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Synlett 2002(8): 1257-1260
DOI: 10.1055/s-2002-32956
LETTER
© Georg Thieme Verlag Stuttgart · New York

A New Convergent Approach to α-Branched Alkynes

Delphine Renard, Hadi Rezaei, Samir Z. Zard*
Laboratoire de Synthèse Organique associé au CNRS, Ecole Polytechnique, 91128 Palaiseau, France
Fax: +3(1)69333851; e-Mail: zard@poly.polytechnique.fr;
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Publication History

Received 7 June 2002
Publication Date:
25 July 2002 (online)

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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

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-Et2O, 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 Et2O (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 Et2O (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 CH2Cl2 (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.