2162
J. Liu et al. / Tetrahedron Letters 53 (2012) 2160–2163
Table 3
electron-withdrawing groups, were decomposed under our condi-
tions. In addition, alkynylation reactions of the more sterically hin-
dered 10-acetonaphthone (1m) and o-methylacetophenone (1n)
with phenylacetylene gave products in only 65% and 33% yields,
respectively (Table 3, entries 13 and 14). Finally, addition reactions
of non-enolizable aromatic ketones, such as benzophenone (1p)
and 4-fluorobenzophenone (1q), occurred smoothly and gave
excellent product yields (Table 3, entries 16 and 17).
Reactions of ketones with alkynes using TBAC as the catalyst and solid KOH as the
base
Entry Ketone (R1, R2)
R
Product Yielda Lit. yieldb
Conclusion
(%)
(%)
In conclusion, the effort described above has led to the develop-
ment of a mild and efficient method for alkynylation of a diverse
array of aromatic ketones with arylacetylenes. By using catalytic
amount of tetrabutylammonium chloride as a promoter and solid
KOH as a base in THF, these processes took place in high yields un-
der transition-metal-free condition. Aliphatic ketones also gave
satisfactory results under these conditions. An asymmetric version
of our method is currently undergoing development.
1
2
3
4
5
6
7
8
1a (2-Naph, Me)
1b (Ph, Me)
1c (Ph, CF3)
–Ph
–Ph
–Ph
3a
3b
3c
3d
3e
3f
3g
3h
3i
82
80
/
38c, 35d
e
_
_
/
/
/
/
/
/
e
1d (4-NO2C6H4, Me) –Ph
1e (4-CF3C6H4, Me)
1f (4-ClC6H4, Me)
1g (4-FC6H4, Me)
–Ph
–Ph
–Ph
88
86
81
45f
83
82
81
78
65
33
79
99
98
85
94
95
93
77
1h (4-MeOC6H4, Me) –Ph
9
1i (3-CF3C6H4, Me)
1j (3-ClC6H4, Me)
1k (3-BrC6H4, Me)
1l (3-MeOC6H4, Me) –Ph
1m (1-Naph, Me) –Ph
1n (2-CH3C6H4, Me) –Ph
–Ph
–Ph
–Ph
10
11
12
13
14
15
16
17
18
19
20
21
22
23
3j
3k
3l
/
/
/
/
/
/
/
/
Acknowledgments
3m
3n
3o
3p
3q
3r
3s
3t
The authors thank Professor Patrick S. Mariano for editing the
manuscript. This work was financially supported by the State Key
Lab of Structural Chemistry, Fujian Institute of Research on the
Structure of Matter of the Chinese Academy of Sciences and the
Scientific Research Foundation for the Returned Overseas Chinese
Scholars, State Education Ministry.
1o (Ph, Et)
1p (Ph, Ph)
–Ph
–Ph
–Ph
–Ph
–Ph
–Ph
–Ph
1q (Ph, 4-FC6H4)
1r (3-Pyridyl, Me)
1s (nPr, Me)
1t (Et, Et)
1u (-(CH2)5-)
1v (Ph, Me)
/
/
81c, 70g
3u
95c,88d, 88h
–2-Thiophenyl 3v
–nC4H9 3w
/
/
e
1w (Ph, Me)
—
Supplementary data
a
b
c
Isolated yield.
Other transition-metal-free catalytic methods.
See Ref. 13.
See Ref. 15.
No product was detected.
Isolated yield in 6 days.
See Ref. 11a.
Supplementary data associated with this article can be found, in
d
e
f
References and notes
g
h
See Ref. 12.
1. (a) Modern Acetylene Chemistry; Stang, P. J., Diederich, F., Eds.; VCH: Weinheim,
1995. For recent reviews, see; (b) Pu, L. Tetrahedron 2003, 59, 9873; (c) Trost, B.
M.; Weiss, A. H. Adv. Synth. Catal 2009, 351, 963; (d) Tejedor, D.; Lopez-Tosco,
S.; Cruz-Acosta, F.; Mendez-Abt, G.; Garcia-Tellado, F. Angew. Chem., Int. Ed
2009, 48, 2090; (e) Ding, C.-H.; Hou, X.-L. Chem. Rev 2011, 111, 1914.
2. For recent reviews, see Ref. 1, also see: (a) Frantz, D. E.; Fassler, R.; Tomooka, C.
S.; Carreira, E. M. Acc. Chem. Res 2000, 33, 373; (b) Ramon, D. J.; Yus, M. Angew.
Chem., Int. Ed 2004, 43, 284; (c) Cozzi, P. G.; Hilgraf, R.; Zimmermann, N. Eur. J.
Org. Chem. 2004, 8, 4095; (d) Lu, G.; Li, Y.-M.; Chan, A. S. C. Coord. Chem. Rev.
2005, 249, 1736; (e) Garcia, C.; Martin, V. Curr. Org. Chem 2006, 10, 1849; (f)
Hatano, M.; Miyamoto, T.; Ishihara, K. Curr. Org. Chem 2007, 11, 127; (g) Cozzi,
P. G.; Hilgraf, R.; Zimmermann, N. Eur. J. Org. Chem 2007, 5969; (h) Hatano, M.;
Miyamoto, T.; Ishihara, K. Synthesis 2008, 1647.
3. For recent representative examples, see: (a) Tanaka, K.; Kukita, K.; Ichibakase,
T.; Kotani, S.; Nakajima, M. Chem. Commun 2011, 47, 5614; (b) Li, F.-Q.; Zhong,
S.; Liu, G.; Chan, A. S. C. Adv. Synth. Catal 2009, 351, 1955; (c) Zhang, G.-W.;
Meng, W.; Ma, H.; Nie, J.; Zhang, W.-Q.; Ma, J.-A. Angew. Chem., Int. Ed 2011, 50,
3538; (d) Yue, Y.; Turlington, M.; Yu, X.-Q.; Pu, L. J. Org. Chem. 2009, 74, 8681;
(e) Zhong, J.-C.; Hou, S. C.; Bian, Q. H.; Yin, M. M.; Na, R. S.; Zheng, B.; Li, Z. Y.;
Liu, S. Z.; Wang, M. Chem. Eur. J. 2009, 15, 3069; (f) Blay, G.; Cardona, L.;
Fernandez, I.; Marco-Aleixandre, A.; Munoz, M. C.; Pedro, J. R. Org. Biomol. Chem
2009, 7, 4301; (g) Du, X.; Wang, Q.; He, X.; Peng, R.-G.; Zhang, X.; Yu, X. Q.
Tetrahedron: Asymmetry 2011, 22, 1142; (h) Bauer, T.; Smolinski, S.; Gawel, P.;
Jurczak, J. Tetrahedron Lett. 2011, 52, 4882.
the outcomes of reactions performed by using other transition-me-
tal-free catalytic methods that afforded the adducts in only 38%13
and 35%15 yields. Reactions of aliphatic ketones with phenylacety-
lene employing the optimized conditions also proceeded smoothly
giving adducts in >90% yield, that are either similar to or higher
than those reported transition-metal-free catalytic meth-
ods11a,12,13,15 (Table 3, entries 19–21). Alkynylation of acetophe-
none (1b) with aromatic 2-ethynylthiophene, led to high yield as
well (Table 3, entry 22), but no product was detected with aliphatic
1-hexyne (Table 3, entry 23).
Further investigations demonstrated that substituent effects
influence the yields of tertiary propargylic alcohols formation in
the alkynylation reactions of aromatic ketones. The data in
Table 3 show that a substituent with positive substituent constant
r
value, which has electron-withdrawing ability, enhances the
reactivity of acetophenone, whereas a substituent with negative
4. Selected examples for Cu: (a) Lu, G.; Li, X.; Jia, X.; Chan, W. L.; Chan, A. S. C.
Angew. Chem., Int. Ed 2003, 42, 5057; (b) Motoki, R.; Kanai, M.; Shibasaki, M.
Org. Lett 2007, 9, 2997; (c) Asano, Y.; Hara, K.; Ito, H.; Sawamura, M. Org. Lett
2007, 9, 3901; (d) Asano, Y.; Ito, H.; Hara, K.; Sawamura, M. Organometallics
2008, 27, 5984.
5. Selected examples for Zn salt: (a) Anand, N. K.; Carreira, E. M. J. Am. Chem. Soc
2001, 123, 9687; (b) Yamashita, M.; Yamada, K.; Tomioka, K. Adv. Synth. Catal
2005, 347, 1649; (c) Ekstrom, J.; Zaitsev, A. B.; Adolfsson, H. Synlett 2006, 885.
6. Selected examples for In: (a) Harada, S.; Takita, R.; Ohshima, T.; Matsunaga, S.;
Shibasaki, M. Chem. Commun. 2007, 948; (b) Wei, C.; Li, C.-J. Green Chem. 2002,
4, 39; (c) Takita, R.; Yakura, K.; Ohshima, T.; Shibasaki, M. J. Am. Chem. Soc 2005,
127, 13760; (d) Takita, R.; Fukuta, Y.; Tsuji, R.; Ohshima, T.; Shibasaki, M. Org.
Lett 2005, 7, 1363.
substituent constant
r value, which has electron-donating ability,
has the opposite effect.18 These phenomena were demonstrated
by the comparative yields of reactions of acetophenone (1b) and
its 4-trifluoromethyl (1e) and 4-mexthoxy (1h) analogs with phen-
ylacetylene which took place in respective yields of 80%, 88%, and
45% (Table 3, entries 2, 5 and 8). Compared to the negative
r value
at p-position, methoxy substituent at m-position has positive value
and the alkynylation reaction of 3-methoxyacetophenone (1h) with
phenylacetylene took place in 78% yield. However, 4-nitroaceto-
phenone and a,a,a-trifluoroacetophenone which have very strong