Intramolecular carbonyl olefination of esters. Regioselective preparation of enol ethers of cyclic ketones by the titanocene(II)-promoted reaction of alkyl ω,ω-bis(phenylthio)alkanoates

Article abstract of DOI:10.1039/b010156g

The treatment of alkyl ω,ω-bis(phenylthio)alkanoates with Cp₂Ti[P(OEt)₃]₂ produced enol ethers of 5-, 6-, 7-, and 9-membered cyclic ketones.

Full text of DOI:10.1039/b010156g

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Intramolecular carbonyl olefination of esters. Regioselective preparation of
enol ethers of cyclic ketones by the titanocene(II)-promoted reaction of alkyl
w,w-bis(phenylthio)alkanoates
Md. Abdur Rahim, Hironori Sasaki, Jun Saito, Tooru Fujiwara and Takeshi Takeda*
Department of Applied Chemistry, Tokyo University of Agriculture and Technology, Koganei, Tokyo 184-8588,
Japan. E-mail: takeda-t@cc.tuat.ac.jp
Received (in Cambridge, UK) 19th December 2000, Accepted 21st February 2001
First published as an Advance Article on the web 14th March 2001
The treatment of alkyl w,w-bis(phenylthio)alkanoates with
Cp2Ti[P(OEt)3]2 produced enol ethers of 5-, 6-, 7-, and
9-membered cyclic ketones.
its application to the synthesis of cyclic vinyl ethers. Un-
fortunately the attempt to prepare monocyclic vinyl ethers by
Table 1 Intramolecular carbonyl olefination of alkyl w,w-bis(phenyl-
thio)alkanoates 2
Intramolecular reactions of phosphorous ylides and related a-
phosphorous carbanions with ketones and aldehydes have been
used by a number of workers for the preparation of cycloalk-
enes, including complex natural products.1 However, intra-
molecular carbonyl olefinations of esters using the phosphorous
carbanions are generally unsuccessful because these reactions
end up with the formation of acylation products.2 Only the
preparation of certain five- and six-membered cyclic com-
pounds, in which the formation of a double bond is facilitated by
p-conjugation with a carbonyl group or an aromatic ring, has
been achieved.3 Transition metal–carbene complexes and
related reagents have been employed for this transformation.
Stille and Grubbs have described the formation of titanium–
carbene complexes by the ring-opening metathesis of strained
norbornylene derivatives and their intramolecular reaction with
an ester carbonyl.4 Although tungsten–carbene complex pro-
moted transformation of benzyl 2-benzylhex-5-enoate into
3-benzyl-2-benzyloxycyclopentene via olefin metathesis–car-
bonyl olefination was reported, the experimental details includ-
ing the yield of the product were not disclosed.5 Mortimore and
Kociénski reported the cyclization of 4,4-dibromobutyl benzo-
ate utilizing a TiCl4–Zn–TMEDA system.6 The olefination
product, 6-phenyl-3,4-dihydro-2H-pyran, however, was ob-
tained in only a poor yield. The intramolecular McMurry
coupling of keto esters is regarded as a formal intramolecular
olefination of esters, and various cyclanones have been
prepared by this method.7 Although this reaction is useful for
the preparation of furans and benzofurans,8 its application to the
synthesis of alicyclic vinyl ethers has yet to appear. Formal
intramolecular carbonyl olefination consisting of the inter-
molecular carbonyl olefination of esters and subsequent ring
closing metathesis has been employed for the synthesis of cyclic
vinyl ethers.9 The studies described above indicate that the
intramolecular carbonyl olefination of esters still remains a
problem to be solved.
Recently we reported a new method for carbonyl olefination
using a thioacetal–Cp2Ti[P(OEt)3]2 1 system.10 Since this
reaction is useful for the olefination of esters, we have studied
Scheme 1
DOI: 10.1039/b010156g
Chem. Commun., 2001, 625–626
This journal is © The Royal Society of Chemistry 2001
625

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the titanocene(II)-promoted olefination of w,w-bis(phenyl-
thio)alkyl alkanoates was unsuccessful owing to the concomi-
tant formation of oligomers.11 Herein we describe the intra-
molecular reaction of alkyl w,w-bis(phenylthio)alkanoates 2.
This reaction proceeds by way of the titanium–carbene
complexes 3 to produce a wide variety of vinyl ethers of cyclic
ketones 4 without formation of any oligomer (Scheme 1).
When methyl 2-phenyl-7,7-bis(phenylthio)heptanoate 2i was
treated with the low-valent titanium species 1 (4 equiv.) at room
temperature for 1 h, the complete disappearance of the starting
material was observed. Column chromatography using basic
alumina gave the cyclic vinyl ether 4i in 59% yield. The
cyclization of 2i in refluxing THF produced 4i in better yield
(Table 1, Entry 9). In a similar manner, the enol ethers of five-,
six-, and seven-membered cyclic ketones were obtained in good
yields by the reaction of alkyl a-substituted w,w-bis(phenyl-
thio)alkanoates. The substituent a to the carbonyl group is not
crucial for the present olefination. The reactions of the esters
carrying a substituent at the b-position also produced the
corresponding cyclic compounds 4d–f.† It was found that the
tert-butyl esters gave better yields than the corresponding ethyl
esters in these reactions (see Entries 5 and 6). In some case, we
observed the partial isomerization of the initial olefination
product to the tetrasubstituted cycloalkene. This isomerization,
however, was absolutely depressed when the reaction was
carried out at 15 °C (Entry 2).
The advantage of the present preparation is that the starting
materials are easily prepared by the use of organosulfur building
blocks. Thus the esters 2k and l were obtained by the
Williamson ether synthesis utilizing w,w-bis(phenylthio)alk-
anols and were transformed into the nine-membered cyclic
vinyl ethers 4k and l with high stereoselectivity. The E-
configuration of their double bonds was determined by
NOESY.
All the experiments described above were carried out on a
small scale (0.5 mmol). Since an intramolecular reaction
generally requires high dilution conditions to prevent the
competitive intermolecular reaction, decrease in the yield is
sometimes a serious problem upon scale up. We examined a
gram-scale reaction of 2i to confirm the synthetic utility of the
present reaction. Using a slightly modified procedure,12 the
cycloheptene 4i was obtained in better yield (73%) than for the
smaller scale reaction (Entry 9).
Culture, of Japanese Government (No. 11119214 and
11440213).
Notes and references
† A typical experimental procedure: to 6 ml of a THF solution of the
titanocene(II) reagent 1, prepared from titanocene dichloride (498 mg, 2.0
mmol), magnesium turnings (58 mg, 2.4 mmol), triethyl phosphite (0.69 ml,
4.0 mmol), and finely powdered molecular sieves 4 Å (200 mg),13 was
added 10 ml of a THF solution of 2f (237 mg, 0.50 mmol) dropwise over 20
min at room temperature under argon. After stirring for 3 h, the reaction was
quenched by addition of 1 M NaOH (20 ml). The insoluble materials were
filtered off through Celite and washed with ether (10 ml). The layers were
separated, and the aqueous layer was extracted with ether (3 330 ml). The
combined organic extracts were washed with 1 M NaOH (20 ml) and dried
over K2CO3. After removal of the solvent, the residue was chromatographed
over alumina gel (deactivated with 5% of H2O; eluted with 1%
triethylamine in hexane) to afford 92 mg (75%) of 4f.
1 K. B. Becker, Tetrahedron, 1980, 36, 1717; B. E. Maryanoff and A. B.
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In conclusion, we have established the first versatile method
for the regioselective preparation of vinyl ethers of cyclic
ketones by the intramolecular carbonyl olefination of esters.
Further study on the application of this methodology to the
synthesis of a variety of heterocycles is currently in progress.
This work was supported by a Grant-in-Aid for Scientific
Research from the Ministry of Education, Science, Sports, and
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12 For the preparation of the titanocene(II) reagent 1 on a large scale, see T.
Fujiwara, K. Yanai, K. Shimane, M. Takamori and T. Takeda, Eur. J.
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13 T. Fujiwara, Y. Kato and T. Takeda, Tetrahedron, 2000, 56, 4859.
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