Lewis acid-catalyzed nucleophilic substitutions of propargylic and allylic silyl ethers with enol silyl ethers

Article abstract of DOI:10.1021/ol0271537

(Matrix presented) Nucleophilic reactions of various enol silyl ethers with carbocation species generated from propargyl silyl ethers by the action of a Lewis acid have been developed. The present method is highly useful for the introduction of allenic or

Full text of DOI:10.1021/ol0271537

ORGANIC
LETTERS
2003
Vol. 5, No. 1
51-54
Lewis Acid-Catalyzed Nucleophilic
Substitutions of Propargylic and Allylic
Silyl Ethers with Enol Silyl Ethers
Teruhiko Ishikawa,* Toshiaki Aikawa, Yumiko Mori, and Seiki Saito*
Department of Bioscience and Biotechnology, School of Engineering,
Okayama UniVersity, Tsushima, Okayama, Japan 700-8530
seisaito@biotech.okayama-u.ac.jp
Received October 23, 2002
ABSTRACT
Nucleophilic reactions of various enol silyl ethers with carbocation species generated from propargyl silyl ethers by the action of a Lewis acid
have been developed. The present method is highly useful for the introduction of allenic or enyne functionalities into the r-position of
substituted ketones.
Enol silyl ethers have been widely used in carbon-carbon
bond-forming processes such as nucleophilic additions or
cycloaddition reactions1 because of their high reactivity and
ready availability with reasonable thermal stability. Although
in most of the nucleophilic additions the enol silyl ethers
attack activated carbonyl compounds, the nucleophilic reac-
tion of the enol silyl ethers with propargylic or allylic cations
has been limited to a few examples.2 In the course of our
research concerned with carbon-carbon bond-forming reac-
tions using carbocations produced from substituted propargyl
silyl ethers by the action of trimethylsilyl triflate (TMSOTf),
we found that enol silyl ether (1a) can play a role as a
nucleophile to smoothly react with propargyl silyl ethers (2a
or 2f) leading to a substituted allene (3a) or alkyne derivative
(6a), respectively (Scheme 1).3 Since then, we have been
making extensive efforts to develop the reaction of this class
into a general organic reaction for carbon-carbon bond
formation. Thus, various enol silyl ethers (1a-k)4 and
Scheme 1a
(1) (a) Mukaiyama, T.; Kobayashi, S. Org. React. 1994, 46, 1-103. (b)
Bednarski, M. D.; Lyssikatos, J. P. In ComprehensiVe Organic Synthesis;
Trost, B. M., Fleming, I., Eds.; Pergamon: Oxford, 1991; Vol. 2, Chapter
2.5.
(2) (a) Itoh, A.; Oshima, K.; Yamamoto, H.; Nozaki, H. Bull. Chem.
Soc. Jpn. 1980, 53, 2050-2054. (b) Mayr, H.; Heilmann, W.; Lammers,
R. Tetrahedron 1986, 42, 6663-6668. See also: Hibino, M.; Koike, T.;
Yoshimatsu, M. J. Org. Chem. 2002, 67, 1078-1083.
(3) Ishikawa, T.; Okano, M.; Aikawa, T.; Saito, S. J. Org. Chem. 2001,
66, 4635-4642. Only three examples, including those shown in Scheme 1,
were reported therein.
a Reaction conditions: (i) TMSOTf (0.1 equiv), 1a (1.6 equiv)/
CH2Cl2/from -78 °C to rt, 8 h; (ii) TMSOTf (0.1 equiv), 1a (1.2
equiv)/CH2Cl2/-30 °C, 15 min.
10.1021/ol0271537 CCC: $25.00 © 2003 American Chemical Society
Published on Web 12/14/2002

It was clearly observed in our previous work that the
regioselectivity of nucleophilic trapping of cationic species
produced from substituted propargyl silyl ethers by the action
of TMSOTf could be specified depending on the structure
of 2. This is summarized in Scheme 2. When 2 bears a phenyl
group on the oxygen-centered carbon (R ) Ph), a B-type
cation was usually trapped by nucleophiles such as arenes
or allylsilanes to give allenyl frameworks (E) whereas the
formation of propargyl product (F) was highly sensitive to
the nature (the type of remaining substituent R′) or situation
(inter- or intramolecular attack) of the nucleophiles. When
2 bears a vinyl group such as a styryl group, a D-type
conjugated enyne cation was trapped by the nucleophiles to
exclusively afford conjugated enyne products (G) without
fail.
Again these previous trends were observed in the case of
1 as a nucleophile. When 2a or 2b was employed as a
partner, the reaction proceeded to result in trapping allenyl
cations by 1a or 1e,f to give allenic products (3a-c)
exclusively (entries 1-3 in Table 1), whereas the reaction
of 2c with 1a exclusively afforded alkyne 4a (entry 4). On
the other hand, the combination of 1c with 2a led to a mixture
of type E (3d) and F (4b) products in preference to 4b (entry
5).7 It should be mentioned with regard to entry 2 that only
1f led to the expected product 3b.8 The operational simplicity
Figure 1. Enol silyl ethers (1a-k) and propargylic and allylic silyl
ethers (2a-h).
propargyl silyl ethers (2a-h)5 listed in Figure 1 were
subjected to systematic experiments, and we have succeeded
in establishing the generality of the reaction. In addition, the
recent report by Matsuda and Ito concerned with the same
kind of reaction promoted by an iridium complex6 has
prompted us to quickly report our own efforts in this field.
This paper will disclose our recent findings in nucleophilic
reactions of carbocation species generated from 2a-h with
1a-k by the action of a Lewis acid as a catalyst.
Table 1. Synthesis of Allenic Frameworksa
Scheme 2
a Conducted with alkynes 1 (1.2 equiv) and 10 mol % BF3‚OEt2 based
on 2 unless otherwise indicated. b Yields for isolated products; yield in
square bracket (entry 2) was based on consumed 2. c Conducted with 1.4
equiv of 1e,f. d Result for TMSOTf.
52
Org. Lett., Vol. 5, No. 1, 2003

of this synthesis should be also mentioned: the addition of
Lewis acid (TMSOTf or BF3‚OEt2) in a catalytic amount to
a mixture of 1 and 2 in dichloromethane is sufficient to effect
the reaction, and BF3‚OEt2 usually afforded better results in
terms of product yields than TMSOTf.9
Table 3. Synthesis of Cyclic Conjugated Enynesa
Thus, the synthesis of conjugated acyclic and cyclic enynes
could be realized by the combination of 2d-g with 1. Results
pertinent to this synthesis are summarized in Tables 2 and
3, respectively. In all cases, the substitution reactions
regioselectively proceeded to afford conjugated enynes (5a-j
or 6a-h). Type D intermediate (Scheme 2) was trapped by
Table 2. Synthesis of Acyclic Conjugated Enynesa
a Conducted with 1 (1.2 equiv) and 10 mol % BF3‚OEt2 based on 2.
b Structures were determined by NMR, MS, IR, and elemental analysis.
c Yields for isolated products; dr (diastereomer ratio) was determined by
NMR analysis. Relative configuration was not determined. d Yields in square
brackets are for byproducts (7a or 7b). e Conducted with 1.5 equiv of 1e,f
or 1h,i.
1. For the reaction of acyclic silyl ethers 2d,e, highly
Z-selective enyne formation (10:1) was observed in general.10
On the other hand, diastereomeric ratios for newly generated
two or three stereogenic centers turned out to be low (entries
5-9 in Table 2).11 Although additional limitations were
found,12 the yields are very high in general. Particularly
interesting are the cases of chiral enol ethers such as 1j or
1k13 in which a mixture of unequal amounts of diastereo-
(4) Enol silyl ethers except for 1j and 1k were prepared from ketones
by means of TBDMSOTf (1.2 equiv) and Et3N (2 equiv) using CH2Cl2 (5
mL/1 mmol of ketone) as a solvent at 0 °C for 1.5 h.
(5) Prepared from ketones for 2a-c or enones for 2d-h with corre-
sponding acetylide anions followed by O-silylation; see ref 3.
(6) (a) Matsuda, I.; Komori, K.; Itoh, K. J. Am. Chem. Soc. 2002, 124,
9072-9073. (b) Matsuda, I.; Wakamatsu, S.; Komori, K.; Makino, T.; Itoh,
K. Tetrahedron Lett. 2002, 43, 1043-1046.
(7) Selectivity of this class is difficult to explain only on the basis of
the steric effect, and clarification of the other factors, if any, must await
future studies.
(8) Similar trends were reported in alkoxide-promoted Michael addition
reactions using simple ketones; for example, see: (a) House, H. O.; Roelofs,
W. L.; Trost, B. M. J. Org. Chem. 1966, 31, 646-655. (b) Ishikawa, T.;
Kadoya, R.; Arai, M.; Takahashi, H.; Kaisi, Y.; Mizuta, T.; Yoshikai, K.;
Saito, S. J. Org. Chem. 2001, 66, 8000-8009.
a Conducted with 1 (1.2 equiv) and 10 mol % BF3‚OEt2 based on 2.
b Structures were determined by NMR, HRMS, IR, and elemental analysis.
c Yields for isolated products; dr (diastereomer ratio) for (Z)-isomers.
Relative configuration was not determined. d Data for TMSOTf. e Carried
out with 1.4 equiv of 1. f Yields in square brackets for consumed 2. g (Z)-
Isomer as a major product.
Org. Lett., Vol. 5, No. 1, 2003
53

isomers was obtained, indicative of asymmetric induction
by means of carbocations (entries 8 and 9 in Table 2). When
a mixture of 1f and 1e (1e,f) was treated with 2d under the
given conditions, 1f (more hindered than 1e) led to the
coupled product 5e. Similarly, 1h,i (a mixture of 1h and 1i)
afforded 5g in which 1i (more hindered than 1h) was
embedded (entries 5 and 7 in Table 2).
Table 3 summarizes the reactions of cyclic substrates 2f-
h, and again the same regioselectivity as that for the acyclic
versions was observed without fail. Most striking in this
series is that the ring-to-ring coupling reactions could be
achieved so easily that functionalized ring-assemblies such
as 6f-h (entries 5-7, Table 3) were obtained in a rapid and
simple manner: the construction of complex molecules of
this class should be highly beneficial to organic synthesis
and are otherwise difficult to access.
Entries 5 and 7 in Table 3 show that the same events as
those in entry 2 in Table 1 or entries 5 and 7 in Table 2
occurred again. Thus, the more substituted sp2-carbon of enol
silyl ethers has higher reactivity toward the cationic species
in general. These cases efficiently provide quaternary carbon
centers. Clarification of the exact reason responsible for the
unique chemoselectivity8 of this class must await future
theoretical and/or experimental studies.
In conclusion, we have demonstrated highly effective
coupling reactions between enol silyl ethers and carbocation
species that deserve consideration as a practical method for
carbon-carbon bond formation. Substrates 2a-c or 2d-h
can easily be prepared from ketones or enones, respectively,
with corresponding acetylide anions followed by O-silyl-
ation.5 This requires no special skill, conditions, or reagents.
Also, enol silyl ethers 1a-k were available through tradi-
tional protocol uneventfully.4 Thus, the present method is
highly convenient and useful for the introduction of allenic
or enyne functionalities to the R-position of substituted
ketones. Further explorations of this chemistry, including
complex natural product syntheses, are under investigation.
(9) General procedure: to a solution of 1 (0.5 mmol) and 2 (0.6 mmol)
in CH2Cl2 (5 mL) was added Lewis acid (0.05 mmol) at -30 °C. The
reaction was stirred at -30 °C until the disappearance of 1 was indicated
by TLC. To the mixture was added water (20 mL), and the resulting mixture
was extracted several times with 1:3 ethyl acetate-hexane. The combined
organic layers were dried over anhydrous Na2SO4 and concentrated to give
a crude residue, which was purified by column chromatography on silica
gel using ethyl acetate-hexane to afford 4, 5, or 6. For the reaction of 1a
with 2a, TMSOTf afforded 60% yield of 3a (Scheme 1) and BF3‚OEt2
afforded 80% yield (Table 1). Therefore, in this work, BF3‚OEt2 was used
as the Lewis acid except for the case of entry 4 in Table 2, where TMSOTf
was used.
Acknowledgment. This research was supported by a
Grant-in-Aid for Scientific Research from the Ministry of
Education, Culture, Sports, Science and Technology, Japan.
(10) The reason for the preferential formation of (Z)-enynes was already
discussed; see ref 3.
(11) Structures and isomer ratios for the products were determined by
careful analysis of NMR spectra, although the relative configurations of
major isomers were not determined yet; see also Supporting Information.
(12) Reactions of 1l with 2a,d, 2i with 1a, and 2j with 1a,d did not take
place under the given reaction conditions.
Supporting Information Available: Experimental pro-
cedures and spectroscopic data for coupling products 3-6
1
and copies of H and 13C NMR spectra for representative
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
(13) Denmark, S. E.; Pham, S. M. Org. Lett. 2001, 3, 2201-2204.
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