c]
1
2
3
4
5
6
7
8
9
1a
1b
1b
1b
1a
1b
1a
1b
1b
2a (Ph)
2a
2b (p-tol)
2c (p-CF3C6H4)
2d (p-ClC6H4)
2e (m-MeOC6H4)
2 f (o-MeOC6H4)
2 f
3a
63
60
57
59
55
68
52
58
41
91
91
91
90
90
93
92
92
92
Entry
Ligand
t [h]
Yield 3a/4a [%][b]
ee 3a [%][c]
3a’
3b’
3c’
3d
3e’
3 f
1
2
3
4
5
6
7
8
(R)-H-mop
(S)-monophos
(S,S,S)-5
(R,S,S)-5
(R,R)-6
22
180
180
180
180
20
90
48
48
33
30:68
46:36
10:85
11:87
39:49
43:46
52:32
53:47
51:33
33:66
33:64
33:66
12:78
20 (R)
49 (R)
15 (S)
35 (R)
24 (S)
57 (S)
79 (S)
92 (S)
91 (S)
69 (S)
70 (S)
62 (S)
78 (S)
3 f’
3g’
(R,R)-7
(R,R)-8
(R,R)-9
(R,R)-9
(R,R)-10
(R,R)-11
(R,R)-12
(R,R)-13
2g (1-naphthyl)
[a] Reaction conditions: 1 (0.45 mmol) and 2 (0.30 mmol) in THF
(0.1 mL) were stirred at room temperature in the presence of [Ni(cod)2]
(30 mmol) and (R,R)-9 (33 mmol). [b] Yield of isolated product. [c] Deter-
mined by HPLC analysis on a chiral stationary phas.
9[d]
10
11
12
13
33
17
180
[a] Reaction conditions: 1a (0.050 mmol), 2a (0.15 mmol), [Ni(cod)2]
(0.005 mmol), and ligand (0.010 mmol) were stirred in toluene
(0.05 mL) at room temperature. [b] Yield determined by 1H NMR
spectroscopy. [c] Determined by HPLC on a chiral stationary phase.
[d] 0.006 mmol ligand was used.
The enantioenriched products are useful building blocks
in asymmetric organic synthesis. One example is the con-
version of the siloxyalkyl group, which is often utilized as a
protecting group for a terminal alkyne,[15] into other organic
groups by catalytic transformation. The silyl moiety of the
siloxyalkyl group is removed by treatment with citric acid
(Scheme 1). The hydroxyalkyl group at the sp carbon atom
Scheme 1. Desilylation of hydroalkynylation product 3a followed by
rhodium-catalyzed conjugate addition to MVK. MVK=methyl vinyl
ketone.
was directly converted into the 3-oxobutyl group by rhodium-
catalyzed conjugate addition to methyl vinyl ketone (MVK),
À
fluoromethyl- and para-chloro-substituted 1-phenyl-1,3-buta-
dienes afforded their corresponding hydroalkynylation prod-
ucts with high enantioselectivities (Table 2, entries 4 and 5).
meta- and ortho-methoxyphenyl derivatives also gave the
desired products in high enantioselectivity (Table 2, entries 6–
8). As with the reaction of the 1-naphthyl derivative, high ee
values were obtained with moderate reaction yield (Table 2,
entry 9).
which proceeded through C C bond cleavage at the alkynyl
carbon atom.[16] The enantiomeric purity was conserved
throughout the transformation, resulting in the isolation of
functionalized alkyne 15 with 91% ee. The two C(sp) C(sp )
bonds in 15 were formed by two different catalytic C C bond-
forming reactions. This demonstrates the potential applic-
ability of the enantioselective catalytic hydroalkynylation
reactions in asymmetric organic synthesis.
3
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Experimental Section
General procedure for hydroalkynylation of 2 with 1: [Ni(cod)2]
(8.3 mg, 0.030 mmol) and (R,R)-9 (25.6 mg, 0.033 mmol) were placed
in a reaction vessel under a nitrogen atmosphere. trans-1,3-Diene
(0.30 mmol) and THF (0.10 mL) were added successively, and the
reaction mixture was stirred under a nitrogen atmosphere at room
temperature. Alkyne 1a or 1b (0.45 mmol) was added to the solution
using a syringe pump over 82–90 hours. The reaction mixture was
passed through a short pad of silica gel (hexanes/EtOAc = 400:1).
After the evaporation of volatile materials, the residue was purified
further by preparative GPC and/or HPLC (hexane/EtOAc = 400:1).
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Received: February 26, 2010
Published online: April 16, 2010
À
Keywords: alkynes · asymmetric catalysis · C H activation ·
1,3-dienes · nickel
.
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Angew. Chem. Int. Ed. 2010, 49, 3827 –3829
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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