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Synlett 2002(2): 0247-0250
DOI: 10.1055/s-2002-19746
LETTER
© Georg Thieme Verlag Stuttgart · New York

Direct Conversion of Esters to Hydroxyamides on Solid Support - a Key Step en route to Bisoxazoline Ligands

Avi Weissberg, Moshe Portnoy*
School of Chemistry, Raymond and Beverly Sackler Faculty of Exact Sciences, Tel-Aviv University, Ramat Aviv, Tel Aviv 69978, Israel
Fax: +972(3)6409293; e-Mail: portnoy@post.tau.ac.il;
Further Information

Publication History

Received 26 November 2001
Publication Date:
02 February 2007 (online)

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Abstract

A method for converting esters into β-hydroxyamides via their direct reaction with β-aminoalcohols was implemented for the first time on solid support. The transformation is performed under basic conditions and presumably includes transesterification followed by rapid intramolecular O,N-acyl transfer. The technique was successfully tested on monoesters as well as malonates. The transformation of malonates is a key step in the on-resin assembly of bisoxazoline ligands, demonstrated here for the first time.

Key words

solid-phase synthesis - aminoalcohols - amides - aminolysis - oxazolines

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A similar chain of events was proposed in ref. [2] .

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Typical Procedure: LDA (0.6 mL, 2 M solution, 15 equiv) was added dropwise at 10 °C to a solution of ethanolamine (0.l mL, 20 equiv) in dry DMF (2 mL). In another flask 1a (100 mg, 0.08 mmol, 1 equiv) was suspended in dry DMF (2 mL). The solution of the first flask was cannulated into the suspension of 1a and stirred for 18 h at r.t. The resin was then filtered and washed sequentially with DMF, DMF/H2O, H2O, THF, CH2Cl2 and dried under vacuum.The product was analyzed by acidolytic cleavage using 1H NMR, indicating quantitative yield.
IR (on-resin, KBr): ν 3408, 1649 cm-1.
Cleaved product (bis trifluoroacetate ester). 1H NMR (200 MHz, CDCl3/TFA): δ = 7.07 (bs, 1 H), 4.51 (t, J = 5.0 Hz, 2 H), 4.43 (t, J = 6.4 Hz, 2 H), 3.75 (q, J = 5.0 Hz, 2 H), 2.45 (t, J = 7.6 Hz, 2 H), 1.80 (m, 4 H), 1.45 (m, 2 H). 13C NMR (50 MHz, CDCl3/TFA): δ = 173.4, 68.4, 65.4, 39.2, 34.7, 27.0, 24.8, 24.5. MS (CI): found m/z, 368.1, calcd for C12H16F6NO5 (M + 1) 368.1.

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Typical Procedure for Bisoxazoline Assembly on solid Support: The bromohexanol solution (21 µL, 2 equiv) in CH2Cl2 (1.5 mL) was added dropwise to a suspension of Imidate Wang resin (100 mg, 0.08 mmol) in cyclohexane (1.5 mL). The reaction was stirred at r.t. for 5 min. Then BF3·Et2O (5 µL) was added, and the suspension was stirred at r.t. for another 10 min. The resin was filtered and washed with CH2Cl2, THF, CH2Cl2. The resin was dried under vacuum, and then suspended in anhyd DMF (3 mL). In another flask diethyl malonate was added dropwise to the suspension of NaH (20 mg, 5 equiv) in dry DMF (3 mL). After 5 min stirring this solution was cannulated to the resin suspension and the reaction mixture was stirred for 24 h at 60 °C. The resin was filtered, washed and dried under vacuum, and then suspended in anhyd THF (3 mL) to which LDA (0.2 mL, 2 M solution, 25 equiv) was added. The reaction mixture was stirred for 1 h. Then CH3I (50 µL, 10 equiv) was added and the reaction mixture was stirred for an additional 22 h at r.t. The resin was filtered washed and dried under vacuum. The conversion to diamide was executed as above (ref. [10] ). Afterwards, the resin was suspended in anhyd THF (3 mL) for 10 min, and then DIPEA (1.5 mL) and MsCl (2 mL) were added at 10 °C. The reaction mixture was stirred for 48 h at r.t. The resin was filtered, washed and dried under vacuum. The resin was suspended in anhyd THF to which LDA (1 mL, 2 M solution, 12.5 equiv) was added. The reaction mixture was stirred for 24 h at r.t. The resin was filtered, washed and dried under vacuum. According to acidolytic cleavage the product was obtain in overall 75% yield.
Gel-phase 13C NMR (100 MHz, C6D6): δ = 168.3, 71.9, 66.7, 53.9, 36.5, 29.5 (3 carbons), 25.7, 24.0, 21.3.