Alkylidenation of esters on solid support and traceless synthesis of 2- substituted benzofurans

Article abstract of DOI:10.1016/S0040-4039(00)00753-X

Polymer-supported esters are smoothly converted into enol ethers using a titanocene alkylidene prepared by treatment of 2-tert- butyldimethylsilyloxybenzaldehyde diphenyldithioacetal with the low valent titanium species Cp₂Ti[P(OEt)₃]₂. Treatment of the enol ethers with acid leads to the release of ketones from the Wang resin in high yield. Traceless solid-phase synthesis of 2-substituted benzofurans is achieved in a three- step termination procedure. (C) 2000 Published by Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)00753-X

Tetrahedron Letters 41 (2000) 4987±4990
Alkylidenation of esters on solid support and traceless
synthesis of 2-substituted benzofurans
Emma J. Guthrie,a Jackie Macritchieb and Richard C. Hartleya,*
aDepartment of Chemistry, University of Glasgow, Glasgow G12 8QQ, UK
bAventis CropScience UK Ltd, Chesterford Park, Sa€ron Walden, Essex CB10 1XL, UK
Received 20 March 2000; accepted 8 May 2000
Abstract
Polymer-supported esters are smoothly converted into enol ethers using a titanocene alkylidene prepared
by treatment of 2-tert-butyldimethylsilyloxybenzaldehyde diphenyldithioacetal with the low valent tita-
nium species Cp2Ti[P(OEt)3]2. Treatment of the enol ethers with acid leads to the release of ketones from
the Wang resin in high yield. Traceless solid-phase synthesis of 2-substituted benzofurans is achieved in a
three-step termination procedure. # 2000 Published by Elsevier Science Ltd.
Keywords: solid-phase synthesis; benzofurans; titanium and compounds; thioacetals.
Takeda and co-workers recently reported the alkylidenation of carbonyl compounds 1 using
thioacetals 2 and a low valent titanium complex, Cp2Ti[P(OEt)3]2 (Scheme 1).1,2
Scheme 1.
* Corresponding author.
0040-4039/00/$ - see front matter # 2000 Published by Elsevier Science Ltd.
PII: S0040-4039(00)00753-X

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Esters 1 (XˆOR) can be converted into enol ethers 3 (XˆOR) using this procedure and like the
reagents developed by Tebbe3 and Petasis,4 the active species is believed to be titanocene(IV)
alkylidene 4, but unlike these other reagents, R1 and R2 can have hydrogen atoms beta to the
titanium atom. Furthermore, the thioacetal reactants are more easily made than the 1,1-
dibromoalkanes required for the related Takai reagents,5 which we have used extensively.6
We here report the ®rst use of the Takeda reaction in solid-phase synthesis.7,8 The new procedure
avoids the problematic work-up that resulted in low yields of enol ethers when we used Takeda
alkylidenation of esters in solution phase. We also report a novel alkylidenating agent that allows
cyclative termination of solid-phase synthesis to give 2-substituted benzofurans. Substrates are
often attached to polymer supports such as Merri®eld, Wang or Tentagel resins by an ester link.
After substrate modi®cations cleavage from the resin generally leaves a carboxylic acid derivative
or alcohol at the site of attachment. This unnecessary functionality may contribute to the
physiochemical and biological properties of the ®nal compound, and so distort structure±activity
relationships when used in agrochemical or pharmaceutical research. The benzofurans produced
by our method show no trace of the site of attachment to the solid support and may, in theory,
have substituents at any site.
We used 1,3-diisopropylcarbodiimide to couple carboxylic acids to Wang-resin (loading 1.7
mmol/g) contained in macrokans (0.29 mmol of alcohol per IRORI macrokan) to give resin-
bound esters 5 (Scheme 2). Thioacetal 6 was synthesised in two steps from salicaldehyde (Scheme
3) and used to generate a novel alkylidenating reagent under Takeda conditions. Esters 5 were
smoothly converted into enol ethers 7 using this reagent and the work-up consisted of simply
washing the resin with various solvents. In each case, disappearance of the carbonyl absorption in
the IR spectrum of esters 5 (obtained using the Golden Gate IR apparatus) and an appropriate
weight gain con®rmed complete conversion to enol ethers 7. The steric bulk of R had little e€ect
on the reaction (Table 1). Cleavage from the resin using 50% aqueous tri¯uoroacetic acid (TFA)
in dichloromethane for 30 min gave pure ketones 8 in good overall yield from esters 5. No
chromatography was necessary.
Scheme 2.
Scheme 3.

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Table 1
Enol ethers similar to enol ethers 7, synthesised by palladium(0)-catalysed cross-coupling
reactions, had been cyclised in solution phase using polyphosphoric or p-toluenesulfonic acid.9
We attempted cleavage and cyclisation of enol ethers 7 using dry TFA over magnesium sulfate,
but this gave a mixture of products. Consequently, phenol 9 was generated using tetra-
butylammonium ¯uoride (TBAF), and treated with 50% aqueous TFA in dichloromethane for
30 min. This resulted in smooth cleavage from the resin to give benzofurans in good yield. Again,
no chromatography was necessary.
Typical procedure for alkylidenation reaction: Triethylphosphite (4.0 ml, 23.3 mmol) in dry
THF was added to titanocene dichloride (2.93 g, 11.8 mmol), magnesium (0.40 g, 16.5 mmol) and
4 A molecular sieves (1.15 g) and the mixture was stirred at room temperature under argon for
3.5 h. A solution of thioacetal 6 (1.27 g, 2.90 mmol) in dry THF (11 ml) was added and the
mixture stirred for a further 15 min. The resulting reagent was syringed into a dry ¯ask containing
two kans of preswollen (in 3 ml of dry THF) resin-bound ester 5 (0.29 mmol each of Wang resin
with a loading of 1.7 mmol of ester/g). The mixture was stirred or shaken for 18 h, the THF
removed and the kans washed (30 ml each wash) with THF, then alternately with methanol and
CH2Cl2 (Â4), then methanol and ®nally ether. The resin-bound enol ether 7 was then dried under
vacuum.
Procedure for deprotection reaction: TBAF (1 ml of a 1 M solution in THF) was added to one
kan of resin-bound enol ether 7 (0.29 mmol) swollen in dry THF (5 ml) under argon and the
mixture was shaken for 3 h. The THF was removed and the kan washed (30 ml each wash) with
THF (Â3), and then as above. The resin-bound phenol 9 was dried under vacuum.
Procedure for cleavage: One kan of resin-bound enol ether 7 or 9 (0.29 mmol) was swollen in
CH2Cl2 (4 ml) and treated with 50% aqueous TFA solution (2.5 ml). After 30 min stirring or
shaking, the kan was washed with CH2Cl2 (3Â30 ml). The washings were combined, dried
(MgSO4) and the solvent removed under reduced pressure to give ketone 8 or benzofuran 10.
Traces of TBAF were removed from benzofuran 10 by dissolving in ether (30 ml) and washing
with water (6Â30 ml), before drying (MgSO4), and removing the solvent under vacuum.
In summary, we have demonstrated that the Takeda reaction can be performed on solid-
phase and have developed a procedure for the traceless solid-phase synthesis of 2-substituted
benzofurans.
Acknowledgements
Aventis CropScience UK Ltd and EPSRC for funding.

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