9822
Figure 2.
The one exception was cyclobutanone (entry i), which condensed quite well to yield the
expected alcohol 10i in 73% yield. These results can be explained by the facile enolization of
both cyclopentanone and acetophenone when II is present, while the enolate of cyclobutanone
possesses high skeletal strain and so is less readily formed. In this case the enolization is not
thermodynamically favored and so the reaction with II can occur. Furthermore, the driving
force of the condensation in this case could be associated with a release of strain when
cyclobutanone reacts with II.
The final step was the acid-catalyzed cyclodehydration of the benzylic alcohols 10. Methane-
sulfonic acid was initially used, producing the expected heterocycle 11 in high yield. However,
4-pyridine carbaldehyde required more vigorous conditions (reflux temperature), probably due
to the protonation of the basic nitrogen atom. For the five-membered heterocyclic aldehydes
(Table 1, entries b–d), trifluoroacetic acid, a weaker acid, was used yielding the expected
products in good yields in the case of the thiophene carbaldehydes and a very poor yield (24%)
for the furyl derivative. The sensitivity of the furan ring toward acid media required the
cyclization of 10d to be run at low temperature (−30°C, saturated ethereal solution of hydrogen
chloride) in order to obtain a reasonable (70%) yield of 11d. Finally, in the case of alcohols 10
derived from aliphatic aldehydes (Table 1, entries f and g), the dehydration to the corresponding
alkene was a competing process, this being the sole isolated product in the case of 10g (70%),
while 11f was isolated in 67% yield, with only a 15% yield of the alkene side product.
Representative experimental procedure:
Compound 10: To a solution of the iodo derivative 9 (1.0 g, 2.94 mmol) in dry THF (30 mL)
stirred at 0°C was added a 3 M solution of methyl magnesium bromide (2.15 mL, 6.47 mmol).
The mixture was stirred for 1 h and then cooled to −78°C. A 1.7 M solution of tert-BuLi (3.8
mL, 6.47 mmol) was added and the solution stirred at this temperature for 30 min, then the
carbonyl derivative (1.2 mol) was added at −78°C. The mixture was then heated to room
temperature. After 1 h at this temperature, the reaction mixture was quenched with saturated
ammonium chloride solution and extracted into CH2Cl2 (3×25 mL). The combined organic
phases were dried over Na2SO4, filtered, and evaporated to dryness. The residue was purified by
flash chromatography using hexane/EtOAc (8:2) as eluent.
Compound 11: To a solution of the benzylic alcohol 10 (1 mmol) in CH2Cl2 (15 mL) was
added the corresponding acid (5 mmol) and the mixture was stirred as described for each case
(see footnotes to Table 1). The reaction mixture was quenched with saturated NaHCO3 solution
and worked-up as indicated above for 10. The crude mixture was purified by flash chromatog-
raphy using hexane/EtOAc (8:2) as eluent. The oily product obtained crystallized as a white
powder on standing with hexane.
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