Ruthenium- and copper-catalyzed enantioselective propargylic alkylation of propargylic alcohols with β-keto phosphonates

Article abstract of DOI:10.1021/om300219f

The enantioselective propargylic alkylation of propargylic alcohols with β-keto phosphonates in the presence of a thiolate-bridged diruthenium complex and a copper complex as cocatalysts gives the corresponding propargylic alkylated products in excellent yields with high diastereo- and enantioselectivities (up to 97% ee).

Full text of DOI:10.1021/om300219f

Article
pubs.acs.org/Organometallics
Ruthenium- and Copper-Catalyzed Enantioselective Propargylic
Alkylation of Propargylic Alcohols with β-Keto Phosphonates
Kazuki Motoyama, Masahiro Ikeda, Yoshihiro Miyake, and Yoshiaki Nishibayashi*
Institute of Engineering Innovation, School of Engineering, The University of Tokyo, Yayoi, Bunkyo-ku, Tokyo 113-8656, Japan
S
* Supporting Information
ABSTRACT: The enantioselective propargylic alkylation of
propargylic alcohols with β-keto phosphonates in the presence
of a thiolate-bridged diruthenium complex and a copper
complex as cocatalysts gives the corresponding propargylic
alkylated products in excellent yields with high diastereo- and
enantioselectivities (up to 97% ee).
n our continuing studies of the cooperative dual catalytic
reactions1 and enantioselective propargylic substitution
the propargylic alkylation of propargylic alcohols using a similar
reaction system. In fact, the propargylic alkylation of
propargylic alcohols with β-keto phosphonates proceeded in
the presence of a thiolate-bridged diruthenium complex and a
copper complex as cocatalysts to give the corresponding
propargylic alkylated products in excellent yields with high
diastereo- and enantioselectivities. This is the first successful
example of β-keto phosphonates as carbon-centered nucleo-
philes in the enantioselective propargylic alkylation. Typical
results are described here.
I
reactions,2 we have quite recently found the ruthenium- and
copper-catalyzed propargylic alkylation of propargylic alcohols
with β-keto esters to give the corresponding propargylic
alkylated products in high yields with excellent enantioselec-
tivity.3 In this reaction system, both transition-metal catalysts
(ruthenium and copper complexes) activate propargylic
alcohols and β-keto esters, respectively, and cooperatively
promote the propargylic alkylation enantioselectively (Scheme
1). The enolates generated in situ from copper complexes4,5
RESULTS AND DISCUSSION
■
Scheme 1
Treatment of 1-(1-naphthyl)-2-propyn-1-ol (1a) with 3 equiv
of diethyl 2-oxocyclopentylphosphonate (2a) in the presence of
catalytic amounts of the thiolate-bridged diruthenium com-
plex9,10 [Cp*RuCl(μ2-SMe)]2 (Cp* = η5-C5Me5; 3a), the
copper complex Cu(OTf)2, and (4R,4′R,5S,5′S)-2,2′-(cyclo-
propane-1,1-diyl)bis(4,5-diphenyl-4,5-dihydrooxazole) (4a),
and NH4BF4 in tetrahydrofuran (THF) at room temperature
for 40 h gave diethyl 1-(1-(naphthalen-1-yl)prop-2-ynyl)-2-
oxocyclopentylphosphonate (5a) in 63% isolated yield as a
mixture of two diastereoisomers (anti-5a/syn-5a = 15/1) with
89% ee of anti-5a (Table 1, entry 1). This result is in sharp
contrast to that when ethyl 2-oxocyclopentanecarboxylate was
used as a carbon-centered nucleophile under the same reaction
conditions (87% yield, anti/syn = 6/1, 7% ee (anti)).3 The
reaction was carried out in other solvents such as dichloro-
methane, 1,4-dioxane, diethyl ether, and toluene; unsatisfactory
results were observed in all cases (Table 1, entries 2−5). Other
bis(oxazoline) ligands such as 4b worked effectively, but
substantially lower diastereo- and enantioselectivities were
and β-keto esters have been used as carbon-centered
nucleophiles, but successful examples are limited to the
enantioselective addition to carbonyls and their related
compounds. This finding is the first application of the enolates
to asymmetric propargylic substitution reactions. We believe
that the method described in this article provides a new type of
enantioselective dual catalytic reaction using a pair of distinct
transition-metal catalysts.6,7
In the cooperative catalytic reactions, we have now envisaged
that the use of other carbon-centered nucleophiles in place of
the β-keto esters, such as β-keto phosphonates,8 may promote
Received: March 19, 2012
Published: March 27, 2012
© 2012 American Chemical Society
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a
Table 1. Enantioselective Propargylic Alkylations of Propargylic Alcohol (1a) with β-Keto Phosphonate (2a)
b
c
d
run
amt of 2a (equiv)
4
solvent
THF
temp (°C)
yield of 5 (%)
anti-5/syn-5
ee of anti-5 (%)
1
2
3.0
3.0
3.0
3.0
3.0
3.0
3.0
3.0
1.5
1.5
1.5
4a
4a
4a
4a
4a
4b
4c
4d
4a
4a
4a
room temp
room temp
room temp
room temp
room temp
room temp
room temp
room temp
room temp
0
63
7
15/1
>20/1
14/1
13/1
11/1
16/1
89
92
78
86
80
70
CH2Cl2
1,4-dioxane
Et2O
3
78
26
23
59
0
4
5
toluene
THF
6
7
THF
8
THF
18
77
89
99
>20/1
19/1
92
87
91
82
9
THF
10
THF
>20/1
>20/1
e
11
THF
0
a
All reactions of 1a (0.20 mmol) with 2a were carried out in the presence of 3a (0.010 mmol), Cu(OTf)2 (0.020 mmol), 4 (0.022 mmol), and
b
c
d
e
1
NH4BF4 (0.020 mmol) in 2 mL of solvent. Isolated yield. Determined by H NMR. Determined by HPLC. 3b was used instead of 3a.
a
Table 2. Enantioselective Propargylic Alkylations of Propargylic Alcohols (1) with β-Keto Phosphonate (2a)
b
c
d
run
Ar
yield of 5 (%)
anti-5/syn-5
ee of anti-5 (%)
1
2
3
4
5
6
7
8
1-naphthyl (1a)
2-naphthyl (1b)
Ph (1c)
89 (5a)
94 (5b)
97 (5c)
94 (5d)
95 (5e)
93 (5f)
93 (5g)
82 (5h)
>20/1
3/1
91
96
81
87
82
89
64
97
2/1
p-MeC6H4 (1d)
p-ClC6H4(1e)
4/1
7/1
p-MeOC6H4 (1f)
o-MeOC6H4 (1g)
4-methyl-1-naphthyl (1h)
2/1
>20/1
>20/1
a
All reactions of 1 (0.20 mmol) with 2a (0.30 mmol) were carried out in the presence of 3a (0.010 mmol), Cu(OTf)2 (0.020 mmol), 4a (0.022
b
c
d
1
mmol), and NH4BF4 (0.020 mmol) in 2 mL of solvent. Isolated yield. Determined by H NMR. Determined by HPLC.
observed when 4c,d were used as bis(oxazoline) ligands (Table
1, entries 6−8). Only the use of 1.5 equiv of 2a with respect to
1a was enough to promote the propargylic alkylation (Table 1,
entry 9). The reaction proceeded smoothly even at 0 °C, higher
diastereo- and enantioselectivities being observed (Table 1,
entry 10). Other diruthenium complexes such as the complex
bearing the sterically more demanding SiPr moiety [Cp*RuCl-
(μ2-SiPr)]2 (3b) exhibited a lower enantioselectivity (Table 1,
entry 11). Separately, we confirmed that the use of only 3a or
copper complex did not promote the propargylic alkylation.
This result indicates that both 3a and copper complex worked
cooperatively as catalysts to promote the catalytic reaction
enantioselectively.
Next, propargylic alkylation of a variety of propargylic
alcohols was carried out by using 3a and the copper complex
with 4a as cocatalysts. Typical results are shown in Table 2.
Similarly, a high enantioselectivity was observed when 1-(2-
naphthyl)-2-propyn-1-ol (1b) was used as a substrate (Table 2,
entry 2). Introduction of a methyl or a chloro group at the para
position of the benzene ring of propargylic alcohols did not
greatly affect the reactivity and enantioselectivity of the
propargylic alkylated products (Table 2, entries 4 and 5), but
a high enantioselectivity was observed when a methoxy group
was introduced at the para position of the benzene ring of the
propargylic alcohol (Table 2, entry 6). Interestingly, the
introduction of a methoxy group at the ortho position of the
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benzene ring of propargylic alcohols substantially decreased the
enantioselectivity (Table 2, entry 7). When a methyl group was
introduced at the 4-position of the naphthalene ring of
propargylic alcohol, the enantioselectivity was dramatically
improved up to 97% ee (Table 2, entry 8). No reaction
occurred at all under the same reaction conditions when 1-
cyclohexyl-2-propyn-1-ol was used as a substrate, indicating that
the presence of an aryl moiety at the propargylic position of 1 is
necessary to achieve the reaction.
Propargylic alkylation with other β-keto phosphonates also
proceeded smoothly to give the corresponding propargylic
alkylated products with a high enantioselectivity. Typical results
are shown in Table 3. When methyl, propyl, and butyl groups
two diastereoisomers (eq 2). These results indicate that the use
of the β-keto phosphonates bearing a tertiary carbon at the α
position is necessary to achieve a high diastereoselectivity.
However, the reaction with diethyl 1-methyl-2-oxo-2-phenyl-
ethylphosphonate under the same reaction conditions did not
proceed at all. As a result, a high enantioselectivity was
observed when 2-oxocyclopentylphosphonate derivatives were
used as carbon-centered nucleophiles in the present alkylation.
The diastereoselectivity of the corresponding propargylic
alkylated products in the present alkylation was higher than
that of the previous alkylated products where β-keto esters were
used as carbon-centered nucleophiles.3
A proposed reaction pathway is shown in Scheme 2. The
initial step is the formation of an allenylidene complex (B) by
Table 3. Enantioselective Propargylic Alkylations of
Propargylic Alcohol (1a) with β-Keto Phosphonates (2)
a
Scheme 2
a
All reactions of 1a (0.20 mmol) with 2 (0.30 mmol) were carried out
in the presence of 3a (0.010 mmol), Cu(OTf)2 (0.020 mmol), 4a
(0.022 mmol), and NH4BF4 (0.020 mmol) in 2 mL of solvent.
b
c
d
1
Isolated yield. Determined by H NMR. Determined by HPLC.
were used as ester moieties in place of the ethyl group in 2a, a
similar high enantioselectivity was observed in all cases (Table
3, entries 2−4). The reaction of 1a with β-keto phosphonate
bearing an indane skeleton (2e) under the same reaction
conditions gave the corresponding alkylated product in 92%
yield with 82% ee (Table 3, entry 5). Unfortunately, the
reaction of 1c with 2-oxocyclohexylphosphonate (2f) gave only
a mixture of two diastereoisomers in 49% yield with moderate
enantioselectivity (eq 1). The use of acyclic phosphonates such
as diethyl 2-oxo-2-phenylethylphosphonate (2g) afforded the
corresponding alkylated product with 72% ee, but a mixture of
the reaction of propargylic alcohol 1 with 3 via a vinylidene
complex (A). Subsequent attack of an enolate (E), generated in
situ from β-keto phosphonates 2 and Cu(OTf)2 bearing 4, on
the γ carbon of B results in the formation of another vinylidene
complex (D) via an alkynyl complex (C). After transformation
of the vinylidene complex D into the corresponding π-alkyne
complex, the alkylated product 5 is formed by ligand exchange
with another molecule of propargylic alcohol 1.
After one recrystallization of anti-5a, the enantiomerically
pure anti-5a was isolated, and its absolute configuration was
determined as 1S,1′R by X-ray analysis.11 To account for the
enantio- and diastereoselective formation of (1S,1’R)-5, we
propose transition states between the ruthenium allenylidene
complex and the copper enolate complex in Scheme 3.12 In this
Scheme 3
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by Jørgensen and co-workers13 attacks the Si face of the
allenylidene complex from the Si face of the enolate, leading to
the carbon−carbon bond formation. We consider that this is
another successful example of the enantioselective propargylic
alkylation of propargylic alcohols by using a cooperative
catalytic system, where the corresponding propargylic alkylated
products have a highly enantioselective tetrasubstituted carbon
at the homopropargylic position.
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In summary, we have found the ruthenium- and copper-
catalyzed enantioselective propargylic alkylation of propargylic
alcohols with β-keto phosphonates to give the corresponding
propargylic alkylated products in excellent yields with high
diastereo- and enantioselectivities (up to 97% ee). This catalytic
reaction is considered to provide a new type of enantioselective
propargylic substitution reaction,14 where the enolates
generated in situ from the copper complex and β-keto
phosphonates enantioselectively attack the ruthenium-allenyli-
dene complexes. In the present reaction system, both
transition-metal catalysts (ruthenium complex and copper
complex) activate propargylic alcohols and β-keto phospho-
nates, respectively, and both catalysts cooperatively and
simultaneously work to promote the propargylic alkylation
enantioselectively. The produced propargylic alkylated products
have a highly enantioselective tetrasubstituted carbon at the
homopropargylic position. We believe that the finding
described herein will open up not only a new type of
enantioselective propargylic substitution reaction but also a new
aspect of cooperative catalytic reactions using distinct transition
metals to achieve more valuable transformations that could not
be realized by single catalysts. Further work is currently in
progress to apply this strategy to other reaction systems.
ASSOCIATED CONTENT
* Supporting Information
■
S
Text, figures, and tables giving experimental procedures and
spectroscopic data for all compounds and a CIF file giving
crystallographic data for anti-5a. This material is available free
of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*E-mail: ynishiba@sogo.t.u-tokyo.ac.jp.
■
Notes
(8) (a) Kjærsgaard, A.; Jørgensen, K. A. Org. Biomol. Chem. 2005, 3,
804. (b) Bernardi, L.; Zhuang, W.; Jørgensen, K. A. J. Am. Chem. Soc.
2005, 127, 5772. (c) Kim, S. M.; Kim, H. R.; Kim, D. Y. Org. Lett.
2005, 7, 2309. (d) Hamashima, Y.; Suzuki, T.; Takano, H.; Shimura,
Y.; Tsuchiya, Y.; Moriya, K.; Goto, T.; Sodeoka, M. Tetrahedron 2006,
62, 7168. (e) Chen, Z.; Yakura, K.; Matsunaga, S.; Shibasaki, M. Org.
Lett. 2008, 10, 3239.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by the Funding Program for Next
Generation World-Leading Researchers (GR025). M.I. is a
recipient of the JSPS Predoctoral Fellowship for Young
Scientists and acknowledges the Global COE program for
Chemistry Innovation. We also thank the Research Hub for
Advanced Nano Characterization at The University of Tokyo
for X-ray analysis.
(9) (a) Dev, S.; Imagawa, K.; Mizobe, Y.; Cheng, G.; Wakatsuki, Y.;
Yamazaki, H.; Hidai, M. Organometallics 1989, 8, 1232. (b) Matsuzaka,
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