One-Pot Synthesis of 3,4-Disubstituted 2-Methylcyclopent-2-enols as Useful Building Blocks

Abstract

The present study refers to the synthesis of cyclopentene subunits possessing three differentiable functional groups. A tri­phenylphosphine triggered one-pot Michael–intramolecular Wittig reaction between di-tert-butyl acetylenedicarboxylate and butanedione was made reproducible and scalable, delivering in good yield the desired tricarbonylated building block. Simple and selective transformations of this functionalized cyclopentene were performed.

Key words

tandem reaction - Michael addition - intramolecular Wittig reaction - cyclization - regioselectivity - diastereoselectivity

• References and Notes


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Selected recent examples for the synthesis of related trisubstituted cyclopentenoids (see also references cited herein):
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Pauson–Khand cyclization:
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Intramolecular pseudo Pauson–Khand cyclization:
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• 12b Mechanistically, this reaction involves an initial conjugate addition of triphenylphosphine onto the acetylenic electrophile 7 to give the intermediate zwitterionic species A which deprotonates butanedione 8 to give its corresponding enolate B as well as the vinyl phosphonium ion C. Further nucleophilic addition of B onto acceptor C yields ylide D prone to deliver the final Wittig annelation adduct 9 (Scheme 6). It is worth noting that when performed on the corresponding diethyl ester of 7, this reaction leads to γ-lactone formation due to the addition of the diethyl ester zwitterion corresponding to A onto one of the butanedione carbonyl groups followed by γ-lactone annelation and subsequent ethanolysis of the phosphonium residue.
• 13 For recent examples of the search for such solutions, see: Bechara WS, Pelletier G, Charette AB. Nature Chem. 2012; 4: 228 ; and references herein
• 14 Study to be published elsewhere. Although different experiments were performed to understand the requirement of a large excess of butanedione (syringe pump additions, the presence or the absence of traces of a protic sources such as H₂O or t-BuOH), the reason for the need of such an excess still remains unclear.
• 15 Experimental Procedure for 9: To a solution of triphenylphosphine (25.5 g, 97.4 mmol, 1.1 equiv) and butanedione (155 mL, 1.77 mol, 20 equiv) in anhyd CH₂Cl₂ at –5 °C was added dropwise di-tert-butylacetylene dicarboxylate (20 g, 88.5 mmol). The reaction mixture was allowed to warm to r.t. and stirred for 3 h. The solvent and the excess of butanedione were removed under reduced pressure and the residue was purified by flash column chromatography (heptane–EtOAc, 1:0 up to 3:1) to give pure cyclopentenone adduct 9 (16.4 g, 63% yield, see supporting information for full characterization).
• 16 For the analogous cyclopentenone diester 24 lacking the vinylic Me group α to the carbonyl, reduction with NaBH₄ led to a 6:1 mixture of cis/trans-25 diastereoisomers (Scheme 7). see: Thorstensson F, Wångsell F, Kvarnström I, Vrang L, Hamelink E, Hallberg A, Rosenquist Å, Samuelsson B. Bioorg. Med. Chem. 2007; 15: 827
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• 18 Preparation of 16: A suspension of N,O-dimethylhydroxylamine hydrochloride (3.69 g, 38.0 mmol, 1.2 equiv) in anhyd CH₂Cl₂ at –5 °C was added dropwise to a 2 M solution of AlMe₃ in toluene (19.0 mL, 38 mmol, 1.2 equiv) and the reaction mixture was stirred at the same temperature for 1 h. A solution of dimethyl ester 15 (6.78 g, 31.7 mmol, 1 equiv) in CH₂Cl₂ (60 mL) was then added dropwise to the reaction mixture which was then allowed to warm to r.t. and stirred overnight. A saturated solution of Rochelle salt was added and the mixture was extracted with CH₂Cl₂ (3 ×). The combined organic layers were washed with brine, dried with MgSO₄ and filtered. The solvent was removed in vacuo and the crude product was purified by flash column chromatography (heptane–EtOAc, 1:0 up to 1:3) to give the pure Weinreb monoamide 16 as a yellow oil (6.78 g, 88%); R_f 0.10 (heptane–EtOAc, 1:1). IR: 3395, 2949, 1716, 1651, 1435, 1274, 1220, 1131, 1046 cm^–1. ¹H NMR (360 MHz, CDCl₃): δ = 4.42 (br d, J = 6.8 Hz, 1 H), 4.28 (br d, J = 8.2 Hz, 1 H), 3.80 (s, 3 H), 3.71 (s, 3 H), 3.22 (s, 3 H), 2.26 (br dd, J = 14.5, 7.7 Hz, 1 H), 2.22 (d, J = 1.4 Hz, 3 H), 1.72 (d, J = 14.1 Hz, 1 H). ¹³C NMR (90.6 MHz, CDCl₃; DEPT): δ = 176.6, 166.1, 159.4, 128.6, 81.0 (+), 61.9 (+), 51.7 (+), 45.1 (+), 36.6 (–), 32.8 (+), 14.6 (+). HRMS (ESI): m/z [M + Na]⁺ calcd for [C₁₁H₁₇NO₅ + Na]: 266.1004; found: 266.0999.
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• 21 To avoid epimerization of 18 at C-1, column chromatography separations were performed on commercial pH 7 neutralized silica Chromagel (SDS silica 60 AC.C 70–200 μm).
• 22 Due to the low cost and the easy removal of butanedione by rotary evaporation, the need for a high excess of this reactant is not insuperable for practical scale-up of the procedure.