Synthesis of β-branched Morita-Baylis-Hillman-type adducts from 1,3-diaryl-2-propynyl trimethylsilyl ethers and aldehydes catalyzed by potassium tert-butoxide

Article abstract of DOI:10.1016/j.tetlet.2005.11.118

1,3-Diaryl-2-propynyl trimethylsilyl ethers were easy to isomerize into the corresponding siloxyallenes using a catalytic amount of potassium tert-butoxide under very mild conditions. The siloxyallenes reacted in situ with various aldehydes to afford Z-selective β-branched Morita-Baylis-Hillman-type adducts in a one-pot reaction after acid treatment.

Full text of DOI:10.1016/j.tetlet.2005.11.118

Tetrahedron
Letters
Tetrahedron Letters 47 (2006) 757–761
Synthesis of b-branched Morita–Baylis–Hillman-type adducts
from 1,3-diaryl-2-propynyl trimethylsilyl ethers and
aldehydes catalyzed by potassium tert-butoxide
Kazuhiro Yoshizawa* and Takayuki Shioiri
Graduate School of Environmental and Human Sciences, Meijo University, Shiogamaguchi, Tempaku, Nagoya 468-8502, Japan
Received 19 October 2005; revised 7 November 2005; accepted 18 November 2005
Available online 9 December 2005
Abstract—1,3-Diaryl-2-propynyl trimethylsilyl ethers were easy to isomerize into the corresponding siloxyallenes using a catalytic
amount of potassium tert-butoxide under very mild conditions. The siloxyallenes reacted in situ with various aldehydes to afford
Z-selective b-branched Morita–Baylis–Hillman-type adducts in a one-pot reaction after acid treatment.
Ó 2005 Elsevier Ltd. All rights reserved.
Morita–Baylis–Hillman-type adducts have attracted wide
interest among numerous researchers as useful inter-
mediates. To the best of our knowledge, b-branched
Morita–Baylis–Hillman-type adducts are not always
obtained by the general Morita–Baylis–Hillman reaction,
so improved methods to acquire these compounds have
been developed to overcome this limitation. Most of
the improved methods involve 1-acylethenyl or allenoxy
metal intermediates derived from a,b-acetylenic carbo-
nyl or a-halo-a,b-unsaturated carbonyl compounds,
followed by coupling with the appropriate aldehydes or
ketones.1 It has also been reported that b-branched
Morita–Baylis–Hillman-type adducts can be obtained
via the intermediates from 2-alkynyl alcohols or their
derivatives.2 As a method not using metals, there are
methods using the a-carbanion generated from a-silyl-
a,b-unsaturated carbonyl derivatives.3 Moreover, a few
approaches to the adduct using siloxyallenes derived
from silyl ketones have been reported.4
We recently reported that quaternary ammonium fluo-
rides derived from cinchonine catalyzed the reaction of
1-phenyl-2-(trimethylsilyl)acetylene with aromatic alde-
hydes to produce the Z-selective b-branched Morita–
Baylis–Hillman-type adducts substituted by poly-aryl
groups.5 It was also reported that a base besides the
fluoride ion might play a key role in this reaction. Dur-
ing the course of the study about the mechanism, it was
found that 1,3-diaryl-2-propynyl trimethylsilyl ethers 1
were easy to isomerize into the corresponding siloxyal-
lenes 4 using a catalytic amount of potassium tert-
butoxide (KOt-Bu) under very mild conditions, and
siloxyallenes 4 reacted in situ with various aldehydes 2
to afford Z-selective b-branched Morita–Baylis–Hill-
man-type adducts 3 in a one-pot reaction after acid
treatment, as shown in Scheme 1. We now wish to report
this novel synthesis of b-branched Morita–Baylis–Hill-
man-type adducts from the silyl derivatives of 2-alkynyl
alcohols.
O
H
O
H R
OH
Ar2
R
H
OSiMe3
H+
H
OSiMe3
Ar2
KOt-Bu
2
Ar1
Ar2
Ar1
Ar1
1
4
3
Scheme 1.
Keywords: Morita–Baylis–Hillman adduct; Siloxyallene; Stereoselectivity; Isomerization.
*
Corresponding author. Fax: +81 479 46 4958; e-mail: k2-yoshizawa@hhc.eisai.co.jp
0040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.11.118

758
K. Yoshizawa, T. Shioiri / Tetrahedron Letters 47 (2006) 757–761
PhCHO (2a, 1.2 eq), KOt-Bu (10 mol%)
1N HCl
MeCN
OSiMe3
82%
85%
DMF, -20 oC, 1 h
OH
1) KOt-Bu (10 mol%), THF, -78 oC, 10 min
1N HCl
MeCN
O
1a
2) PhCHO (2a, 1.2 eq), -78 to 0 oC, 1.5 h
3a
H
H
1) KOt-Bu (10 mol%), THF, -78 oC, 10 min
2) AcOH, -78 to 0 oC, 30 min
1N HCl
MeCN
5: 74%
(Z:E = 93:7)
O
H
OSiMe3
PhCHO (2a)
(1.2 eq)
1N HCl
MeCN
KOt-Bu (10 mol%)
THF, -78 oC, 10 min
45%
(2 steps)
3a
DMF, r.t.
1 h
4a
Isolated as crude product
(IR : 1928 cm-1)
Scheme 2.
First of all, the reaction was investigated using the rep-
resentative 1,3-diaryl-2-propynyl trimethylsilyl ether 1a
and benzaldehyde (2a), as shown in Scheme 2. Although
a mixture of silyl ether 1a and benzaldehyde (2a) in
DMF efficiently and selectively afforded the Z-adduct
3a using a catalytic amount of KOt-Bu at À20 °C after
acid treatment (method A), 3a was also obtained by the
treatment of silyl ether 1a with KOt-Bu in THF at
À78 °C followed by the addition of 2a after acid treat-
ment (method B). The treatment of the mixture in
DMF did not react at À78 °C similar to a stepwise pro-
cess. When acetic acid was used instead of benzaldehyde
(2a), the uncommon Z-chalcone 5 was stereoselectively
obtained.4a,6 This procedure is expected to become an
option as a method for the synthesis of the Z-chalcone
derivatives. After the treatment of the silyl ether 1a with
KOt-Bu in THF, 1a isomerized into siloxyallene 4a
within 10 min, and allene 4a could be isolated as a crude
product, which could not be purified by silica gel column
chromatography. The isomerization progressed under
very mild conditions compared with the general isomer-
ization from alkynes to allenes.7 In DMF, 4a could not
be isolated as in THF due to its decomposition. The
Though the reaction of 1a and aldehydes substituted
by some other functional groups progressed by method
A, the products were obtained in higher yield when
using method B (entries 5–9). Especially, 4-nitrobenzal-
dehyde (2f), which did not react at all by method A,
underwent the reaction to give 3f using method B. The
sterically hindered aldehyde 2g also gave adduct 3g
without any extreme decrease in the yield (entry 10).
The reaction with heterocyclic aldehydes 2h–j also
proceeded to give adducts 3h–j (entries 11–14). How-
ever, the yield of 3j was relatively low. When trans-cin-
namaldehyde reacted with 1a, adduct 3k was obtained
in moderate yield and the corresponding 1,4-adduct
was not observed (entries 15 and 16). In the case of
the aliphatic aldehydes, the reaction smoothly pro-
ceeded if the activated proton was not at the a-position
(entry 17). In the reaction with isobutyraldehyde and
valeraldehyde, many structural unknown compounds
were observed by method A, and no adducts were
obtained. However, method B effectively produced 3m
and 3n, respectively (entries 18–21).
Next, the combination of substituents of trimethylsilyl
ether 19 and aldehydes or ketones 2 was continuously
investigated, as shown in Table 2. As for the substituents
of the products, various combinations were possible,
and the difference between the electron-donating and
withdrawing groups did not influence the reaction simi-
lar to the results in Table 1 (entries 1–5). Though 3t and
3u substituted by heterocyclic groups were obtained by
method A in good yields, method B was effective for
the synthesis of 3v (entries 6–9). When silyl ether 1
had the cinnamyl moiety at the propargylic position
instead of the aryl group, 1w was deactivated and the
yield of adduct 3w was lower (entries 10 and 11). The
product was formed in low yield or not obtained at all
when either of the substituents of silyl ethers, 1x and
1y, is an alkyl group. Isomerization of the silyl ether 1
structure of 4a was confirmed by specific infrared
absorption of the allene moiety at about 1928 cmÀ1
.
8
Furthermore, it was observed that the crude siloxyallene
4a reacted with 2a to afford 3a in DMF not using any
catalysts. In THF, the crude 4a did not react with 2a.
Various aldehydes 2 undergo the reaction of 1,3-diphen-
yl-2-propynyl trimethylsilyl ether 1a to give the
Morita–Baylis–Hillman-type adducts
3 having the
Z-configuration in moderate to good yields, as shown
in Table 1. In all cases, when the reaction did not easily
proceed by method A, method B was effective, and all
aldehydes gave products 3. The difference between the
electron-donating and withdrawing groups on the aro-
matic ring did not influence the reaction (entries 1–4).

K. Yoshizawa, T. Shioiri / Tetrahedron Letters 47 (2006) 757–761
759
Table 1. Reaction of silyl ether 1a (Ar1, Ar2 = Ph) with aldehydes 2
11%
11%
7%
8%
Entry Product
R
Methoda Yield (%)b
1
2
3
4
5
6
7
8
3a
3a
3b
3c
3d
3d
3e
3f
C6H5
C6H5
4-ClC6H4
A
B
A
A
A
B
B
A
B
A
A
A
A
B
A
B
A
A
B
A
B
82
85
76
72
35
74
83
—
67
68
95
83
35
54
52
66
67
—
69
—
67
Cl
H
H
O
H
H
OH
OH
O
4-MeOC6H4
4-Me2NC6H4
4-Me2NC6H4
4-MeO2CC6H4
4-NO2C6H4
4-NO2C6H4
2,6-Me2C6H3
2-Furyl
2-Thienyl
2-Pyridyl
2-Pyridyl
trans-C6H5CH@CH
trans-C6H5CH@CH
(CH3)3C
(CH3)2CH
(CH3)2CH
O
OMe
3r
3u
Figure 1.
9
3f
10
11
12
13
14
15
16
17
18c
19c
20c
21c
3g
3h
3i
uration of the olefin of the other products 3 was
assigned by analogy.
3j
3j
The proposed mechanism is depicted in Scheme 3 for the
reaction. KOt-Bu serves as an initiator of the reaction,
not as a catalyst in the cycle, because there was no
change in the deuterium ratio of the product obtained
from the silyl ether substituted by deuterium in the pres-
ence of t-BuOH (Scheme 4). Next, the allenic anion was
protonated by the remaining 1 to give siloxyallene 4.
Finally, the aldol reaction of 4 with 2 was promoted
by a Lewis base10 to afford the Z-isomer 3. Though this
reaction was attempted using a catalytic amount of
n-BuLi instead of KOt-Bu to confirm whether the reac-
tion progresses even if other general bases are used, the
isomerization hardly progressed. The reaction did not
progress even when the amine, for example, N,N-diiso-
propylethylamine, was used.
3k
3k
31
3m
3m
3n
3n
CH3CH2CH2CH2
CH3CH2CH2CH2
a For method A or B, see Ref. 11.
b Isolated yield.
c Aldehyde (1.5 equiv) was used.
into the corresponding siloxyallene by method B was
not observed (entries 12 and 13). In the case of the reac-
tion with ketones, general ketones, for example, 3-penta-
none and acetophenone, did not produce any products.
However, trifluoroacetophenone gave product 3z in
good yield (entry 14).
In summary, we have found the high reactivity of 1,3-
diaryl-2-propynyl trimethylsilyl ethers 1, which were
easy to isomerize into the corresponding siloxyallenes
4 by a catalytic amount of KOt-Bu under very mild con-
ditions. Siloxyallenes 4 reacted in situ with various alde-
hydes 2 and trifluoroacetophenone to selectively afford
the Z-b-branched Morita–Baylis–Hillman-type adducts
3 in a one-pot reaction after acid treatment. A further
extension of this reaction is now actively in progress.
In all cases, only the Z-isomers 3 were obtained and the
signals assumed to be the E-isomer were difficult to ob-
serve in the H NMR spectra of the crude product. The
stereochemistries of the products were confirmed by a
1H NMR (NOE) experiment of the representative prod-
ucts, 3r and 3u, shown in Figure 1. The relative config-
1
Table 2. Reaction of silyl ethers 1 with aldehydes 2
Entry
Product
Ar1
Ar2
R
Methoda
Yield (%)b
1
2
3
4
5
6
7
8
3o
3p
3q
3r
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
n-C4H9
C6H5
C6H5
4-ClC6H4
4-ClC6H4
4-MeOC6H4
4-MeOC6H4
4-MeOC6H4
2-Furyl
2-Thienyl
2-Pyridyl
2-Pyridyl
trans-C6H5CH@CH
trans-C6H5CH@CH
C6H5
n-C4H9
C6H5
C6H5
4-MeOC6H4
C6H5
4-ClC6H4
4-MeOC6H4
C6H5
C6H5
C6H5
C6H5
C6H5
A
A
A
A
A
A
A
A
B
A
B
A
A
B
74
71
83
83
79
80
76
40
78
28
50
23
—
78e
3s
3t
3u
3v
3v
3w
3w
3x
3y
3z
9
10
11
12c
13
14d
C6H5
C6H5
C6H5
C6H5COCF3
a For method A or B, see Ref. 11.
b Isolated yield.
c KOt-Bu (20 mol %) was used.
d C6H5COCF3 (1.5 equiv) was used instead of aldehyde.
e Product was obtained as trimethylsilyl ether of 3z.

760
K. Yoshizawa, T. Shioiri / Tetrahedron Letters 47 (2006) 757–761
OSiMe3
Ar
H
Ph
1
t-BuO
O
Ar
H
DMF
and
Ot-Bu
OSiMe3
Ar
R
H
H
OSiMe3
Ar
Si
2
O
O
Ph
Ph
Ph
4
R
H
H+
R
OSiMe3
H
H
OSiMe3
Ar
Ar
Ph
OH
Ph
Ph
O
Ar
1
3
Scheme 3.
D
Ph
OH
Ph
OSiMe3
A) KOt-Bu (10 mol%)
DMF, -20 oC
D
H+
Ph
Ph
PhCHO
+
B) KOt-Bu (10 mol%)
t-BuOH (100 mol%)
DMF, -20 oC
Ph
O
2a
D = 99%
A : y. 48%, D = 96%
B : y. 43%, D = 93%
Scheme 4.
allenes, see: (c) Tius, M. A.; Hu, H. Tetrahedron Lett.
1998, 39, 5937–5940; (d) Kaur, A.; Kaur, G.; Trehan, S.
Indian J. Chem. 1998, 37B, 1048–1050; (e) Stergiades, I.
A.; Tius, M. A. J. Org. Chem. 1999, 64, 7547–7551; (f) Li,
G.; Wei, H.-X.; Phelps, B. S.; Purkiss, D. W.; Kim, S. H.
Org. Lett. 2001, 3, 823–826.
Acknowledgments
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. The
calculated data of the infrared absorption was per-
formed by Dr. T. Matsumoto of Tohoku University,
and the HRMS data were taken by Mr. D. Furuta of
Meijo University, to whom our thanks are due.
5. Yoshizawa, K.; Shioiri, T. Tetrahedron Lett. 2005, 46,
7059–7063.
6. For recent reports about the synthesis of E-chalcone from
2-alkynyl alcohols, see: (a) Ishikawa, T.; Mizuta, T.;
Hagiwara, K.; Aikawa, T.; Kudo, T.; Saito, S. J. Org.
Chem. 2003, 68, 3702–3705; (b) Lee, N. Y.; Kim, T.-J.;
Shim, S. C. J. Heterocycl. Chem. 2004, 41, 409–411.
7. For the isomerization from alkynes to allenes, see: Modern
Allene Chemistry; Krause, N., Hashmi, A. S. K., Eds.;
Wiley-VCH: Weinheim, 2004; Vol. 1, and references cited
therein.
References and notes
1. For recent reports about the synthesis of the b-branched
Morita–Baylis–Hillman-type adducts and applications,
see: (a) Basavaiah, D.; Rao, A. J.; Satyanarayana, T.
Chem. Rev. 2003, 103, 811–891; (b) Xue, S.; He, L.; Han,
K.-Z.; Liu, Y.-K.; Guo, Q.-X. Synlett 2005, 1247–1250; (c)
8. The calculated value of infrared absorption using RHF/6-
31G(d) was 1968 cmÀ1
.
9. Trimethylsilyl ether 1 was synthesized as follows. The
alkyne lithiated with n-BuLi reacted with aldehydes to
afford 2-alkynyl alcohols, followed by trimethylsilylation
using triethylamine and chloro trimethylsilane.
´
Concellon, J. M.; Huerta, M. J. Org. Chem. 2005, 70,
4714–4719, and references cited therein.
2. (a) Trost, B. M.; Oi, S. J. Am. Chem. Soc. 2001, 123, 1230–
1231; (b) Gudimalla, N.; Fro¨hlich, R.; Hoppe, D. Org.
Lett. 2004, 6, 4005–4008.
3. (a) Sato, Y.; Takeuchi, S. Synthesis 1983, 734–735; (b)
Yamazaki, T.; Takita, K.; Ishikawa, N. Nippon Kagaku
Kaishi 1985, 2131–2139; (c) Matsumoto, K.; Oshima, K.;
Utimoto, K. Chem. Lett. 1994, 1211–1214.
4. For the synthesis of the b-branched Morita–Baylis–Hill-
man-type adducts from siloxyallenes, see: (a) Kato, M.;
Kuwajima, I. Bull. Chem. Soc. Jpn. 1984, 57, 827–830; (b)
Reich, H. J.; Eisenhart, E. K.; Olson, R. E.; Kelly, M. J. J.
Am. Chem. Soc. 1986, 108, 7791–7800. For synthesis of
other Morita–Baylis–Hillman-type adducts from siloxy-
10. For the aldol reaction of trimethylsilyl enolate with an
aldehyde catalyzed by tert-butoxide as a Lewis base, see:
Fujisawa, H.; Nakagawa, T.; Mukaiyama, T. Adv. Synth.
Catal. 2004, 346, 1241–1246.
11. A typical procedure for the preparation of the Morita–
Baylis–Hillman-type product 3 is as follows. Method A:
To a solution of 1 (1.0 mmol) and 2 (1.2 mmol) in DMF
(2 mL) was added KOt-Bu (0.1 mmol) at À20 °C under
Ar. After 1 h, 1 N aq HCl (1 mL) and acetonitrile (2 mL)
were added, and the mixture was stirred at room temper-
ature for a few minutes. Water and EtOAc were added,
and the separated organic layer was washed with water
and brine, and dried over MgSO4. After removal of the

K. Yoshizawa, T. Shioiri / Tetrahedron Letters 47 (2006) 757–761
761
solvent in vacuo, the residue was purified by silica gel
column chromatography to give adduct 3. Method B: To a
solution of 1 (1.0 mmol) in THF (2 mL) was added 1 M
KOt-Bu in THF (0.1 mmol) at À78 °C under Ar. After
10 min, 2 (1.2 mmol) was added, then the mixture was
warmed to 0 °C in 30 min. After 1 h, 1 N aq HCl (1 mL)
and acetonitrile (2 mL) were added, followed by a work-
up procedure similar to that of method A.