Lithium acetylides as alkynylating reagents for the enantioselective alkynylation of ketones catalyzed by lithium binaphtholate

Article abstract of DOI:10.1039/c1cc10734h

Chiral lithium binaphtholate effectively catalyzed the enantioselective alkynylation of ketones using lithium acetylide as an alkynylating agent. This is the first example of the catalytic enantioselective addition of lithium acetylide to carbonyl compoun

Full text of DOI:10.1039/c1cc10734h

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COMMUNICATION
Lithium acetylides as alkynylating reagents for the enantioselective
alkynylation of ketones catalyzed by lithium binaphtholatew
Kana Tanaka,a Kenji Kukita,a Tomonori Ichibakase,a Shunsuke Kotanib and Makoto Nakajima*a
Received 8th February 2011, Accepted 18th March 2011
DOI: 10.1039/c1cc10734h
Chiral lithium binaphtholate effectively catalyzed the enantio-
selective alkynylation of ketones using lithium acetylide as an
alkynylating agent. This is the first example of the catalytic
enantioselective addition of lithium acetylide to carbonyl
compounds without the aid of other metal sources.
lithium acetylide is reactive toward the carbonyl compounds
even in the absence of a catalyst. Here we report the first
example of employing lithium acetylide in catalytic enantio-
selective alkynylation without the aid of other metals, using
lithium binaphtholate as a catalyst.
Optically active propargylic alcohols are useful and versatile
building blocks for the synthesis of a wide range of natural
products and pharmaceuticals. The enantioselective alkynyl-
ation of carbonyl compounds is an important process for the
preparation of chiral propargylic compounds. During this
process, C–C bonds are formed with concomitant creation
of a stereogenic center.1
The first enantioselective alkynylation of carbonyl compounds
was reported by Mukaiyama et al., who employed lithium
acetylide as an alkynylating reagent using 4 equivalents of a
chiral amino alkoxide ligand.2 The catalytic process for the
enantioselective alkynylation was developed by Niwa and
Soai, who employed zinc acetylide as an alkynylating reagent
with an amino alcohol as a catalyst.3 Since then, several
catalytic enantioselective alkynylations were reported using
various metal acetylides, including in situ generation, in the
presence of a variety of metal catalysts.4–7 However, there is a
limited number of successful reports for the alkynylation of
ketones because of their low reactivities.1c,e,f,8 We have previously
reported the enantioselective alkynylation of aldehydes and
ketones with trimethoxysilylalkyne9 using lithium binaphtholate
as a catalyst.10 While investigating the reaction mechanism, we
were surprised to find that a high enantioselectivity was
observed in the reaction of lithium acetylide in the presence
of catalytic amounts of lithium binaphtholate. In the literature,2
excess amounts of the chiral ligand were required for the
asymmetric addition of lithium acetylide to carbonyl com-
pounds in order to achieve high enantioselectivities, because
ð1Þ
First we investigated the alkynylation of benzaldehyde (2a)
with lithium phenylacetylide, generated in situ from phenyl-
acetylene (3a) and butyllithium in the presence of lithium
diphenylbinaphtholate, in situ generated from the corresponding
binaphthol (1) and butyllithium (eqn (1)) at 0 1C. No asymmetric
induction was observed in toluene (89% yield, 1% ee),
however, a significant enantioselectivity was observed in
THF (85% yield, 33% ee). As the reaction proceeded in the
absence of a catalyst, our result shows that the catalyst
increased the reactivity of lithium acetylide toward the carbonyl
carbon. In order to reduce the non-catalytic pathway, we
then investigated the reaction of the less reactive substrate,
acetophenone (2b).
Although no enantioselectivity was again observed in
toluene (72% yield, 3% ee), good enantioselectivity was
achieved in THF at 0 1C (67% yield, 76% ee). After screening
the ligands and reaction conditions,11,12 we found that the
corresponding adduct was obtained in high chemical and
optical yields at ꢀ78 1C using the catalyst prepared from 1
and BuLi (96% yield, 93% ee, Table 1, entry 1).
a Graduate School of Pharmaceutical Sciences, Kumamoto University,
5-1 Oe-honmachi, Kumamoto, Japan.
With the optimal conditions and catalyst in hand,13 we next
investigated the reaction of acetophenone (2b) with various
acetylenes. Acetylenes 3b or 3c gave high selectivities (entries 2
and 3), but acetylene 3d with a bulky substituent at the
opposite side of the acetylene decreased the selectivity (entry 4).
We then investigated the phenylethynylation of various ketones
using phenylacetylene (3a) as an alkynylating reagent.
E-mail: nakajima@gpo.kumamoto-u.ac.jp; Fax: +81 96 362 7692;
Tel: +81 96 371 4680
b Priority Organization for Innovation and Excellence, Kumamoto
University, 5-1 Oe-honmachi, Kumamoto, Japan
w Electronic supplementary information (ESI) available: Experimental
details for the enantioselective alkynylation and determination of
absolute configurations of 4ca, 4fa, and 4ga, spectroscopic data for
new compounds, and HPLC data for the alkynylated products. See
DOI: 10.1039/c1cc10734h
c
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Table 1 Enantioselective alkynylation of ketones catalyzed by Li salt of 1
Entry
Ketone (R1, R2)
Alkyne (R3)
Product
%Yielda
%eeb,c
1
2
3
4
5
6
7
8
2b (Ph, Me)
2b (Ph, Me)
2b (Ph, Me)
2b (Ph, Me)
3a (Ph)
3b (Bu)
3c (BnOCH2)
3d (tBu)
3a (Ph)
3a (Ph)
3a (Ph)
3a (Ph)
3a (Ph)
3a (Ph)
3a (Ph)
3a (Ph)
3a (Ph)
3a (Ph)
4ba
4bb
4bc
4bd
4ca
4da
4ea
4fa
4ga
4ha
4ia
96
89
97
88
93
99
91
99
93
95
93
89
94
96
93
87
86
55
73
7
57
39
88
92
92
91
85
87
2c (Ph, Et)
2d (Ph, iPr)
2e (cHex, Me)
2f (PhCH2CH2, Me)
2g (4-MeC6H4, Me)
2h (4-MeOC6H4, Me)
2i (3,4,5-(MeO)3C6H2, Me)
2j (4-FC6H4, Me)
2k (2-Naph, Me)
2l (3-Py, Me)
9
10
11
12
13
14
4ja
4ka
4la
a
b
c
Isolated yields. For the reaction conditions, see ref. 13. Determined by chiral HPLC. For the absolute configurations of the product,
see ref. 14.
Propiophenone 2c gave a decreased selectivity (entry 5), and
isobutyrophenone 2d gave an almost racemic product (entry 6),
suggesting that the bulkiness of the aliphatic group has an
inferior effect on selectivity. Aliphatic ketones 2e and 2f gave
lower selectivities than acetophenone, but again the difference
of steric bulkiness between the two substituents around ketone
plays an important role in enantiocontrol (entries 7 and 8). An
electron-donating or -deficient substituent on the benzene ring
of acetophenone did not affect the selectivity. Most acetophenone
derivatives gave results similar to that of acetophenone itself
(entries 9–13).
Asymmetry, 2009, 20, 1837–1841; (d) J.-C. Zhong, S.-C. Hou,
Q.-H. Bian, M.-M. Yin, R.-S. Na, B. Zheng, Z.-Y. Li, S.-Z. Liu
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5 Ti catalysts with alkynylzinc: (a) G. Gao, D. Moore, R.-G. Xie and
L. Pu, Org. Lett., 2002, 4, 4143–4146; (b) X.-S. Li, G. Lu,
W. H. Kwok and A. S. C. Chan, J. Am. Chem. Soc., 2002, 124,
¨
12636–12637; (c) H. Koyuncu and O. Dogan, Org. Lett., 2007, 9,
3477–3479.
6 Metal triflate catalysts: (a) M. Yamaguchi, A. Hayashi and
T. Minami, J. Org. Chem., 1991, 56, 4091–4092;
(b) D. E. Frantz, R. Fassler and E. M. Carreira, J. Am. Chem.
¨
¨
Soc., 1999, 121, 11245–11246; (c) D. E. Frantz, R. Fassler and
E. M. Carreira, J. Am. Chem. Soc., 2000, 122, 1806–1807;
(d) N. K. Anand and E. M. Carreira, J. Am. Chem. Soc., 2001,
123, 9687–9688; (e) M. Yamashita, K. Yamada and K. Tomioka,
Adv. Synth. Catal., 2005, 347, 1649–1652.
7 Other catalyses: (a) E. J. Corey and K. A. Cimprich, J. Am. Chem.
Soc., 1994, 116, 3151–3152; (b) T. Ooi, T. Miura, K. Ohmatsu,
A. Saito and K. Maruoka, Org. Biomol. Chem., 2004, 2,
3312–3319; (c) R. Takita, Y. Fukuta, R. Tsuji, T. Ohshima and
M. Shibasaki, Org. Lett., 2005, 7, 1363–1366; (d) R. Takita,
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Our protocol could be applied to the asymmetric synthesis
of bioactive compounds. Using the above conditions, the
reaction of 3-acetylpyridine 2l and phenylacetylene 3a gave
the product 4la, which has antifungal activity,15 in high
chemical and optical yields. These yields were the highest of
those reported for the enantioselective alkynylation of
acetylpyridines.
In summary, we have developed an enantioselective
alkynylation of ketones using lithium acetylide in the presence
of chiral lithium binaphtholate as a catalyst. This is the first
example of catalytic enantioselective addition of lithium acetylide
to carbonyl compounds without the aid of other metal sources.
Studies on the mechanism as well as the design of chiral
catalysts to further enhance enantioselectivity are currently
in progress.
8 Selected examples for the enantioselective alkynylation of ketones:
(a) A. S. Thompson, E. G. Corley, M. F. Huntington and E. J.
J. Grabowski, Tetrahedron Lett., 1995, 36, 8937–8940; (b) L. Tang,
C.-y. Chen, R. D. Tillyer, E. J. J. Grabowski and P. J. Reider,
Angew. Chem., Int. Ed., 1999, 5, 711–713; (c) P. G. Cozzi, Angew.
Chem., Int. Ed., 2003, 42, 2895–2898; (d) G. Lu, X. Li, X. Jia,
W. L. Chan and A. S. C. Chan, Angew. Chem., Int. Ed., 2003, 42,
5057–5058; (e) B. Saito and T. Katsuki, Synlett, 2004, 1557–1560;
(f) P. G. Cozzi and S. Alesi, Chem. Commun., 2004, 2448–2449;
(g) Y. Zhou, R. Wang, Z. Xu, W. Yan, L. Liu, Y. Kang and Z. Han,
Org. Lett., 2004, 6, 4147; (h) L. Liu, R. Wang, Y.-F. Kang, C. Chen,
X.-Q. Xu, Y.-C. Zhou, M. Ni, H.-Q. Cai and M.-Z. Gong, J. Org.
Chem., 2005, 70, 1084–1086; (i) G. Lu, X. Li, Y.-M. Li, F. Y. Kwong
and A. S. C. Chan, Adv. Synth. Catal., 2006, 348, 1926–1933;
(j) C. Chan, L. Hong, Z.-Q. Xu, L. Liu and R. Wang, Org. Lett.,
2006, 8, 2277–2280; (k) K. Pathak, A. P. Bhatt, S. H. R. Abdi,
R. I. Kureshy, N.-U. H. Khan, I. Ahmad and R. V. Jasra, Chirality,
2007, 19, 82–88; (l) R. Motoki, M. Kanai and M. Shibasaki, Org.
Lett., 2007, 9, 2997–3000.
Notes and references
1 (a) L. Pu, Tetrahedron, 2003, 59, 9873–9886; (b) P. G. Cozzi,
R. Hilgraf and N. Zimmermann, Eur. J. Org. Chem., 2004,
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Trost and A. H. Weiss, Adv. Synth. Catal., 2009, 351, 963–983.
2 T. Mukaiyama, K. Suzuki, K. Soai and T. Sato, Chem. Lett., 1979,
447–448.
9 (a) K. Tanaka, T. Ueda, T. Ichibakase and M. Nakajima, Tetra-
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T. Ichibakase, Y. Orito and M. Nakajima, Tetrahedron, 2010,
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3 S. Niwa and K. Soai, J. Chem. Soc., Perkin Trans. 1, 1990,
937–943.
4 Amino alcohol catalysts with alkynylzinc: (a) B. M. Trost,
A. H. Weiss and A. J. von Wangelin, J. Am. Chem. Soc., 2006,
128, 8–9; (b) S. Dahmen, Org. Lett., 2004, 6, 2113–2116;
(c) P.-Y. Wu, H.-L. Wu, Y.-Y. Shen and B.-J. Uang, Tetrahedron:
10 Recent examples of using lithium binaphtholate as a catalyst:
(a) R. Schiffers and H. B. Kagan, Synlett, 1997, 1175–1178;
(b) I. P. Holmes and H. B. Kagan, Tetrahedron Lett., 2000, 41,
7453–7456; (c) M. Nakajima, Y. Orito, T. Ishizuka and
S. Hashimoto, Org. Lett., 2004, 6, 3763–3765; (d) M. Hatano,
T. Ikeno, T. Miyamoto and K. Ishihara, J. Am. Chem. Soc., 2005,
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127, 10776–10777; (e) Y. Orito, S. Hashimoto, T. Ishizuka and
M. Nakajima, Tetrahedron, 2006, 62, 390–400; (f) T. Ichibakase,
Y. Orito and M. Nakajima, Tetrahedron Lett., 2008, 49, 4427–4429;
(g) M. Hatano, T. Ikeno, T. Matsumura, S. Torii and K. Ishihara,
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and K. Ishihara, J. Am. Chem. Soc., 2010, 132, 56–57.
THF (1.3 mL) at ꢀ78 1C. To the mixture, acetophenone (2b)
(56 mg, 0.47 mmol) in THF (0.5 mL) was added dropwise at the same
temperature and the solution was stirred for 12 h. The reaction was
quenched with NH4Cl sat. aq. and the mixture was extracted by
AcOEt. The organic layer was washed with NaHCO3 and brine.
After drying over Na2SO4, the solvent was removed and the residue
was purified by silica gel column chromatography (hexane/CH2Cl2 =
1/1), affording 4ba (100 mg, 96%) as an oil. The ee was determined by
chiral HPLC (Daicel OD-H) to be 93% ee.
11 Chemical yield and enantioselectivities using binaphthols with
other substituents on the 3,30-position, H: 90%, 2% ee; Me:
94%, 15% ee; Br: 78%, 17% ee.
12 Equivalents of BuLi and alkyne affected chemical yields but not
enantioselectivities.
13 The representative procedure for the enantioselective alkynylation:
under an Ar atmosphere, BuLi (1.65 M in hexane, 0.57 mL,
0.94 mmol) was added to the solution of binaphthol 1 (20.7 mg,
0.047 mmol) and phenylacetylene (3a) (0.10 mL, 0.94 mmol) in
14 The absolute configuration of 4ba was determined by comparison
of [a]D data with ref. 9b. The absolute configurations of 4ca, 4fa,
and 4ga were determined by the derivatization to the known
methyl esters via reduction to olefin and the following ozonolysis.
15 A. Arnoldi, E. Betto, G. Farina, A. Formigoni, R. Galli and
A. Griffini, Pestic. Sci., 1982, 13, 670–678.
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5616 Chem. Commun., 2011, 47, 5614–5616
This journal is The Royal Society of Chemistry 2011