Preparation of enol ethers by carbonyl olefination utilizing an alkoxymethyl chloride-titanocene(II) system

Article abstract of DOI:10.1016/j.tetlet.2003.09.013

Aldehydes, ketones, esters and lactones are transformed into enol ethers or 1,2-dialkoxy-1-alkenes by treatment with organotitanium species prepared from alkoxymethyl chlorides and a titanocene(II) complex.

Full text of DOI:10.1016/j.tetlet.2003.09.013

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 7897–7900
Preparation of enol ethers by carbonyl olefination utilizing an
alkoxymethyl chloride–titanocene(II) system
Takeshi Takeda,* Tomohiro Shono, Kenji Ito, Hironori Sasaki and Akira Tsubouchi
Department of Applied Chemistry, Tokyo University of Agriculture and Technology, Koganei, Tokyo 184-8588, Japan
Received 26 July 2003; revised 29 August 2003; accepted 3 September 2003
Abstract—Aldehydes, ketones, esters and lactones are transformed into enol ethers or 1,2-dialkoxy-1-alkenes by treatment with
organotitanium species prepared from alkoxymethyl chlorides and a titanocene(II) complex.
© 2003 Elsevier Ltd. All rights reserved.
the conventional Wittig route as shown in Scheme 1.
Enol ethers are useful intermediates in organic synthesis
The present reaction enjoys the advantage that the
and a variety of methods for their preparation have
halides 3 are used as olefination agents without any
been investigated. Among them alkoxymethylenation of
carbonyl compounds by the Wittig reaction using
alkoxymethylenephosphoranes has been most fre-
quently employed as a useful method for the one
pre-transformation, and the starting materials 3 were
readily prepared from the corresponding alcohols by
the reaction with paraformaldehyde and hydrogen
chloride.5
carbon homologation of carbonyl compounds to alde-
hydes.1 The similar methoxymethylenation by the
Treatment of benzyloxymethyl chloride 3a with the
Peterson reaction utilizing methoxy(trimethylsilyl)-
titanocene(II) species 1 at −20°C for 5 min and 25°C
methyllithium was also reported.2 A serious drawback
for 10 min produced certain organotitanium species,
of these conventional reactions is that they cannot be
employed for the olefination of carboxylic acid deriva-
tives due to the preferential acylation. On the other
hand, methoxymethylenation utilizing titanium-based
reagents eliminates such limitation; a variety of car-
bonyl compounds are transformed into enol ethers by
the treatment with methoxymethylidene–titanocene(II)
species 1.3 However, inaccessibility of various dithio-
orthoformates has prevented the use of this procedure
as a versatile method for alkoxymethylenation.
which afforded the enol ether 4a in 66% yield on
treatment with 1,5-diphenyl-3-pentanone 2a (Table 1,
Entry 1). When the reaction of the organotitanium
species with 2a was carried out under reflux in THF,
the yield of the enol ether 4a slightly increased (Entry
2). Similar reactions of aldehydes and ketones 2b–e
with various alkoxymethyl chlorides 3 were performed
and the enol ethers 4b–h were obtained in good yields
(Entries 3–9).6
The following is a typical experimental procedure.
Finely powdered molecular sieves 4 A (175 mg), magne-
Recently, we found a new carbonyl olefination utilizing
an alkyl halide–titanocene(II) system.4 We further
investigated the application of this new methodology to
the synthesis of various olefins, and here we report a
versatile method for the alkoxymethylenation of car-
bonyl compounds 2 utilizing alkoxymethyl chlorides 3
and titanocene(II) 1 leading to the formation of enol
ethers or 1,2-dialkoxy-1-alkenes 4. It largely simplifies
Keywords: carbonyl compounds; enol ethers; olefination; titanium
and compounds.
* Corresponding author. Tel.: +81 42 388 7034; fax: +81 42 388 7034;
e-mail: takeda-t@cc.tuat.ac.jp
Scheme 1. Titanocene(II)-promoted alkoxymethylenation of
carbonyl compounds with alkoxymethyl chlorides.
0040-4039/$ - see front matter © 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2003.09.013

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T. Takeda et al. / Tetrahedron Letters 44 (2003) 7897–7900
Table 1. Alkoxymethylenation of carbonyl compoundsa

T. Takeda et al. / Tetrahedron Letters 44 (2003) 7897–7900
7899
sium turnings (43 mg, 1.8 mmol) and Cp2TiCl2 (436
mg, 1.75 mmol) were placed in a flask and dried by
heating with a heat gun under reduced pressure (2–3
mmHg). After cooling, THF (3.5 ml) and P(OEt)3 (0.60
mL, 3.5 mmol) were added successively with stirring at
room temperature under argon, and the reaction mix-
ture was stirred for 2.8 h. The mixture was cooled to
−20°C and a THF (1 mL) solution of 3a (235 mg, 1.5
mmol) was added. After being stirred for 5 min, the
mixture was warmed up to 25°C and stirring was
continued for further 10 min at the same temperature.
A THF (1.5 mL) solution of 2a (119 mg, 0.50 mmol)
was added to the mixture. After refluxing for 3 h, the
reaction was quenched by addition of 1 M NaOH. The
insoluble materials were filtered off through Celite and
washed with ether. The layers were separated, and the
aqueous layer was extracted with ether. The combined
organic extracts were dried over K2CO3. After removal
of the solvent, the residue was purified by silica gel
PTLC (hexane/ethyl acetate=95/5, v/v) to afford 105
mg (70%) of 4a. CAUTION Alkoxymethyl chlorides
are powerful alkylating agents and potential
carcinogens.
The present alkoxymethyl chloride–titanocene(II) 1 sys-
tem can be applied to esters and lactones 2f–i. Using a
similar procedure,10 these carbonyl compounds were
transformed into the 1,2-dialkoxy-1-alkenes 4j–m in
good yields (Entries 12–15).
As illustrated in Scheme 2, we assume that the reaction
proceeds through the formation of the alkoxymethyl-
idene complex of titanium 6. The complex 6 is gener-
ated by a-elimination of dialkyltitanocene 7, produced
by the oxidative addition of the chloride
3 to
titanocene(II) species, and subsequent disproportiona-
tion of the resulting alkyltitanocene 8.11 Similarly to
other titanium carbene complexes, the titanocene–
alkoxymethylidene 6 reacts with a carbonyl compound
2 to afford the corresponding olefin 4 via the formation
of oxatitanacyclobutane intermediate 9.
In the present alkoxymethylidenation of esters and
lactones, the E isomers always predominated.12 The
observed selectivity is different from that of the alkyl-
idenation of carboxylic acid derivatives with titanocene-
alkylidenes, in which Z-isomers are always dominant
products.13 This is probably due to the unfavorable
formation of the oxatitanacyclobutane intermediate 9b,
which is destabilized by the dipole–dipole repulsion
between two alkoxy substituents (Scheme 3).
As shown in Entry 10, the reaction of methoxymethyl
chloride 3e with 2a resulted in the formation of the enol
ether 4i in unsatisfactory yield probably due to hydro-
gen chloride formed by the partial hydrolysis of the
halide during weighting. Based on our previous obser-
vation that a gem-dihalide–titanocene(II) 1 system olefi-
nated the carbonyl compounds through the formation
of an alkylidene titanocene as an intermediate,7 we
explored the use of dichloromethyl methyl ether 5 for
the methoxymethylenation of 2a and found that the
enol ether 4i was obtained in better yield (Entry 11).8 It
is of interest that the both reactions using the
monochloride and the dichloride afford the same enol
ether.9 Since the dihalide 5 is commercially available,
In summary, we have established the first general
method for the alkoxymethylenation of carbonyl com-
pounds using alkoxymethyl chlorides and titanocene(II)
species, which is operationally straightforward and
needs no strong base such as alkyllithium. Further
study on the synthetic application of an alkyl halide–
titanocene(II) system is currently under way.
Acknowledgements
this reaction is
a
good alternative for the
methoxymethylenation with 3e.
This research was supported by a Grant-in Aid for
Scientific Research (No. 14340228) and a Grant-in-Aid
for Scientific Research on Priority Areas (A) ‘Exploita-
tion of Multi-Element Cyclic Molecules’ (No.
14044022) from the Ministry of Education, Culture,
Sports, Science and Technology, Japan. This work was
carried out under the 21st Century COE program of
‘‘Future Nano-materials’’ in Tokyo University of Agri-
culture & Technology.
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Scheme 2. Plausible pathway for the formation of enol ethers.
Scheme 3. Oxatitanacyclobutane intermediates in the
alkoxymethylenation of esters and lactones.

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T. Takeda et al. / Tetrahedron Letters 44 (2003) 7897–7900
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