Convenient stereoselective synthesis of (Z)-chalcone derivatives from 1,3-diaryl-2-propynyl silyl ethers

Article abstract of DOI:10.1016/j.tetlet.2006.05.021

Various (Z)-chalcone derivatives were easily synthesized in a stereoselective manner from 1,3-diaryl-2-propynyl silyl ethers by a catalytic reaction using potassium tert-butoxide under very mild conditions after acid treatment.

Full text of DOI:10.1016/j.tetlet.2006.05.021

Tetrahedron Letters 47 (2006) 4943–4945
Convenient stereoselective synthesis of (Z)-chalcone
derivatives from 1,3-diaryl-2-propynyl silyl ethers
Kazuhiro Yoshizawa* and Takayuki Shioiri
Graduate School of Environmental and Human Sciences, Meijo University, Shiogamaguchi, Tempaku, Nagoya 468-8502, Japan
Received 11 April 2006; revised 2 May 2006; accepted 2 May 2006
Available online 30 May 2006
Abstract—Various (Z)-chalcone derivatives were easily synthesized in a stereoselective manner from 1,3-diaryl-2-propynyl silyl
ethers by a catalytic reaction using potassium tert-butoxide under very mild conditions after acid treatment.
Ó 2006 Elsevier Ltd. All rights reserved.
Chalcone derivatives are very versatile as physiologically
active compounds1a and substrates for the evaluation of
various organic reactions.1b,c However, most interests
are concerned with the (E)-chalcone derivatives, which
are synthesized far more easily than the (Z)-isomer,
and there have been only a few reports concerning the
synthesis of the (Z)-isomers.1,2 Moreover, the general
synthetic method for the (Z)-chalcone is only the photo-
isomerization of the corresponding (E)-isomers, and it
takes time to produce the (Z)-chalcones.3 We recently
reported that KO-t-Bu catalyzed the isomerization of
the 1,3-diphenyl-2-propynyl trimethylsilyl ether (1a) to
the corresponding siloxyallene 2a to produce the (Z)-
chalcone (3a) after acid treatment in a one-pot reaction
(Scheme 1).4 This procedure is expected to become a
useful approach to produce (Z)-chalcone derivatives
and suitable for the multi-scale synthesis because special
equipment is unnecessary. We now report the applica-
tions of this novel synthesis of the (Z)-chalcone (3a) to
the synthesis of various (Z)-chalcone derivatives 3.
The results of such applications to the various 1,3-di-
aryl-2-propynyl trimethylsilyl ethers 15 to produce the
corresponding (Z)-chalcone derivatives 3 are shown in
Table 1. The typical procedure is as follows: To a solu-
tion of 1 (1.0 mmol) in THF (2 mL) was added 1 M KO-
t-Bu in THF (0.1 mmol, 0.1 mL) at ꢀ78 °C under N2.
After 10 min, concd H2SO4 in 1,2-dimethoxyethane
(2 M solution, 1 mL) was added, and the mixture was
stirred at ꢀ78 °C for 10 min. Water and EtOAc were
added, and the separated organic layer was washed with
water then brine, and dried over MgSO4. After removal
of the solvent in vacuo, the residue was purified by silica
gel column chromatography (hexane/EtOAc) to give the
(Z)-chalcone derivative 3.6 The Z/E ratio of the product
1
was determined by H NMR in DMSO-d6.7
First of all, the (Z)-chalcone derivatives 3 with several
aryl groups were synthesized. The chalcone 3b was
produced with good stereoselectivity like the formation
of the (Z)-chalcone (3a), and the (Z)-chalcone 3c
H
OSiMe3
H
OSiMe3
KOt-Bu (10 mol%)
1N HCl
MeCN
.
THF, -78 oC
H
O
1a
3a
2a
Scheme 1.
Keywords: (Z)-Chalcone; Stereoselectivity; Siloxyallene; Isomerization.
*
Corresponding author. Fax: +81 479 46 4958; e-mail: k2-yoshizawa@hhc.eisai.co.jp
0040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.05.021

4944
K. Yoshizawa, T. Shioiri / Tetrahedron Letters 47 (2006) 4943–4945
Table 1.
H
O
H2SO4
OSiMe3
Ar2
Ar1
H
OSiMe3
Ar2
H
KOt-Bu (10 mol%)
in 1,2-dimethoxyethane
Ar1
.
THF, -78 oC
10 min
-78 oC
10 min
Ar2
Ar1
3
1
2
Entry
1
Product
Ar1
Ar2
Yielda (%)
82
Z:Eb
3a
93:7
2
3
4
5
6
7
3b
3c
3d
3e
3f
66
73
—
83
76
—
97:3
88:12
—
OMe
Cl
NO2
93:7
95:5
—
O
S
3g
8
9
3h
3i
75
76
80:20 (84:16)
E only (25:75)
MeO
10
3j
54
85:15 (89:11)
O
O
11
12
13
3k
3l
71
85
82
54
90:10
Cl
80:20 (95:5)
97:3
3m
3n
S
14
70:30
a Isolated yield.
1
b Z/E ratio was determined by H NMR analysis. Parentheses are Z/E ratio of crude product. No parentheses depicts no isomerization during the
purification step.
Ar2
H
SiMe3
substituted by the 4-chlorophenyl group showed moder-
ate selectivity. For 3d, the isomerization from the silyl
ether 1d to siloxyallene 2d did not proceed at even
0 °C. The reactions using heterocyclic compounds 1e
and 1f proceeded to give the (Z)-isomers 3e and 3f,
.
O
H
Ar1
2
Figure 1.

K. Yoshizawa, T. Shioiri / Tetrahedron Letters 47 (2006) 4943–4945
4945
H
O
OSit-BuMe2
H2SO4
H
OSit-BuMe2
KOt-Bu (10 mol%)
in 1,2-dimethoxyethane
.
-78 oC
10 min
THF, -78 oC
10 min
H
4
3a
74%, Z:E = >99:1
5
Scheme 2.
respectively, with good stereoselectivity. However, the
sterically hindered 20,60-dimethyl derivative 1g did not
yield 2g at all. The alkyne 1h having the (E)-styryl group
afforded the chalcone derivative 3h in good yield.
for the synthesis of (Z)-chalcone derivatives 3 since the
procedure is very simple.
Acknowledgements
Next, the (Z)-chalcone derivatives 3 substituted by var-
ious aryl groups (Ar1) at the vinyl position were synthe-
sized. Although only the (E)-isomer 3i was formed, the
product 3i seemed to be easily isomerized during the
reaction. However, 1j substituted with the tetrahydro-
pyranyl group instead of the methyl group afforded
the (Z)-isomer 3j with moderate stereoselectivity. The
reaction using 1k and 1l also produced the (Z)-chalcones
3k and 3l, respectively, and 3m substituted by the thienyl
group was produced with good selectivity. The 2,6-di-
methyl derivative 3n was obtained in low yield with
low stereoselectivity. In this case, conversion of the silyl
ether 1n to 2n was not complete and 1n remained after
the reaction. From the results of 3g and 3n, the steric
factor at the 2 or 20 position of the aryl group was re-
vealed to significantly influence the reaction. Although
some products were isomerized from the (Z) to (E)-iso-
mer during the purification step, it is expected that the
isomerization will be prevented if a suitable treatment
of each compound is applied. The (Z)-geometry prefer-
ence of the product 3 will be explained by the preferred
protonation, in which the reaction exclusively
occurs from the less hindered site of the siloxyallene 2
(Fig. 1).
We thank Eisai Co., Ltd., for partial support of this
research and financial support to K.Y. This work was
also financially supported in part by a Grant-in-Aid
for Scientific Research from the Ministry of Education,
Culture, Sports, Science and Technology, Japan.
References and notes
1. For recent reports about the (Z)-chalcone derivatives as
physiologically active compounds and substrates for the
evaluation of organic reactions, see: (a) Iwata, S.; Nishino,
T.; Inoue, H.; Nagata, N.; Satomi, Y.; Nishino, H.;
Shibata, S. Biol. Pharm. Bull. 1997, 20, 1266–1270; (b)
Kelly, D. R.; Caroff, E.; Flood, R. W.; Heal, W.; Roberts,
S. M. Chem. Commun. 2004, 2016–2017; (c) Takahashi, Y.;
Yamamoto, Y.; Katagiri, K.; Danjo, H.; Yamaguchi, K.;
Imamoto, T. J. Org. Chem. 2005, 70, 9009–9012.
2. For the synthesis of (Z)-selective a,b-unsaturated silyl
ketone from 2-propynyl trimethylsilyl ether, see: Kruithof,
K. J. H.; Klumpp, G. W. Tetrahedron Lett. 1982, 23, 3101–
3102.
3. (a) Lutz, R. E.; Jordan, R. H. J. Am. Chem. Soc. 1950, 72,
4090–4091; (b) Black, W. B.; Lutz, R. E. J. Am. Chem. Soc.
1953, 75, 5990–5997.
4. Yoshizawa, K.; Shioiri, T. Tetrahedron Lett. 2006, 47, 757–
761.
When the tert-butyldimethylsilyl ether 4 was treated by
a catalytic amount of KO-t-Bu, the siloxyallene 5 and
the crude (Z)-chalcone (3a, Z/E = 92/8) were quantita-
tively obtained without decomposition as observed in
the case of the trimethylsilyl ether 1a. In addition, the
nearly pure (Z)-chalcone (3a) was obtained in 74% yield
by only crystallization of the crude product from n-hex-
ane (Scheme 2).
5. The trimethylsilyl ethers 1 were synthesized as follows.
Alkynes lithiated with n-BuLi reacted with aldehydes to
afford 2-alkynyl alcohols, followed by trimethylsilylation
with triethylamine and chloro trimethylsilane. Alkynes were
synthesized from the corresponding aldehydes and lithium
trimethylsilyldiazomethane (TMSC(Li)N2). Miwa, K.;
Aoyama, T.; Shioiri, T. Synlett 1994, 107–108.
6. The reaction was not performed under the shading
conditions.
7. The main product (Z)-3 readily isomerized to (E)-3 upon
standing in CDC13. The ratio of (Z)-3 and (E)-3 was
determined by 1H NMR analysis of the vinyl proton, which
showed the characteristic doublet peak, J = ca. 12.5 and
15.5 Hz, respectively.
In summary, we have developed the stereoselective syn-
thesis of (Z)-chalcone derivatives 3 from 1,3-diaryl-2-
propynyl silyl ethers 1 by a catalytic reaction using
potassium tert-butoxide under very mild conditions
after acid treatment. The method will be quite useful