Synthesis of Morita-Baylis-Hillman-type adducts by unprecedented reaction of 1-phenyl-2-(trimethylsilyl)acetylene with aromatic aldehydes catalyzed by quaternary ammonium fluorides derived from cinchonine

Article abstract of DOI:10.1016/j.tetlet.2005.08.057

The quaternary ammonium fluoride derived from cinchonine efficiently catalyzed the reaction of 1-phenyl-2-(trimethylsilyl)acetylene with aromatic aldehydes to give the β-branched Morita-Baylis-Hillman-type adducts.

Full text of DOI:10.1016/j.tetlet.2005.08.057

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 7059–7063
Synthesis of Morita–Baylis–Hillman-type adducts by
unprecedented reaction of 1-phenyl-2-(trimethylsilyl)acetylene
with aromatic aldehydes catalyzed by quaternary
ammonium fluorides derived from cinchonine
Kazuhiro Yoshizawa* and Takayuki Shioiri
Graduate School of Environmental and Human Sciences, Meijo University, Shiogamaguchi, Tempaku, Nagoya 468-8502, Japan
Received 11 July 2005; revised 3 August 2005; accepted 5 August 2005
Available online 26 August 2005
Abstract—The quaternary ammonium fluoride derived from cinchonine efficiently catalyzed the reaction of 1-phenyl-2-(trimethyl-
silyl)acetylene with aromatic aldehydes to give the b-branched Morita–Baylis–Hillman-type adducts.
Ó 2005 Elsevier Ltd. All rights reserved.
Quaternary ammonium fluorides derived from cinchona
alkaloids have been found to be useful catalysts for the
enantioselective carbon–carbon bond forming reac-
tions.1,2 However, their applications to organic synthe-
ses are still limited in contrast to tetrabutylammonium
fluoride (TBAF), which is widely used as a synthetic
reagent for many fluoride-assisted reactions, desilyl-
ation, and fluorination as well as a base.3 Thus, the qua-
ternary ammonium fluorides from cinchona alkaloids
are expected to be used for a variety of organic
reactions.
perature than in CH2Cl2 or toluene. In CH2Cl2 or tolu-
ene, the reaction did not proceed at À20 °C (entries 1–
4). Less than 1 h is sufficient to complete the reaction,
and the crude silylated product was then treated with
hydrochloric acid to give the product 3a. The preferred
procedure to produce 3a was the addition of the acetyl-
ene 1 to a mixture of the catalyst 5a and benzaldehyde
(2a). No reaction occurred when the acetylene 1 was first
mixed with the catalyst 5a and then the aldehyde 2a was
added.8 The free hydroxyl group of the catalyst 5a af-
fected the reaction to produce 3a, since its O-allyl and
O-benzyl derivatives, 5b and 5c, afforded a mixture of
3a and 4a (compare entries 5–7). The structure of the
major product 3a suggested that 2 equiv of the aldehyde
2a would be necessary. However, the use of 1.25–
1.50 equiv of the aldehyde 2a will be suitable to save
the valuable silyl acetylene 1. Interestingly, the use of
less than 1.0 equiv of 2a also gave the Morita–Baylis–
Hillman-type adduct 3a as the major product (entries
8–11). To our surprise, the use of TBAF afforded the
simple addition product 4a as the major one together
with a small amount of 3a.7,9
As an extension of our interests1b,d,e in this topic, we
explored the addition reaction of 1-phenyl-2-(trimethyl-
silyl)acetylene (1) to benzaldehyde (2a) catalyzed by the
ammonium fluorides 5 derived from cinchonine, shown
in Scheme 1.4,5 The major product proved to be not a
single addition product 4a but an unexpected b-
branched Morita–Baylis–Hillman-type adduct 3a.6 We
now wish to describe this unprecedented reaction of 1
with aromatic aldehydes 2.7
The results from the investigation of the reaction condi-
tions for the reaction of 1 and 2a are shown in Table 1.
The reaction in THF or DMF proceeded at a lower tem-
In all cases, the stereochemistry of the product 3a
proved to be the Z-configuration and no signals of the
E-isomer were observed in the H NMR spectra of the
1
crude product. However, the enantiomeric excess of
the product 3a was less than 10% in most cases.
Keywords: Quaternary ammonium fluoride; Cinchonine; Allenolate;
Morita–Baylis–Hillman adduct.
*
Aldehydes having substituents on the aromatic rings will
Corresponding author. Fax: +81 479 46 4958; e-mail: k2-yoshizawa@
hhc.eisai.co.jp
afford two possible structurally isomeric adducts, 3 and
0040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.08.057

7060
K. Yoshizawa, T. Shioiri / Tetrahedron Letters 46 (2005) 7059–7063
OH
H
SiMe3
O
Catalyst 5
(10 mol%)
1N HCl
MeOH
OH
H
+
+
O
4a
(minor product)
1
2a
3a
(major product)
RO
5a : R = H
5b : R = Allyl
5c : R = Bn
N+
F-
N
Scheme 1.
Table 1. Reaction of the acetylene 1 with benzaldehyde (2a)a
Entry
Catalyst
Solvent
Temp (°C)
2a (equiv)
Yield (%)d
3ae
4af
1
2
3
4
5b
6
7
8
5a
5a
CH2Cl2
Toluene
THF
DMF
THF
À20 to rt
À20 to rt
À20
1.1
1.1
1.1
1.1
1.1
1.1
1.1
0.8
1.25
1.5
2.0
1.1
90
73
73
78
80
49
45
46
86
83
58
10
—
—
—
—
—
18
27
9
2
2
4
63
5a
5a
À20
5a
5b
À20
THF
THF
À20
5c
5a
À20
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
THF
À20 to rt
À20 to rt
À20 to rt
À20 to rt
À20
9
5a
5a
10
11
12b
5a
TBAFc
a To a mixture of the catalyst 5 and benzaldehyde (2a) was added the acetylene 1.
b To a mixture of the acetylene 1 and benzaldehyde (2a) was added the catalyst 5.
c THF solution was purchased and used directly.
d Isolated yield.
e Yield based on 2a.
f Yield based on 1.
H
O
Ar
Ar
H
O
Ar
OH
Ar
OH
6
3
F
O
OH
H
H
2d
F
OH
F
O=V(OSiPh3)3
Cl(CH2)2Cl
80 oC, 20 h
23%
7a
F
O
6a
F
O
OH
H
H
O
H
O
2d
F
+
OH
OH
O=V(OSiPh3)3
Cl(CH2)2Cl
80 oC, 20 h
18%
7b
F
F
8
3d
F
F
(3d : 8 = 3 : 2)
Scheme 2.

K. Yoshizawa, T. Shioiri / Tetrahedron Letters 46 (2005) 7059–7063
7061
Table 2.
H
O
Ar
Ar
OH
Ar
ArCHO (2, 1.5 mmol)
5a (0.1 mmol)
1N HCl
MeOH
OH
+
1
CH2Cl2
(1.0 mmol)
-20 to 0 oC, 1 h
4
3
Entry
ArCHO
2
Yield (%)a
3b
4c
1
2
3
4
5
6
7
2a
2b
2c
2d
2e
2f
92
87
37
89
89
—
23
7
CHO
H3C
MeO
F
—
52
—
—
—
26
CHO
CHO
CHO
Cl
CHO
O2N
MeO
CHO
CHO
2g
MeO
O
8
2h
2i
87
85
54
49e
—
—
—
27
O
CHO
9
CHO
10
11d
2j
CHO
CHO
O
2k
CHO
a Isolated yield.
b Yield based on ArCHO.
c Yield based on 1.
d Phthalaldehyde (0.75 mmol) was used. The crude product was a mixture of stereoisomers (Z:E = 13:87).
e Product:
O
H
Ph
OH
9
.
6. To clarify the structure of the adduct, 4-fluorobenzal-
dehyde (2d) reacted with the propargyl alcohols 7a and
7b using tris(triphenylsilyl)vanadate according to the
procedure developed by Trost and Oi.10 The product
6a obtained from 7a was not identical to the adduct 3d,
but the major product from 7b was identical to 3d, as
shown in Scheme 2. Thus the structure of the Morita–
Baylis–Hillman-type adduct proved to be 3 and not 6.

7062
K. Yoshizawa, T. Shioiri / Tetrahedron Letters 46 (2005) 7059–7063
O
OSiMe3
Ar
OSiMe3
Ar
H
H
H
2
Ar
5a
1
SiMe3
11
10
O
H
O
Ar
Ar
Ar
H
H
2
OH
SiMe3
O
Ar
O
Ar
3
H
12
Scheme 3.
1
3a
Various aldehydes 2 undergo the reaction of 1 to give
the Morita–Baylis–Hillman-type adducts 3 having the
Z-configuration in moderate to good yields, as summa-
rized in Table 2. 4-Methylbenzaldehyde (2b) smoothly
afforded the adduct 3b while 4-methoxybenzaldehyde
(2c) afforded a mixture of 3c and 4c in preference of
the latter. In contrast, the reaction with p-nitrobenzalde-
hyde (2f) did not proceed at all. Piperonal (2h) proved to
be a good substrate for the new reaction, but the reac-
tion with 3,4-dimethoxybenzaldehyde (2g) sluggishly
proceeded to give both adducts 3g and 4g in low yields.
The major product from phthalaldehyde (2k) was
revealed to be the intramolecularly cyclized product 9.
Although the E-isomer 9 was mainly obtained in this
case, it is considered that the isomerization during the
reaction is responsible for the formation of the E-iso-
mer.11 Application of aliphatic aldehydes or aliphatic
trimethylsilylacetylene to this reaction gave the Morita–
Baylis–Hillman-type adducts in trace yields with the
simple addition-type products being the major products.
1) 5a (10 mol%)
(0.5 mmol)
(0.71 mmol)
CH2Cl2, 0 oC
+
+
2a
(1.5 mmol)
+
2a
(0.35 mmol)
+
2) 1N HCl
MeOH
4a
10
(0.04 mmol)
(0.5 mmol)
Scheme 4.
In summary, we have developed the unprecedented reac-
tion of 1-phenyl-2-(trimethylsilyl)acetylene (1) with aro-
matic aldehydes 2 to produce the Z-selective b-branched
Morita–Baylis–Hillman-type adducts 3 catalyzed by the
quaternary ammonium fluoride 5a derived from cincho-
nine, and revealed the unusual reactivity of the ammo-
nium fluoride 5a compared with TBAF. The method
will be quite useful for the synthesis of b-branched Mor-
ita–Baylis–Hillman-type adducts since the b-substituted
olefinic substrates do not normally undergo the usual
Morita–Baylis–Hillman reaction. A further extension
of this reaction is now actively in progress.
We now propose the mechanism depicted in Scheme 3
for the reaction. The first step involves the addition reac-
tion of the silylacetylene 1 to the aldehyde 2 catalyzed by
the fluoride 5a to form the propargylic silyl ether 10.
Next, isomerization of the acetylene 10 affords the silyl
allenolate 11, followed by the addition of the allenolate
toward the second aldehyde 2 at the central carbon of
the allenolate.12 Although no isomerization of 10 was
promoted with the quaternary ammonium fluoride 5a
at all, treatment of a mixture of 1, 2a, and 10 with the
catalyst 5a gave evidence of the conversion of the prop-
argylic silyl ether 10 to the adduct 3a, as shown in
Scheme 4.
The typical procedure for the preparation of the Mori-
ta–Baylis–Hillman-type product 3a is as follows: To a
solution of the catalyst 5a (40 mg, 0.1 mmol) and benz-
aldehyde (2a) (0.153 mL, 1.5 mmol) in CH2Cl2 (2 mL)
was added 1-phenyl-2-(trimethylsilyl)acetylene (1)
(0.197 mL, 1.0 mmol) at À20 °C under Ar, then the mix-
ture was immediately warmed to 0 °C. After 1 h, 1 N aq
HCl (1 mL) and methanol (4 mL) were added, and the
mixture was stirred for only a few minutes. Water, brine,
and EtOAc were added, and the separated organic layer
was washed with brine and dried over MgSO4. After
removal of the solvent in vacuo, the residue was purified
by silica gel column chromatography (hexane/EtOAc,
10:1) to give the Morita–Baylis–Hillman-type adduct
3a (219 mg, 92%) and the single addition product 4a
(15 mg, 7%). The spectroscopic data of the main product
were indistinguishable from those of 3a reported by
Trost and Oi.10
Thus, the base probably generated in situ is considered
to participate in the deprotonation at the propargyl
position of 10 and catalyze the isomerization. The Z-
geometry preference of the product 3 will be explained
by the preferred transition state 12, in which the reaction
exclusively occurs from the less hindered site of the
allenolate 11. Detailed mechanism about the reaction
is still under investigation.

K. Yoshizawa, T. Shioiri / Tetrahedron Letters 46 (2005) 7059–7063
7063
R.; Popelis, J.; Mazeika, I.; Lukevics, E. J. Organomet.
Chem. 1999, 586, 184–189.
Acknowledgments
6. For recent reports about the Morita–Baylis–Hillman
reactions and applications, see: (a) Basavaiah, D.; Rao,
A. J.; Satyanarayana, T. Chem. Rev. 2003, 103, 811–891;
(b) Yeo, J. E.; Yang, X. L.; Kim, H. J.; Koo, S. Chem.
Commun. 2004, 236–237; (c) Xue, S.; He, L.; Han, K.-Z.;
Liu, Y.-K.; Guo, Q.-X. Synlett 2005, 1247–1250, and
references cited therein.
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.
7. The addition of a-silyl-a,b-unsaturated ketones to alde-
hydes catalyzed by TBAF affords the Morita–Baylis–
Hillman-type adduct. See: Matsumoto, K.; Oshima, K.;
Utimoto, K. Chem. Lett. 1994, 1211–1214.
8. The quaternary ammonium acetylide was considered to be
generated in situ. Isolation or physical evidence of the
quaternary ammonium acetylide has not been reported.
See: Ishikawa, T.; Mizuta, T.; Hagiwara, K.; Aikawa, T.;
Kudo, T.; Saito, S. J. Org. Chem. 2003, 68, 3702–3705.
9. The use of anhydrous TBAF also gave the addition
product 4 as the major one. For the preparation of
anhydrous TBAF, see: Sun, H.; DiMagno, S. G. J. Am.
Chem. Soc. 2005, 127, 2050–2051.
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