Cooperative catalytic reactions using organocatalysts and transition-metal catalysts: Enantioselective propargylic alkylation of propargylic alcohols with aldehydes

Article abstract of DOI:10.1002/anie.201002591

Working together: The title reaction proceeds in the presence ofa thiolate-bridged diruthenium complex (2) and a secondary amine (1) to give the corresponding propargylic alkylated products in excellent yields as a mixture of two diastereoisomers, each with high enantioselectivity. The two catalysts activate propargylic alcohols and aldehydes, respectively, and cooperatively promote the enantioselec-tive reaction.

Full text of DOI:10.1002/anie.201002591

Angewandte
Chemie
DOI: 10.1002/anie.201002591
Homogeneous Catalysis
Cooperative Catalytic Reactions Using Organocatalysts and Transition-
Metal Catalysts: Enantioselective Propargylic Alkylation of
Propargylic Alcohols with Aldehydes**
Masahiro Ikeda, Yoshihiro Miyake, and Yoshiaki Nishibayashi*
In the last decade, remarkable progress has been made
toward the development of asymmetric reactions using
organocatalysts under operationally simple and environmen-
tally friendly reaction conditions.[1] Especially secondary
amines derived from naturally available compounds worked
as effective catalysts to promote asymmetric reactions of
electrophiles with carbonyl compounds, such as aldol con-
densations and 1,4-conjugate additions, with high to excellent
enantioselectivity.[2] In these reaction systems, enamines
generated in situ from carbonyl compounds, such as alde-
hydes and ketones, and secondary amines worked as suitable
carbon-centered nucleophiles. Nowadays, the methodology
using organocatalysts realizes the diastereo- and enantiose-
lective preparation of highly functionalized compounds such
as (À)-Oseltamivir.[3,4]
alcohol and aldehyde, respectively, thereby cooperatively
promoting the enantioselective propargylic alkylation
(Scheme 1). We believe that the method herein may provide
a new type of dual catalytic reaction using both organo-
catalysts and transition-metal catalysts.[7,8] Preliminary results
are described herein.
We have previously found that the ruthenium-catalyzed
propargylic alkylation of propargylic alcohols with acetone as
a carbon-centered nucleophile gives the corresponding prod-
ucts with a high enantioselectivity (up to 82% ee).[5]
Unfortunately, the use of an excess amount of simple ketones
such as acetone was necessary to promote the propargylic
alkylation. We have envisaged that the enamines generated
in situ from aldehydes and secondary amines can be applied
as carbon-centered nucleophiles for the asymmetric propar-
gylic alkylation. As an extension of our study on enantiose-
lective propargylic substitution reactions,[6] we have now
found the ruthenium-catalyzed propargylic alkylation of
propargylic alcohols with aldehydes in the presence of a
catalytic amount of a secondary amine as an organocatalyst
gives the corresponding products in high yields with an
excellent enantioselectivity. In the present reaction system,
both the transition-metal catalyst (ruthenium complex) and
organocatalyst (secondary amine) activate the propargylic
Scheme 1. Cooperative catalytic reactions using organocatalysts and
transition-metal catalysts.
Treatment of 1-phenyl-2-propyn-1-ol (1a) with 3-phenyl-
propanal (2a) in the presence of catalytic amounts of (S)-a,a,-
bis[3,5-bis(trifluoromethyl)phenyl]-2-pyrrolidinemethanol
trimethyl silyl ether (3a), methanethiolate-bridged diruthe-
nium complex [{Cp*RuCl(m2-SMe)}2] (Cp* = h5-C5Me5; 4a),
and NH4BF4 in toluene at room temperature for 140 hours
[*] M. Ikeda, Dr. Y. Miyake, Prof. Dr. Y. Nishibayashi
Institute of Engineering Innovation, School of Engineering
The University of Tokyo
gave
2-benzyl-3-phenyl-4-pentynal
(5a)
exclusively
(Scheme 2). After the reduction of 5a using NaBH4 at 08C
for one hour, 2-benzyl-3-phenyl-4-pentyn-1-ol (6a) was iso-
lated in 87% yield as a mixture of two diastereoisomers (syn-
6a/anti-6a = 2.2:1) with 94% ee for syn-6a and 88% ee for
anti-6a. Only two equivalents of 2a relative to 1a were used
as a carbon-centered nucleophile; this is in sharp contrast to
the previous reaction system for propargylic alkylation,
wherein a large amount (i.e., as solvent) of the simple
ketone was necessary to promote the propargylic alkylation.[5]
The reaction proceeded more smoothly when three equiv-
alents of 2a relative to 1a were used under the same reaction
conditions. Other secondary amines such as (5S)-2,2,3-tri-
Yayoi, Bunkyo-ku, Tokyo, 113-8656 (Japan)
Fax: (+81)3-5841-1175
E-mail: ynishiba@sogo.t.u-tokyo.ac.jp
Homepage: http://park.itc.u-tokyo.ac.jp/nishiba/
[**] This work was supported by Grant-in-Aids for Scientific Research for
Young Scientists (S) (No. 19675002) and for Scientific Research on
Priority Areas (No. 18066003) from the Ministry of Education,
Culture, Sports, Science and Technology (Japan). Y.N. thanks the
Ube Industries LTD. M.I. acknowledges the Global COE program for
Chemistry Innovation.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201002591.
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7289

Communications
appended to the propargylic alcohol substan-
tially increased the enantioselectivity (Table 1,
entry 6). Similarly, a high enantioselectivity was
observed when naphthyl-2-propyn-1-ols (1g
and 1 f) were used as substrates (Table 1,
entries 7 and 8). No reaction occurred when 1-
cyclohexyl-2-propyn-1-ol (1i) was used as a
substrate under the same reaction conditions
(Table 1, entry 9). These results indicate that
the presence of an aryl moiety at the propargylic
position of 1 is necessary to promote the
catalytic reaction with a high enantioselectivity.
Propargylic alkylation with other aldehydes
also proceeded smoothly to give the corre-
sponding products with a high enantioselectiv-
ity. Typical results are shown in Table 2. The
reaction of 1a with 3-(4-chloro)phenylpropanal
(2b) under the same reaction conditions gave
the corresponding alkylated product with a
similarly high enantioselectivity (Table 2,
entry 1). When other aldehydes such as hepta-
Scheme 2. Enantioselective propargylic alkylation of propargylic alcohols with alde-
hydes. [a] 1,2-Dichloroethane was used as a solvent in place of toluene. Bn=benzyl,
TMS=trimethylsilyl.
methyl-5-benzyl-4-imidazolidinone (3b) worked effectively,
but a substantially lower diastereo- and enantioselectivity
were observed. Separately, we confirmed that the use of
either 3a or 4a did not promote the propargylic alkylation.
This result indicates that both 3a and 4a cooperatively work
as catalysts to promote the catalytic reaction enantioselec-
tively.
Next, alkylation of a variety of propargylic alcohols was
carried out by using 3a and 4a as co-catalysts. Typical results
are shown in Table 1. The introductuion of methyl, fluoro,
chloro, or methoxy group at the para position of the benzene
ring appended to the propargylic alcohols did not significantly
affect the reactivity and enantioselectivity of the reaction
(Table 1, entries 2–5). Interestingly, the introductuion of a
methoxy group at the ortho position of the benzene ring
nal (2c), 3-cyclohexylpropanal (2d), and 6-chlorohexanal
(2e) were used the corresponding products were obtained in
high yields as a mixture of two diastereoisomers, each with
high enantioselectivity (Table 2, entries 2–4). Reactions of 1-
(2-methoxyphenyl)-2-propyn-1-ol (1 f) with aldehydes also
gave a similar result (Table 2, entries 5–8). These results
indicate that a variety of aldehydes are available for the
propargylic alkylation.
To obtain some information on the enantioselective
propargylic alkylation, the stereochemistry of the product
syn-6p was determined. The reaction of diastereochemically
pure syn-6p with (1S)-10-camphorsulfonyl chloride and
triethylamine in the presence of a catalytic amount of 4-
dimethylaminopyridine (DMAP) was run at room temper-
ature for 18 hours to give syn-7p in 87% yield upon isolation
(Scheme 3). After one recrystallization of syn-7p, the enan-
tio- and diastereomerically pure syn-7p was isolated, and its
absolute configuration was determined as [(2R,3S)] by X-ray
analysis.[9]
Table 1: Enantioselective propargylic alkylation of propargylic alcohols 1
with the aldehyde 2a.[a]
We investigated the stoichiometric and catalytic reactions
to gain insight into the reaction pathway. Treatment of a
ruthenium–allenylidene complex 8g[10] with three equivalents
of 2a and one equivalent of 3a at room temperature for
45 hours and subsequent reduction with NaBH4 gave 6g in
49% yield as a mixture of two diastereoisomers [syn-6g/anti-
6g = 3.0:1; syn-6g (94% ee), anti-6g (86% ee)] as shown in
Scheme 4. Furthermore, the reaction of 1g with 2a in the
presence of catalytic amounts of 8g and 3a at room temper-
Entry
1
t
[h]
Yield
syn-6/
ee [%][d]
of 6[b][%] anti-6[c] syn-6 anti-6
1
2
3
4
5
6
7
8
9
R=Ph (1a)
90 89 (6a)
2.2:1
2.5:1
2.1:1
2.2:1
2.0:1
3.3:1
3.1:1
3.0:1
–
96
97
95
95
92
99
96
97
–
89
86
87
84
68
93
84
86
–
R=p-MeC6H4 (1b)
R=p-FC6H4 (1c)
R=p-ClC6H4 (1d)
50 90 (6b)
120 88 (6c)
120 85 (6d)
R=p-MeOC6H4 (1e) 120 85 (6e)
R=o-MeOC6H4 (1 f)
R=1-naphthyl (1g)
R=2-naphthyl (1h)
R=cyclohexyl (1i)
40 93 (6 f)
90 91 (6g)
120 87 (6h)
90
0 (6i)
[a] Reaction conditions:
1
(0.20 mmol), 2a (0.60 mmol), 3a
(0.01 mmol), 4a (0.01 mmol), and NH4BF4 (0.02 mmol) were combined
in toluene (6 mL) at room temperature. [b] Yield of isolated product.
1
[c] Determined by H NMR analysis. [d] Determined by HPLC analysis.
Scheme 3. The stereochemistry of the propargylic alkylated product.
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Table 2: Enantioselective propargylic alkylation of propargylic alcohols 1 with the aldehydes 2.[a]
mers (syn-5 and anti-5), we propose
transition states between the ruthe-
nium–allenylidene complex and the
enamine as shown in Scheme 7. The
bulky substituents on the pyrroli-
dine ring efficiently shield the
Re face of the favored anti-(E)-
enamine (Scheme 6).[12] For the for-
mation of syn-5 (Scheme 7a), the
Si face of enamine attacks the
Re face of allenylidene complex
leading to the carbon–carbon bond
formation. In contrast, for the for-
mation of anti-5 (Scheme 7b), the
Si face of enamine attacks the
Si face of allenylidene complex for
the carbon–carbon bond formation.
The predominant formation of syn-
5 is a result of the steric repulsion
between the phenyl group at the g-
carbon atom of the allenylidene
Entry
1
2
t
[h]
Yield
syn-6/
ee [%][d]
of 6[b] [%] anti-6[c] syn-6 anti-6
1
2
3
4
5
6
7
8
R1 =Ph (1a)
R1 =Ph (1a)
R1 =Ph (1a)
R1 =Ph (1a)
R2 =p-ClC6H4CH2 (2b) 90
90 (6j)
91 (6k)
81 (6l)
2.2:1
1.7:1
2.1:1
1.8:1
3.0:1
2.1:1
2.1:1
2.5:1
96
92
96
88
97
97
98
98
87
85
78
89
95
52
92
90
R2 =Me(CH2)4 (2c)
R2 =CyCH2 (2d)[e]
R2 =Cl(CH2)4 (2e)
90
90
120 80 (6m)
R1 =o-MeOC6H4 (1 f) R2 =p-ClC6H4CH2 (2b) 40
85 (6n)
90 (6o)
86 (6p)
91 (6q)
R1 =o-MeOC6H4 (1 f) R2 =Me(CH2)4 (2c)
R1 =o-MeOC6H4 (1 f) R2 =CyCH2 (2d)[e]
R1 =o-MeOC6H4 (1 f) R2 =Cl(CH2)4 (2e)
40
70
60
[a] Reaction conditions: 1 (0.20 mmol), 2 (0.60 mmol), 3a (0.01 mmol), 4a (0.01 mmol), and NH4BF4
(0.02 mmol) were combined in toluene (6 mL) at room temperature. [b] Yield of isolated product.
[c] Determined by H NMR analysis. [d] Determined by HPLC analysis. [e] 3-Cyclohexylpropanal. Cy=
cyclohexyl.
1
Scheme 4. The stoichiometric reaction of ruthenium–allenylidene com-
plex with an aldehyde in the presence of an amine.
ature for 90 hours and subsequent NaBH4 reduction afforded
6g in 85% yield as a mixture of two diastereoisomers [syn-6g/
anti-6g = 3.0:1; syn-6g (97% ee), anti-6g (85% ee)]. Inde-
pendently, we confirmed that no reaction occurred when the
reaction of the propargylic alcohol bearing an internal alkyne
moiety was carried out under the same reaction conditions.
These results clearly indicate that this propargylic alkylation
proceeded with ruthenium–allenylidene complexes serving as
the key reactive intermediates.[11]
Scheme 5. Reaction pathway for the propargylic alkylation of propar-
A proposed reaction pathway is shown in Scheme 5. The
initial step is the formation of the allenylidene complex B by
the reaction of propargylic alcohol 1 with 4a via the
vinylidene complex A. Subsequent attack of the enamine E,
generated in situ from aldehyde 2 and amine 3, upon the g-
carbon atom of B results in the formation of the vinylidene
complex D via the alkynyl complex C. Then, the alkylated
product 5 is formed from D by ligand exchange with another
propargylic alcohol 1. As described in our previous reports,[10]
we believe that the synergistic effect between two ruthenium
atoms in the diruthenium complexes is also quite important to
promote this catalytic reaction.
The E conformation of the enamine is energetically
favored over its Z conformation, and the large aryl and silyl
substituents at the a position of the pyrrolidine ring disfa-
vored the syn form of enamine (Scheme 6).[12] To account for
the highly enantioselective formation of both diastereoiso-
gylic alcohols with aldehydes.
Scheme 6. The conformation of enamines generated from amines and
aldehydes.
ligand and the bulky substituents in the enamine. At present,
we observed only the moderate diastereoselectivity of the
alkylated products 5, but this is the first successful example of
the enantioselective propargylation of aldehydes with prop-
argylic alcohols to give the corresponding chiral b-ethynyl
aldehydes.[13]
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Communications
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for the formation of the minor diastereoisomer.
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In summary, we have found the enantioselective prop-
argylic alkylation of propargylic alcohols with aldehydes in
the presence of a thiolate-bridged diruthenium complex and a
secondary amine as the co-catalysts to give the corresponding
propargylic alkylated products in excellent yields as a mixture
of two diastereoisomers, each with high enantioselectivity (up
to 99% ee). This catalytic reaction is considered to be a new
type of enantioselective propargylic substitution reaction,[14]
wherein the enamines generated in situ from aldehydes
enantioselectively attack the ruthenium–allenylidene com-
plexes. In the present reaction system, both the transition-
metal catalyst (ruthenium complex) and organocatalyst
(secondary amine) activate propargylic alcohols and alde-
hydes, respectively, and cooperatively work to promote the
enantioselective propargylic alkylation. We believe that the
finding described herein will open a new aspect of not only
dual catalytic reactions using both organocatalysts and
transition-metal catalysts, but also the enantioselective a-
alkylation of aldehydes.[15,16] Additional work is currently in
progress to apply this strategy to other reaction systems.
[11] For recent reviews of transition metal/allenylidene complexes,
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Received: April 30, 2010
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[13] The produced chiral b-alkynyl aldehydes can be readily con-
verted into the functionalized compounds without loss of
enantioselective purity. For a recent example, see: T. Nishimura,
T. Sawano, T. Hayashi, Angew. Chem. 2009, 121, 8201; Angew.
Chem. Int. Ed. 2009, 48, 8057.
Published online: July 13, 2010
Keywords: alkynes · homogeneous catalysis · organocatalysis ·
.
ruthenium · synthetic methods
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