Highly enantioselective catalytic alkynylation of ketones - A convenient approach to optically active propargylic alcohols

Article abstract of DOI:10.1002/adsc.200606078

The development of highly enantioselective catalysts involving Cu(OTf) ₂ and chiral camphorsulfonamides for the alkynylation of ketone is described. The influences of Lewis acids, reaction conditions and chiral ligands on the outcome of the rea

Full text of DOI:10.1002/adsc.200606078

FULL PAPERS
DOI: 10.1002/adsc.200606078
Highly Enantioselective Catalytic Alkynylation ofKetones – A
Convenient Approach to Optically Active Propargylic Alcohols
Gui Lu,a,b Xingshu Li,b Yue-Ming Li,a Fuk Yee Kwong,a and Albert S. C. Chana,*
a
Open Laboratory of Chirotechnology of the Institute of Molecular Technology for Drug Discovery and Synthesis and
Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University, Hung Hom, Kowloon,
Hong Kong, People’s Republic of China
Phone: (+852)-2766-5222; Fax: (+852)-2364-9932; e-mail: bcachan@polyu.edu.hk
School of Pharmaceutical Sciences, Sun Yat Sen University, Guangzhou, People’s Republic of China
b
Received: March 16, 2006; Accepted: June 19, 2006
Supporting information for this article is available on the WWW under http://asc.wiley-vch.de/home/.
Abstract: The development of highly enantioselec- (up to 97% ee) was obtained in the alkynylation of
tive catalysts involving Cu(OTf)2 and chiral cam- 2’-chloroacetophenone. The scope of the reaction is
G
phorsulfonamides for the alkynylation of ketone is also examined.
described. The influences of Lewis acids, reaction
conditions and chiral ligands on the outcome of the Keywords: alkynylation; asymmetric catalysis; cam-
reaction are discussed. The best enantioselectivity phorsulfonamides; organozinc compounds
Introduction
Grignard reagent) addition to some highly activated
ketones with up to 98% ee for the product, which was
Chiral tertiary alcohols are important building blocks an intermediate for efavirenz, an anti HIV drug.[10]
for organic synthesis, and the construction of such ste- Cozzi used chiral zinc-2 complex (Scheme 1) to cata-
reogenic carbon centers continues to be a considera- lyze the asymmetric alkynylation of unactivated ke-
ble challenge in organic synthesis.[1] Among the differ-
ent strategies, the nucleophilic addition of organome-
tallics (especially mild organozinc reagents) to car-
bonyl compounds is perhaps the most straightforward
and useful method to achieve this goal.
Recently, significant improvements have been
made in the asymmetric alkylation of ketones.[2]
Walsh et al. developed a bis(sulfonamide)diol ligand 1
(Scheme 1) which gave excellent results for the cata-
lytic addition of dialkylzinc to ketones.[3a] Later this
catalyst was found to be highly efficient for a broad
range of substrates including aliphatic ketones, aro-
matic ketones and conjugated enones,[3b–g] and the or-
ganozinc reagents can be either alkylzinc, arylzinc[3h,i]
or vinylzinc[3j–l] compounds. Several examples of enan-
tioselective addition of alkylzinc to a-keto esters have
also been reported.[4–8]
The enantioselective addition of alkynylzinc to ke-
tones has been less studied despite the fact that chiral
tertiary propargylic alcohols are important pharma-
ceutical intermediates and are normally difficult to
generate with high enantioselectivity using other
methodologies.[9] Tan and co-workers reported the
first stoichiometric asymmetric alkynylzinc (which
was prepared in situ from an alkynylithium or a Scheme 1.
1926
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Approach to Optically Active Propargylic Alcohols
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tones in up to 81% ee.[11] In a preliminary communi- ric addition of alkynylzinc to simple ketones, good
cation we also reported the asymmetric addition of al- enantioselectivities (92% ee) were obtained.[14] Some
kynylzinc to aromatic ketones using catalytic amount other chiral ligands 5–8 were also developed for enan-
of the chiral Cu
C
hols were obtained in high yields and up to 97%
In this paper we report the full account of our stud-
ee.[12] To the best of our knowledge, that was among ies on the development of more efficient catalyst sys-
the highest ee’s for the enantioselective addition of al- tems in the alkynylation of various ketone substrates.
kynylzinc reagents to ketones.
The scope of the reaction is also examined.
Subsequently, Katsuki and Saito demonstrated that
chiral salen ligand 4 bearing a 2’-substituted binaphth-
yl unit (Scheme 1) can serve as more efficient catalyst Results and Discussions
than 2 for the asymmetric alkynylation of aliphatic
ketones (up to 91% ee).[13]
Reaction Optimization
Recently Wang et al. used (S)-BINOL and Ti(O-
G
i-Pr)4 as the chiral catalyst for the catalytic asymmet- Effect of Lewis Acids
Our first attempts to apply the chiral Ti(O-i-Pr)4-
G
BINOL catalyst[16] (Table 1 entry 1) and a chiral het-
erobimetallic multifunctional catalyst[17] (entry 2) for
the asymmetric alkynylation of ketones were unsuc-
cessful, and no reaction was observed. The use of Car-
reira’s catalyst system[18] (entry 3) also failed to pro-
duce the desired products. The reason might lie in the
low activity of ketones towards the nucleophile under
these reaction conditions.[19] With the expectation that
the reactivity of ketones might be improved by a
stronger Lewis acid, we used Cu(OTf)2 as promoter
A
and obtained a considerable amount of the tertiary
propargylic alcohol.
Further study revealed that Cu
fonamide (3c) was a promising catalyst for this reac-
A
Scheme 2.
Table 1. Alkynylation of acetophenone using different chiral Lewis acids.[a]
Entry
1
Chiral Lewis acid
Catalyst [mol%]
20
Yield [%][b]
NR
ee [%][c]
Remarks
[21]
(R)-BINOL + Ti
G
-
2[d]
10
NR
-
3[d]
4
5
6
7
3c + Zn
3c + Cu(OTf)2
3c + [Cu(OTf)]2·toluene
3c + CuI
3c + Sc(OTf)3
3c + CuBr
G
120
10
10
10
10
10
-
-
by-product
by-product
92
84
NR
-
88 (+)
89 (+)
-
-
-
ACHTREUNG
8
10
[a]
Acetophenone:phenylacetylene:Me2Zn=0.4:1.04:1.2 (molar ratio), 08C for 48 h.
Isolated yield of the corresponding products.
The enantiomeric excess was determined by HPLC analysis of the alcohol or its derivative using a Chiralcel OD or
[b]
[c]
OD-H column.
Without using dimethylzinc.
[d]
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Gui Lu et al.
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tion. Other Lewis acids such as CuI or CuBr did not enantioselectivities or undesired by-products in the
catalyze the reaction at all, while [Cu(OTf)]2·toluene asymmetric alkynylation of ketones, the camphorsul-
AHCTREUNG
provided a similarly high selectivity as Cu
A
fonamide ligand 3a gave the desired product in 90%
yield and 82% ee (Table 3 entry 5). This preliminary
success prompted us to examine other camphorsulfon-
amide derivatives in this enantioselective reaction. It
was found that a sterically hindered ligand such as 3c
Effect of Reaction Conditions
Thorough screening experiments were performed to gave higher yields than the corresponding less hin-
find the best reaction conditions for the catalytic dered ligands, and ligand 3b with an endo-hydroxy
enantioselective alkynylation of ketones. Acetophe- group gave a very poor ee (entry 6). Similar effects
none and phenylacetylene were chosen as standard had been observed in the titanium complex-catalyzed
substrates, and some common factors such as the alkylation of ketones.
choice of solvent, substrate-to-catalyst ratio, etc. were
Sulfonamides 3f and 3g, prepared through the reac-
examined (Table 2). The enantioselectivities were tion of d-(+)-camphorsulfonyl chloride with (R)-a-
found to be quite sensitive to the solvents used. When methylbenzylamine and (S)-a-methylbenzylamine, re-
the reaction was carried out at 08C in toluene, THF, spectively, were also tested but no desired product
CH3OH, hexane, Et2O and CH2Cl2, the results ranged was obtained. This may be due to the extra steric hin-
from no reaction to high yield and high ee. CH2Cl2 drance of the imines caused by the adjacent extra ste-
was found to be the best solvent for this reaction. The reocenters. Ligands 3a and 3c were superior to 3d and
product ee increased with the increase of catalyst 3e, possibly due to the presence of a flexible CH2
loading and reached a plateau when the catalyst load- group adjacent to the imine, which may help to fix
ing reached 10 mol%. Higher catalyst loadings were the pro-chiral face of the substrate in the transition
not useful because of the poor solubility of the state and therefore result in better selectivity. The bi-
copper salt (in CH2Cl2).
sulfonamide ligand 1 failed to give a good result in
this reaction although it performed well in the alkyla-
tion of ketones. Among all the ligands tested, ligand
3c was found to give the best results.
Effect of Chiral Ligands
While chiral ligands such as binaphthol, amino alco-
hol 9, pybox 10 and sulfonamide 11 gave either poor
Table 2. Alkynylation of acetophenone under different reaction conditions.[a]
Entry
Ligand (mol%)
Solvent
Yield [%][b]
ee [%][c]
1
2
3
4
5
6
7
8
9
3a (10)
3a (10)
3a (10)
3a (10)
3a (10)
3a (10)
3c (20[d])
3c (10)
3c (5)
tetrahydrofuran
toluene
methanol
hexane
ether
dichloromethane
dichloromethane
dichloromethane
dichloromethane
dichloromethane
0
87
0
39
0
90
80
92
88
48
-
36 (+)
-
13 (+)
-
82 (+)
85 (+)
88 (+)
86 (+)
36 (+)
10
3c (1)
[a]
Acetophenone:phenylacetylene:Me2Zn=0.4:1.04:1.2 (molar ratio); 08C for 48 h.
Isolated yield of the corresponding product.
[b]
[c]
[d]
The ee was determined by HPLC analysis of the alcohol or its derivative using a Chiralcel OD or OD-H column.
A large amount of CH2Cl2 (4 mL) was used to dissolve the Cu(OTf)2.
AHCTREUNG
1928
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Approach to Optically Active Propargylic Alcohols
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Table 3. Alkynylation of acetophenone using different chiral ligands.[a]
Entry
Ligand
Yield [%][b]
ee [%][c]
1
2
3
4
(R)-BINOL
ND
ND
29
-
8
3
A
G
racemic product
-
U
5
6
7
8
3a
3b
3c
3d
3e
3f
3g
90
49
92
32
51
-
82
13
88
61
65
-
9
10
11
12
-
50
-
13
(R,R)-1
[a]
Acetophenone:phenylacetylene:Me2Zn=0.4:1.04:1.2 (molar ratio), 08C for 48 h.
Isolated yield of the corresponding product.
The ee was determined by HPLC analysis of the alcohol or its derivative using a Chiralcel OD or OD-H column.
[b]
[c]
Scope ofSubstrates
Aromatic Ketones
kynylation of 2’-chloroacetophenone (entry 5). It is
possible that the steric hindrance of the ortho-sub-
stituent restricted the orientation of the substrate and
thus resulted in higher enantioselectivities for the al-
The alkynylation of different aromatic ketones was kynylation of such ketones. Increasing the size of the
studied using Cu(OTf)2 and ligand 3c as catalyst. substituent at the ortho-position of the substrate led
AHCTREUNG
Without exception, all substrates presented in Table 4 to lower yields, for example, 65% for 2’-bromoaceto-
were alkynylated to the corresponding tertiary prop- phenone (entry 4), 94% for 2’-chloroacetophenone
argylic alcohols with good to excellent enantioselec- (entry 5) and 49% for 2’-methylacetophenone
tivities.
ortho-Substituted aromatic ketones were found to
(entry 7).
The alkynylation product of 4’-ferrocenylacetophe-
give a higher enantioselectivity. For example, 2’- none was isolated in high yield and up to 90% ee
methyl-, 2’-fluoro-, 2’-chloro-, and 2’-bromoacetophe- (Table 4 entry 17), whereas the alkynylation of acetyl-
none all gave excellent ees (Table 4, entries 3–7). The ferrocene gave an unidentified by-product(s). This
best enantioselectivity (97%) was obtained in the al- can be explained by the strong electron-withdrawing
Adv. Synth. Catal. 2006, 348, 1926 – 1933
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Gui Lu et al.
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Table 4. Enantioselective addition of phenylacetylene to various aromatic ketones.[a]
Entry
R1/R2
Ligand
Yield [%][b]
ee [%][c]
1
2
3
4
5
6
7
8
Ph/Me
Ph/Me
3a
3c
3a
3c
3c
3c
3c
3c
3c
3c
3c
3c
3c
3c
3c
3c
3c
90
92
39
65
94
91
49
80
75
72
83
91
77
82
75
57
62
82 (+)
88 (+)
87 (À)
96 (À)
97 (À)
96 (À)
96 (À)
82 (+)
91 (+)
71 (+)
86 (+)
70 (À)
92 (+)
93 (+)
85 (+)
71 (+)
90 (+)
2-BrC6H4/Me
2-BrC6H4/Me
2-ClC6H4/Me
2-FC6H4/Me
2-MeC6H4/Me
3-BrC6H4/Me
4-BrC6H4/Me
4-ClC6H4/Me
3-MeC6H4/Me
3-CF3C6H4/Me
4-MeC6H4/Me
4-CF3C6H4/Me
2-Naphthyl/Me
Ph/Et
9
10
11
12
13
14
15
16
17
4-FerrocenylC6H4/Me
[a]
3a or 3c as chiral ligand; ketone:ligand:Cu(OTf)2:Me2Zn=0.4:0.04:0.04:1.2 (molar ratio), CH2Cl2 as solvent; 08C for
A
48 h.
[b]
[c]
Isolated yield of the corresponding product.
Enantiomeric excess was determined by HPLC analysis of the alcohol or its derivative using a Chiralcel OD or OD-H
column.
properties of the ferrocenyl groups, which strongly ac- different terminal alkynes. Most of the tertiary prop-
tivate the acetylferrocene substrate and therefore argylic alcohols were obtained in good chemical
caused other side reactions.
yields, yet the ees were strongly dependent on the nu-
cleophilic property of the alkyne and the steric hin-
drance of the ketone substrate.
Aliphatic Ketones or Alkynes
Cyclohexyl phenyl ketone was converted to the cor-
responding tertiary propargylic alcohol in low yield
Table 5 summarizes some typical results of the alky- (20%) and low enantioselectivity (nearly racemic).
nylation of various aliphatic or aromatic ketones with Cyclopropyl phenyl ketone failed to react. The alky-
Table 5. Reaction of various ketones with alkynes under optimized reaction conditions.[a]
Entry
Ketone
Alkyne
Yield [%][b]
ee [%][c]
ꢀ
1
2
3
4
5
c-C3H5COCH3
Ph-C C-H
Ph-C C-H
93
90
89
81
76
5
ꢀ
A
88
35
60
54
ꢀ
PhCH2CH2COCH3
PhCOCH3
PhCOCH3
Ph-C C-H
ꢀ
c-C3H5-C C-H
ꢀ
(CH3)3Si-C C-H
[a]
3c as chiral ligand; ketone:ligand:Cu(OTf)2:Me2Zn=0.4:0.04:0.04:1.2 (molar ratio), CH2Cl2 as solvent; 08C for 48 h.
A
[b]
[c]
Isolated yield of the corresponding products.
Enantiomeric excess was determined by HPLC analysis of the alcohol or its derivative using a Chiralcel OD or OD-H
column.
1930
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Approach to Optically Active Propargylic Alcohols
FULL PAPERS
nylation of 2-tetralone also gave a racemic product.
These results might be due to the large steric hin-
drance of these substrates.
The reactions of aliphatic terminal alkynes with
acetophenone gave a low enantioselectivity (54% ee
for trimethylsilylacetylene and 60% ee when cyclo-
propyl acetylene was used, Table 5 entries 4 and 5),
possibly due to the different electronic properties of
the aliphatic alkynes. Aliphatic ketones were general-
ly less selective although results comparable to those
Scheme 4.
of the aryl ketones had been obtained for the reaction 3c as catalyst: 95% yield, 85% ee) than that for the
of 3-methyl-2-butanone (Table 5 entry 2), which might cyclic unsaturated ketones such as 2-cyclohexenone
be partially related with the suitable hindrance and (3c as catalyst: 92% yield, 15% ee).
orientation of the isopropyl group.
Our preliminary study indicates that the mechanism
of the camphorsulfonamide-mediated reaction is quite
similar to that proposed by Noyori et al. in the sulfon-
amide-catalyzed asymmetric conjugate addition of
enones.[20] Further experimental results are needed,
Heteroaromatic Ketones
When 3c was used to catalyze the alkynylzinc addition however, before a mechanistic model can be proposed
to 3-acetylpyridine, the product was obtained with with any certainty.
good yield (81%) but with no enantioselectivity. To
improve the enantioselectivity of the reaction, other
chiral catalysts were also tested. The study showed Conclusions
that BINOL and (R,S,R)-9 gave less than 30% enan-
tiomeric excess, while (R,R)-10, (R,R)-12 and (R)-13 In conclusion, we have demonstrated that Cu(OTf)2
A
gave either racemic product or even no reaction at all and commercially available camphorsulfonamide li-
(Scheme 3). The poor enantioselectivity might be due gands catalyzed the alkynylation of ketones with high
to the strong coordination of the nitrogen atom in the yields and excellent enantioselectivities. The influence
substrate to Cu
ACHTREUNG
both).
To further explore the scope of the substrates, we scope of the reaction has also been examined.
also investigated the effectiveness of catalyst 3c in the
asymmetric alkynylation of unsaturated ketones. It
was found that the catalyst system Cu(OTf)2/3c tends
A
Experimental Section
to catalyze the alkynylation of the C=O double bond
preferentially over the coexisting C=C bond
(Scheme 4). The results revealed that high yields were
obtained for 1,2-addition reactions of both cyclic and
acyclic a,b-unsaturated ketones, and the enantioselec-
tivity for the alkynylation of acyclic unsaturated ke-
tones, such as trans-4-phenyl-3-buten-2-one was sub-
General Considerations
All experiments were carried out under a nitrogen atmos-
phere. Unless otherwise stated, commercial reagents pur-
chased from either Acros or Aldrich chemical companies
were used without further purification. The reactions were
carried out in solvents distilled from standard drying agents.
stantially higher (3a as catalyst: 93% yield, 59% ee; Phenylacetylene and ketones were freshly distilled under
Scheme 3.
Adv. Synth. Catal. 2006, 348, 1926 – 1933
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1931

Gui Lu et al.
FULL PAPERS
normal or reduced pressure before use. 1H NMR spectra
were recorded on a Varian (500 MHz) spectrometer and the
spectra were referenced internally to the residual proton
resonance in CDCl3 (d=7.26), or with tetramethylsilane
(TMS, d=0.00) as the internal standard. Chemical shifts
were reported as parts per million (ppm) in the d scale
downfield from TMS. 13C NMR spectra were recorded on a
Varian 500 spectrometer and referenced to CDCl3 (d=77.0).
Thin layer chromatography was performed on Merck pre-
coated silica gel 60 F254 plates. Silica gel (Merck, 230–400
mesh) was used for flash column chromatography. HPLC
analyses were conducted on a Waters 600 instrument using
Chiralcel columns (0.46 cm diameter × 25 cm length) col-
umns. The absolute configurations of products were deter-
mined based on the comparison of HPLC traces and/or the
direction of optical rotation with known compounds.
C. Carcia, P. J. Walsh, Synlett 2004, 749–760; c) S.-J.
Jeon, P. J. Walsh, J. Am. Chem. Soc. 2003, 125, 9544–
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General Procedure for the Nucleophilic Addition of
Alkynes to Ketones Catalyzed by Copper-
Camphorsulfonamide Catalyst
[5] E. F. DiMauro, M. C. Kozlowski, J. Am. Chem. Soc.
2002, 124, 12668–12669.
[6] K. Funabashi, M. Jachmann, M. Kanai, M. Shibasaki,
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A CH2Cl2 solution (2.0 mL) of sulfonamide ligand 3c
(14.92 mg, 0.04 mmol) and copper(II) triflate (14.79 mg,
0.04 mmol) was stirred at room temperature for 30 min to
prepare the copper complex. Phenylacetylene (114 mL,
1.04 mmol) and a 2.0M solution of dimethylzinc in toluene
(0.6 mL, 1.2 mmol), were added to a dry flask at 08C under
N2 with stirring for 15 min. The copper complex was added
to the flask containing ZnMe2 and phenylacetylene via a sy-
ringe and the homogeneous solution was stirred at 08C for
30 min before acetophenone (46.8 mL, 0.4 mmol) was added.
The mixture was allowed to stir at 08C for 48 h. The reac-
tion was quenched with 2.0 mL of 5% HCl solution. The
product was extracted with ethyl acetate (3×2 mL) and
dried with Na2SO4. The compound was purified via flash
chromatography (silica gel) using 10% ethyl acetate in
hexane as eluent. The enantiomeric excess was determined
by HPLC analysis on a Chiralcel OD or OD-H column.
[7] B. Jiang, Z. Chen, X. Tang, Org. Lett. 2002, 4, 3451–
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[8] M. W. Fennie, E. F. DiMauro, E. M. O’Brien, V. Anna-
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[9] For reviews on asymmetric alkynylation see a) L. Pu,
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[12] G. Lu, X. S. Li, X. Jia, W. L. Chan, A. S. C. Chan,
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[13] B. Saito, T. Katsuki, Synlett 2004, 1557–1560.
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Acknowledgements
We thank the Hong Kong Research Grants Council (project
number PolyU 5001/03P), the University Grants Committee
Area of Excellence Scheme in Hong Kong (Project AoE P/
10–01) and the Hong Kong Polytechnic University ASD
Fund for financial support of this study.
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Adv. Synth. Catal. 2006, 348, 1926 – 1933
© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.asc.wiley-vch.de
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