Observations on the Synthesis and Carbocyclisation Reactions of 6-Oxohexa-2,3-dienoates

Abstract

6-Oxohexa-2,3-dienoates can be readily prepared via an atom economical Claisen rearrangement of propargyl vinyl ethers formed in situ by the reaction of propargylic alcohols with acetals. Preliminary experiments have demonstrated that these functionalised allenic esters undergo a facile amine-induced carbocyclisation under mild reaction conditions, yielding densely functionalised cyclopentanones containing chiral quaternary carbon centres.

Key words

acetals - alcohols - allenes - cyclisation - rearrangements

References and Notes

• 1a Schuster HF. Coppola GM. Allenes in Organic Synthesis   Wiley; New York: 1984. 
• 1b Zimmer R. Dinesh CU. Nandanan E. Khan FA. Chem. Rev.  2000,  100:  3067 
• 1c Ma S. Chem. Rev.  2005,  105:  2829 
• 2 Modern Allene Chemistry   Krause N. Hashmi ASK. Wiley-VCH; Weinheim: 2004. 
• 3 Gray PJ. Motherwell WB. Whitehead AJ. Synlett  2007,  431 
• 4 Brummond KM. DeForrest JE. Synthesis  2007,  795 
• 5 Freiria M. Whitehead AJ. Motherwell WB. Synlett  2003,  805 
• 6a Black DK. Landor SR. J. Chem. Soc.  1965,  5225 
• 6b Saucy G. Marbet R. Helv. Chim. Acta  1967,  50:  1158 
• For a metal-catalysed synthesis of allenes from propargylic alcohols, see:
• 6c Sherry BD. Toste FD. J. Am. Chem. Soc.  2004,  126:  15978 
• 9a Sugita T. Eida M. Ito H. Komatsu N. Abe K. Suama M. J. Org. Chem.  1987,  52:  3789 
• 9b Sigman MS. Eaton BE. Tetrahedron Lett.  1993,  34:  5367 

7

All pyruvic acid esters were purchased from the Aldrich chemical company.

8

General Experimental Procedure for the Synthesis of Allenic Esters 8a-g: A solution of the propargylic alcohol (7.00 mmol), acetal (7.70 mmol) and PTSA (30 mg) in anhyd toluene (30 mL) in a flask fitted with a Dean and Stark separator was heated to a vigorous reflux for 24 h. The cooled solution was concentrated at reduced pressure and the crude oils were purified by flash column chromatography, eluting with PE-EtOAc (20:1) to give the described allenes 8a-g as pale yellow oils. Data for 8f: IR (thin film): 2933 (CH), 2804 (CH), 1957 (s, C=C=C), 1716 (C=O), 1450 cm^-¹. ^¹H NMR (300 MHz, CDCl₃): δ = 1.50-1.80 (m, 10 H, CH₂), 1.87 (d, J = 2.9 Hz, 3 H, Me), 3.72 (s, 3 H, OMe), 5.27 (q, J = 2.9 Hz, 1 H, CH), 9.32 (s, 1 H, CHO). ^¹³C NMR (75 MHz, CDCl₃): δ = 210.7, 201.4, 167.7, 98.2, 95.7, 52.3, 51.5, 30.7, 30.6, 25.5, 22.0, 22.0, 15.0. HRMS: m/z [M + H] calcd for C₁₆H₁₈O₃: 223.13341; found: 223.13276.

10

General Experimental Procedure for the Preparation of Cyclopentanones 20a-c: Pyrrolidine (0.45 mmol) was added to a solution of the allenic ester (0.45 mmol) in MeCN (8 mL) at r.t. The solution was stirred at r.t. for 12 h and then concentrated at reduced pressure. The crude oil was dissolved in THF (10 mL) and 10% aq AcOH (10 mL) was added. The acidic solution was stirred at r.t. for 12 h and then the mixture was poured into sat. aq NaHCO₃ solution (10 mL). The aqueous phase was separated and extracted with EtOAc (3 × 20 mL). The combined organic extracts were washed with brine (20 mL), dried (MgSO₄), filtered and concentrated at reduced pressure. The crude oils were purified by flash column chromatography, eluting with PE-EtOAc (5:1) to give the title cyclopentanones 20a-c. Data for 20c: mp 34-36 ˚C. IR (Nujol): 3496 (br s, OH), 2929, 2856 (CH), 1747 (C=O, ketone), 1728 (C=O, ester), 1452 cm^-¹. Diastereoisomer 1: ^¹H NMR (300 MHz, CDCl₃): δ = 1.30-1.74 [m, 10 H, (CH₂)₅], 1.47 (s, 3 H, Me), 2.27 (d, J = 18.4 Hz, 1 H, CH₂CO), 2.53 (br s, 1 H, OH), 2.82 (d, J = 18.4 Hz, 1 H, CH₂CO), 3.11 [s, 1 H, CH(OH)], 3.70 (s, 3 H, OMe). ^¹³C NMR (75 MHz, CDCl₃): δ = 213.7, 173.6, 77.9, 62.3, 54.2, 49.6, 42.5, 39.0, 29.4, 25.7, 24.3, 22.8, 22.3, 16.4. Diastereoisomer 2: ^¹H NMR (300 MHz, CDCl₃): δ = 1.20-1.75 [m, 10 H, (CH₂)₅], 1.33 (s, 3 H, Me), 2.18 (d, J = 5.6 Hz, 1 H, OH), 2.22 (d, J = 17.4 Hz, 1 H, CH₂CO), 2.59 (d, J = 17.4 Hz, 1 H, CH₂CO), 3.69 (s, 3 H, OMe), 4.39 [d, J = 5.4 Hz, 1 H, CH(OH)]. ^¹³C NMR (75 MHz, CDCl₃): δ = 212.3, 172.9, 85.9, 60.0, 52.8, 47.3, 42.2, 36.7, 29.0, 25.6, 23.3, 22.1, 15.6. HRMS: m/z [M + H] calcd for C₁₃H₂₀O₄: 241.14398; found: 241.14411.