Enantioselective alkynylation of ketones with trimethoxysilylalkynes using lithium binaphtholate as a catalyst

Article abstract of DOI:10.1016/j.tetlet.2010.02.084

Chiral lithium 3,3′-diphenylbinaphtholate successfully catalyzed the alkynylation of ketone with trimethoxysilylalkyne, affording chiral tertiary propargylic alcohols in high chemical yields and high enantioselectivities. The present reaction could be extended to the alkynylation of acetylpyridine, which afforded a biologically active pyridyl propargylic alcohol in good enantioselectivity.

Full text of DOI:10.1016/j.tetlet.2010.02.084

Tetrahedron Letters 51 (2010) 2168–2169
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Enantioselective alkynylation of ketones with trimethoxysilylalkynes
using lithium binaphtholate as a catalyst
*
Kana Tanaka, Tomohiro Ueda, Tomonori Ichibakase, Makoto Nakajima
Graduate School of Pharmaceutical Sciences, Kumamoto Universtiy, Kumamoto 862-0973, Japan
a r t i c l e i n f o
a b s t r a c t
Chiral lithium 3,30-diphenylbinaphtholate successfully catalyzed the alkynylation of ketone with trim-
ethoxysilylalkyne, affording chiral tertiary propargylic alcohols in high chemical yields and high enanti-
oselectivities. The present reaction could be extended to the alkynylation of acetylpyridine, which
afforded a biologically active pyridyl propargylic alcohol in good enantioselectivity.
Ó 2010 Elsevier Ltd. All rights reserved.
Article history:
Received 28 January 2010
Revised 10 February 2010
Accepted 15 February 2010
Available online 18 February 2010
Chiral tertiary propargylic alcohols are important building
blocks for the synthesis of biologically active compounds.1 The
enantioselective alkynylation of ketones is one of the most reliable
methods for the synthesis of these compounds.2 The alkynylation
of aldehydes has been widely investigated,3 however, there is a
limited number of successful reports for the alkynylation of ke-
tones because of their low reactivities.4 Since the first report on
the enantioselective alkynylation of ketones using an amino alco-
hol as a catalyst, alkynylzinc compounds5 were most frequently
used as intermediates for the alkynylations of ketones.6–9
We initially investigated the alkynylation of acetophenone with
trimethoxy(phenylethynyl)silane.13 The dilithium salt of unsubsti-
tuted binaphthol14 was found to promote the alkynylation in THF
at rt, albeit in low chemical yield and enantioselectivity (24% yield,
10% ee). Screening of binaphthol derivatives revealed that the
introduction of phenyl groups to 3 and 30-positions of the binaph-
thol catalyst dramatically increased both the chemical yield and
enantioselectivity.15
After slight modification to optimize the reaction conditions, we
investigated the alkynylation of various ketones using dilithium
salt of 3,30-diphenylbinaphthol (Eq. 1) and the results are shown
in Table 1.16 Similar enantioselectivities and chemical yields were
obtained with 40-substituted acetophenones (entries 1–5). Propio-
phenone gave decreased selectivity (entry 6) and isobutyrophe-
none gave almost racemic product (entry 7), which suggests that
the selectivity of the reaction decreases with increasing bulkiness
of the aliphatic group on the acetophenone derivatives. Aliphatic
ketones gave better chemical yield than acetophenone, but with
Ph
OLi
OLi
ð1Þ
OH
O
(MeO) Si
3
Ph
(10 mol %)
THF, 0ºC
1
R
1
2
+
2
R
R
Ph
R
Ph
Trialkoxysilylalkynes developed by Scheidt represent a novel
class of alkynyl nucleophiles that react with carbonyl com-
pounds.10 Upon activation with alkoxide bases they form hyperva-
lent silicates11 that react with carbonyl compounds. The reactivity
of the trialkoxysilylalkynes is sufficiently high to promote a nucle-
ophilic addition to ketones in high yields. We have already re-
ported that trimethoxysilyl enol ethers were activated by
dilithium salts of binaphthols to react with aldehydes affording al-
dol adducts in high chemical yields and high enantioselectivities.12
In our pursuit to develop a new enantioselective reaction of trime-
thoxysilyl compounds, herein we report the alkynylation of ke-
tones with trimethoxysilylalkynes catalyzed by dilithium salts of
binaphthol derivatives.
Table 1
Enantioselective alkynylation of ketone (R1COR2) with trimethoxy(phenyethy-
nyl)silane catalyzed by dilithium diphenylbinaphtholatea
Entry
R1, R2
Yieldb (%)
ee %c
1d
2
3
4
5
6
7
8
9
Ph, Me
64 (81)
61
71
67
63
82 (82)
81
72
79
75
4-MeOC6H4, Me
4-NO2C6H4, Me
4-FC6H4, Me
4-CF3C6H4, Me
Ph, Et
77
65
61
8
i
Ph, Pr
PhCH2CH2, Me
92
74
64
41
52
43
cHex, Me
10
tBu, Me
a
b
c
Silylalkyne 1.5 equiv, catalyst 10 mol %. See representative procedure in Ref. 16.
Isolated yields.
Determined with chiral HPLC (Daicel chiralcel OD-H).
Data in parentheses: silylalkyne 3 equiv.
* Corresponding author. Tel.: +81 96 371 4680; fax: +81 96 362 7692.
E-mail address: nakajima@gpo.kumamoto-u.ac.jp (M. Nakajima).
d
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.02.084

K. Tanaka et al. / Tetrahedron Letters 51 (2010) 2168–2169
2169
2. The alkylation of ynones is a less reliable alternative method, because the
unstable ynones are prone to decomposition or isomerization.
3. (a) Pu, L. Tetrahedron 2003, 59, 9873; (b) Lu, G.; Li, Y.-M.; Li, X.-S.; Chan, A. S. C.
Coord. Chem. Rev. 2005, 249, 1736.
4. (a) Ramón, D. J.; Yus, M. Angew. Chem., Int. Ed. 2004, 43, 284; (b) Riant, O.;
Hannedouche, J. Org. Biomol. Chem. 2007, 5, 873.
5. (a) Thompson, A. S.; Corley, E. G.; Huntington, M. F.; Grabowski, E. J. J.
Tetrahedron Lett. 1995, 36, 8937; (b) Tang, L.; Chen, C.-y.; Tillyer, R. D.;
Grabowski, E. J. J.; Reider, P. J. Angew. Chem., Int. Ed. 1999, 5, 711; (c) Jiang, B.;
Chen, Z.; Tang, X. Org. Lett. 2002, 4, 3451; (d) Cozzi, P. G. Angew. Chem., Int. Ed.
2003, 42, 2895; (e) Saito, B.; Katsuki, T. Synlett 2004, 1557; (f) Kang, Y.-F.; Liu,
L.; Wang, R.; Zhou, Y.-F.; Yan, W.-J. Adv. Synth. Catal. 2005, 347, 243; (g) Wang,
Q.; Zhang, B.; Hu, G.; Chen, C.; Zhao, Q.; Wang, R. Org. Biomol. Chem. 2007, 5,
1161.
Ph
OLi
OLi
OH
Me
O
(MeO)3Si
+
Ph
(10 mol %)
THF, 0ºC
Py
Py
Me
R
R
R = Ph
3-Pyridyl: 71% yield, 75% ee
4-Pyridyl: 80% yield, 75% ee
6. Cu catalysts: (a) Lu, G.; Li, X.; Jia, X.; Chan, W. L.; Chan, A. S. C. Angew. Chem., Int.
Ed. 2003, 42, 5057; (b) Liu, L.; Wang, R.; Kang, Y.-F.; Cai, H.-Q.; Chen, C. Synlett
2006, 1245; (c) Lu, G.; Li, X.; Li, Y.-M.; Kwong, F. Y.; Chen, A. S. C. Adv. Synth.
Catal. 2006, 348, 1926.
R = CH2OCH2Ph
3-Pyridyl: 52% yield, 66% ee
4-Pyridyl: 59% yield, 60% ee
7. Ti catalysts: (a) Cozzi, P. G.; Alesi, S. Chem. Commun. 2004, 2448; (b) Zhou, Y.;
Wang, R.; Xu, Z.; Yan, W.; Liu, L.; Kang, Y.; Han, Z. Org. Lett. 2004, 6, 4147; (c)
Forrat, V. J.; Ramón, D. J.; Yus, M. Tetrahedron: Asymmetry 2005, 16, 3341.
8. Al catalyst: Liu, L.; Wang, R.; Kang, Y.-F.; Chen, C.; Xu, X.-Q.; Zhou, Y.-C.; Ni, M.;
Cai, H.-Q.; Gong, M.-Z. J. Org. Chem. 2005, 70, 1084.
9. Other metal catalysts: (a) Takita, R.; Fukuta, Y.; Tsuji, R.; Ohshima, T.; Shibasaki,
M. Org. Lett. 2005, 7, 1363; (b) Motoki, R.; Kanai, M.; Shibasaki, M. Org. Lett.
2007, 9, 2997; (c) Dhondi, P. K.; Carberry, P.; Choi, L. B.; Chisholm, J. D. J. Org.
Chem. 2007, 72, 9590.
10. Lettan, R. B.; Scheidt, K. A. Org. Lett. 2005, 7, 3227.
11. Orito, Y.; Nakajima, M. Synthesis 2006, 1391.
12. (a) Ichibakase, T.; Orito, Y.; Nakajima, M. Tetrahedron Lett. 2008, 49, 4427; (b)
Nakajima, M.; Orito, Y.; Ishizuka, T.; Hashimoto, S. Org. Lett. 2004, 6, 3763.
13. Trimethoxylsilylalkyne: (a) Chmielecka, J.; Chojnowski, J.; Eaborn, C.; Stanczyk,
Scheme 1.
lower selectivities (entries 8–10). Increasing the number of equiv-
alents of alkyne provided a better chemical yield with no reduction
of selectivity (entry 1).
A number of pyridyl propargylic alcohol derivatives are known
to have interesting biological activities.17 However, there are no
successful results for the enantioselective alkynylation of acetyl-
pyridines because the basic nitrogen atoms in the pyridine moiety
deactivate the chiral Lewis acid catalysts. Because our catalyst is
basic, we thought that our protocol could be applied to the alkyny-
lation of acetylpyridine. The addition of phenylethyne or ben-
zyloxypropyne to acetylpyridine gave the corresponding alcohols
in good chemical yield and enantioselectivity (Scheme 1). These re-
sults represent the highest chemical yields and enantioselectivities
reported to date for the alkynylation of acetylpyridines.18
Herein we reported the first example of an enantioselective alk-
ynylation of ketones with trialkoxysilylalkyne catalyzed by chiral
bases. These results demonstrate the synthetic utility of our cata-
lytic system for the synthesis of optically active tertiary propargy-
lic alcohols as building blocks for biologically active compounds.19
Further studies to design to enhance the enantioselectivity and to
explore the reaction mechanism are in progress and will be re-
ported in due course.
W. A. J. Chem. Soc., Perkin Trans.
2 1985, 1779; Trimethylsilylalkyne: (b)
Kitazawa, T.; Minowa, T.; Mukaiyama, T. Chem. Lett. 2006, 35, 1002.
14. Lithium binaphtholate as a catalyst: (a) Schiffers, R.; Kagan, H. B. Synlett 1997,
1175; (b) Hatano, M.; Ikeno, T.; Matsumura, T.; Torii, S.; Ishihara, K. J. Am.
Chem. Soc. 2005, 127, 10776; (c) Hatano, M.; Horibe, T.; Ishihara, K. J. Am. Chem.
Soc. 2010, 132, 56.
15. 3,30-Dimethyl-, dichloro-, dibromobinaphthol, or mono lithium salt of the
binaphthol derivatives gave lower yields and/or enantioselectivities.
16. Representative experimental procedure: n-BuLi (0.16 M in hexane, 0.58 mL,
0.094 mmol) was added to a solution of (R)-3,30-diphenylbinaphthol (21 mg,
0.047 mmol) in THF (3 mL) at 0 °C under Ar atmosphere. Trimethoxy-
(phenylethynyl)silane (156 mg, 0.71 mmol) was added to the mixture in one
portion, and then a solution of acetophenone (56 mg, 0.47 mmol) in THF
(0.5 mL) was added over 3 h at the same temperature. After stirring for another
1 h, the reaction was quenched with tetrabutylammonium fluoride (1.0 M in
THF, 4 mL). The mixture was stirred for 0.5 h and extracted with EtOAc. The
organic layer was washed with water and brine successively. Drying over
sodium sulfate and concentration followed by silica gel column
chromatography afforded the alcohol (67 mg, 64%) as a colorless oil.
17. (a) Arnoldi, A.; Betto, E.; Farina, G.; Formigoni, A.; Galli, R.; Griffini, A. Pestic. Sci.
1982, 13, 670; (b) Cussac, M.; Boucherle, A.; Pierre, J.-L.; Hache, J. Eur. J. Med.
Chem. 1974, 9, 651.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2010.02.084.
18. The only reported example for the phenylalkynylation of acetylpyridine shows
an unsatisfactory result (28% yield, 28% ee), see Ref. 6c.
19. 3-Phenyl-1-(3-pyridyl)-2-propyn-1-ol has an antifungal activity, see Ref. 17a.
References and notes
1. (a) Hatano, M.; Ishihara, K. Synthesis 2008, 1647; (b) Trost, B. M.; Weiss, A. H.
Adv. Synth. Catal. 2009, 351, 963.