Abstract
A variety of α-branched alkynes can be easily assembled by
a Knoevenagel type condensation of 4-unsubstituted isoxazolin-5-ones
with aldehydes or ketones, followed by conjugate addition of an
organometallic reagent and nitrosative cleavage of the heterocyclic
ring.
Key words
alkynes - isoxazolin-5-ones - Knoevenagel condensation - conjugate addition
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8 Typical experimental procedures: (A) Condensation of isoxazolinones 1 with aldehydes
and ketones : To a solution of the isoxazolin-5-one (10 mmol)
in propan-2-ol (20 mL) in a 100 mL round bottom flask were added
the corresponding aldehyde (1.2 equiv) or ketone (2 equiv) and a
catalytic amount of piperidine (ca. 0.2 mL). The resulting solution was
then stirred to 50 °C in the case of aldehydes or to reflux in
the case of ketones. When TLC showed complete consumption of the
isoxazolinone, most of the solvent was removed under partial vacuum.
In the case of aldehydes, the products generally precipitated and
were isolated by a filtration and washed with petroleum ether. In
the other cases, an oil was obtained which was washed with a little petroleum
ether-Et2 O, 80:20, dried, and used as such in
next step. (B) Addition of organometallic
reagents to alkylidene isoxazolinone 2
. (a)Addition of Grignard reagents (compounds 3a -g ):
To a solution of the alkylidene isoxazolinone 2 (5
mmol) in dry THF (15 mL) cooled to -70 °C was
added a solution of the Grignard reagent (5 mmol). After stirring
for 15 min. at -70 °C, the mixture was allowed to
warm to r.t. then hydrolyzed with dilute HCl (0.2 M; 40 mL). The
aqueous layer was extracted with Et2 O (2 × 30
mL) and the combined organic layers were washed with brine (20 mL),
dried over MgSO4 , and concentrated under reduced pressure.
The nearly pure products 3a -g were used directly in step (C). (b)Addition of organozinc reagents (compounds 3k ,l
) : To a cooled (-10 °C)
solution of crotyl or allyl magnesium bromide (5.2 mmol) in dry
THF (15 mL) was added under nitrogen a solution of ZnBr2 (1
M/THF). The mixture was cooled to -70 °C
and the alkylidene isoxazolinone 2j or 2k (5 mmol) was added all at once. The mixture
was allowed to warm to r.t. and when TLC showed that no starting
material was left, dilute HCl (0.2 M; 40 mL) was added and the aqueous
layer extracted with Et2 O (2 × 30 mL). The combined
organic layers were washed with a solution of citric acid (0.1 M;
20 mL), brine (20 mL), dried over MgSO4 and concentrated
under reduced pressure. The nearly pure 3j ,k were used directly in step (C). (c)Addition of allenylzinc (compound 3n
) : To
a cooled (-70 °C) solution of trimethylsilyl-3-phenoxyprop-1-yne
(5 mmol) in dry THF (20 mL) was added dropwise a solution of sec- butyllithium [1.3 N] (5.1
mmol, 3.9 mL). After 10 min at -70 °C, a solution
of ZnBr2 (1 M; 5.1 mmol) was added dropwise. After warming
to -30 °C, isoxazolinone 2a was
added and the temperature allowed to rise to r.t. At the end of
the reaction (monitored by TLC), the mixture was hydrolyzed using
the same work-up as in the preceding procedure. Compound 3n thus obtained was used as such in step
(C). (d) Addition of Reformatsky’s
reagent (compounds 3h
,
i ) : 1,2-Dibromoethane
(0.2 mL) was added to zinc dust (15 mmol) in dry THF (10 mL) while
heating to reflux under nitrogen. After 2 min at reflux, the mixture
was cooled down to r.t., TMSCl (0.2 mL) was added, and the solution
refluxed again for 10 min. To this mixture, cooled down to r.t.,
was added dropwise ethyl bromoacetate (5.5 mmol). After stirring
15 min at r.t., the resulting Reformatsky’s reagent was
added to a cold (-10 °C) solution of isoxazolinone 2h or 2i (5 mmol)
in THF (10 mL) then the temperature was allowed to increase to r.t.
At the end of reaction (monitored by TLC) the mixture was hydrolyzed
using again the same work-up as for 2j and 2k . The nearly pure 3h ,i were used directly in step (C). (e)Addition of phenyl copper reagent (compound 3m ): To a suspension of copper bromide-dimethyl
sulfide (6 mmol) under nitrogen in dry THF (20 mL) was added dropwise
at -50 °C a solution of phenylmagnesium bromide
(5.5 mmol). After stirring 15 min at -50 °C, isoxazolinone 2m (5 mmol) was added and the reaction
mixture was stirred while keeping the temperature below -40 °C
until the TLC showed no starting material. The medium was then hydrolyzed
at -60 °C with dilute HCl (0.2 M; 40 mL) and the
aqueous layer extracted with ether (2 × 30 mL). The combined
organic layers were washed with a solution of citric acid (0.1 M;
2 × 20 mL), brine (20 mL), and dried over MgSO4 .
After concentrating under vacuum, the crude product was further
purified by filtration on a silica pad and used directly in step
C. (C) Synthesis of alkynes 4a -n :
To a suspension of ferrous sulfate (5.56 g, 20 mmol, 5.5 equiv)
in acetic acid (15 mL) was added half of a solution of sodium nitrite
(2.1 g, 35 mmol, 10 equiv) in water (10 mL) under an inert atmosphere (all
solutions must also be thoroughly degassed beforehand). The remainder
was added simultaneously with a solution of the isoxazolinone 3 (3.5 mmol) in degassed acid acetic (15 mL)
over 30 minutes at 25 °C. The set-up was then flushed with
nitrogen for 30 minutes; water (150 mL) was added and the reaction
mixture extracted with CH2 Cl2 (3 × 15
mL). The organic extracts were then washed with dilute HCl (0.5
M), saturated NaHCO3 , and dried over NaHCO3 (with
stirring) for 45 minutes. Concentration and purification by chromatography
of the residue provided alkynes 4 in the stated
yields.