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Synlett 2007(6): 0959-0963  
DOI: 10.1055/s-2007-973882
LETTER
© Georg Thieme Verlag Stuttgart · New York

Synthetic Equivalents Based on Weinreb Amide Functionality for Convenient Access to Monoprotected α-Diketones

Sivaraman Balasubramaniam, Indrapal Singh Aidhen*
Department of Chemistry, Indian Institute of Technology-Madras, Chennai 600036, India
Fax: +91(44)22574202; e-Mail: isingh@iitm.ac.in;
Further Information

Publication History

Received 4 January 2007
Publication Date:
26 March 2007 (online)

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Abstract

A convenient new strategy for the synthesis of monoprotected α-diketones has been achieved. The strategy is based on the use of hitherto unreported N-methoxy-N-methyl-1,3-dithiolane-2-carboxamide and N-methoxy-N-methyl-1,3-dithiane-2-carboxamide as synthetic equivalent for an α-dicarbonyl unit with opposing polarity. Nucleophilic addition on the amide functionality followed by alkylation furnished the targeted monoprotected α-diketones in moderate to good yields.

Key words

dithiolanes - dithianes - α-diketones - Weinreb amide

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N -Methoxy- N -methyl-1,3-dithiolane-2-carboxamide (1) Yield 75%; R f = 0.35 (hexane-EtOAc, 8:2), colorless solid, mp 58-59 °C. 1H NMR (300 MHz, CDCl3): δ = 3.21 (s, 3 H), 3.30-3.33 (m, 2 H), 3.46-3.49 (m, 2 H), 3.76 (s, 3 H), 5.36 (s, 1 H). 13C NMR (75 MHz, CDCl3): δ = 32.9, 38.7, 47.9, 61.5, 171.4. IR (CHCl3): 2752, 1674, 1451, 1378, 1242 cm-1. Anal. Calcd for C6H11NO2S2: C, 37.28; H, 5.74; N, 7.25; S,33.18. Found: C, 37.11; H, 5.63; N, 7.31; S, 3310. HRMS (EI): m/z calcd for C6H12NO2S2 [M + H]+: 194.0309; found: 194.0304.
N -Methoxy- N -methyl-1,3-dithiane-2-carboxamide (2) Yield 70%; R f = 0.30 (hexane-EtOAc, 8:2), colorless syrup. 1H NMR (400 MHz, CDCl3): δ = 1.96-2.10 (m, 2 H), 2.49-2.55 (m, 2 H), 3.16 (s, 3 H), 3.50 (m, 2 H), 3.68 (s, 3 H), 4.64 (s, 1 H). 13C NMR (100 MHz, CDCl3): δ = 24.7, 25.6, 31.9, 34.8, 61.2, 170.5. IR (CHCl3): 2966, 1655, 1458, 1421, 1376, 1172 cm-1. HRMS (EI): m/z calcd for C7H14NO2S2 [M + H]+: 208.0466; found: 208.0467.
General Procedure for the Addition of Organometallic Reagent to N -Methoxy- N -methyl-1,3-dithiolane-2-carboxamide (1) and N -Methoxy- N -methyl-1,3-dithiane-2-carboxamide (2) To a stirred solution of 1 or 2 (5 mmol) in 20 mL of anhyd THF, the appropriate solution of organometallic reagent (15 mmol) in 15 mL of anhyd THF was added under inert atmosphere at 0 °C and the mixture was stirred for 2 h. Subsequent hydrolysis was achieved by cautious addition of sat. NH4Cl solution. Aqueous layer was extracted with EtOAc, dried over Na2SO4 and concentrated to get crude product, which was purified by column chromatography using (hexane-EtOAc, 90:10) to afford 1,3-dithiolane ketones 8 and 1,3-dithiane ketones 9.
1-(1,3-Dithiolan-2-yl)nonan-1-one (8b) Yield 88%; R f = 0.50 (hexane-EtOAc, 9:1), colorless syrup. 1H NMR (400 MHz, CDCl3): δ = 0.88 (t, 3 H, J = 7.2 Hz), 1.26-1.31 (m, 10 H), 1.59-1.63 (m, 2 H), 2.63 (t, 2 H, J = 7.2 Hz), 3.36-3.49 (m, 4 H), 4.80 (s, 1 H). 13C NMR (100 MHz, CDCl3): δ = 14.0, 22.7, 24.2, 29.1, 29.2, 29.4, 31.9, 38.5, 38.9, 57.2, 203.1. IR (CHCl3): 2966, 1704, 1450, 1370 cm-1. HRMS (EI): m/z calcd for C12H22OS2Na [M + Na]+: 269.1010; found: 269.1008.
1-(1,3-Dithiolan-2-yl)-5-(tetrahydro-2 H -pyran-2-yloxy)pentan-1-one (8c) Yield 85%; R f = 0.4 (hexane-EtOAc, 8.5:1.5), colorless syrup. 1H NMR (400 MHz, CDCl3): δ = 1.48-1.80 (m, 4 H), 2.10-2.24 (m, 6 H), 2.74 (t, 2 H, J = 7.2 Hz), 3.31-3.37 (m, 4 H), 3.68-3.75 (m, 4 H), 4.57 (m, 1 H), 4.86 (s, 1 H). 13C NMR (100 MHz, CDCl3): δ = 22.2, 25.1, 27.1, 29.5, 29.8, 39.8, 40.1, 46.6, 62.3, 66.4, 98.8, 204.1. IR (CHCl3): 2941, 1710, 1444, 1255, 1153 cm-1. HRMS (EI): m/z calcd for C13H22O3S2Na [M + Na]+: 313.0908; found: 313.0905.

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General Procedure for Alkylating 1,3-Dithiolane Ketones 8a-h with Various Alkyl Halides Leading to Monoprotected α-Diketones To a suspension of paraffin removed NaH (1.5 mmol) in 2 mL anhyd DMF at 0 °C, was added 1,3-dithiolane ketone 8 (1 mmol) in 5 mL of anhyd DMF followed by appropriate electrophile (1.2 mmol). The reaction mixture was stirred at 0 °C for 2 h and the excess NaH was cautiously quenched using 20 mL of sat. NH4Cl solution at 0 °C. The reaction mixture was extracted three times using 25 mL of EtOAc. The organic layers were combined and given H2O wash followed by brine wash and dried over Na2SO4. The organic layer was concentrated under vacuum and the crude compound was purified by column chromatography (hexane-EtOAc) to afford monoprotected α-diketones. Representative spectral data for selected compounds are given below.
1-{2-[(1,3-dioxolan-2-yl)methyl]-1,3-dithiolan-2-yl}pentan-1-one (13)
Yield 58%; R f = 0.45 (hexane-EtOAc, 8:2), colorless syrup. 1H NMR (300 MHz, CDCl3): δ = 0.88 (t, 3 H, J = 7.1 Hz), 1.21-1.27 (m, 2 H), 1.46-1.50 (m, 2 H), 2.22 (t, 2 H, J = 7.1 Hz), 3.01 (d, 2 H, J = 7.1 Hz), 3.31-3.40 (m, 4 H), 3.95-4.15 (m, 4 H), 5.14 (t, 1 H, J = 7.1 Hz). 13C NMR (75 MHz, CDCl3): δ = 13.7, 22.1, 25.5, 38.6, 39.5, 40.7, 64.3, 74.8, 95.1, 201.1. IR (CHCl3): 2927, 1712, 1450, 1375, 1255 cm-1. Anal. Calcd for C12H20O3S2: C, 52.14; H, 7.29; S, 23.20. Found: C, 52.21; H, 7.52; S, 23.12.
1-(2-Allyl-1,3-dithiolan-2-yl)pentan-1-one (14) Yield 65%; R f = 0.6 (hexane-EtOAc, 9:1), colorless syrup. 1H NMR (400 MHz, CDCl3): δ = 0.84 (t, 3 H, J = 7.2 Hz), 1.18-1.29 (m, 2 H), 1.49-1.56 (m, 2 H), 2.70 (t, 2 H, J = 7.2 Hz), 2.81-2.83 (d, 2 H, J = 7.2 Hz), 3.24-3.35 (m, 4 H), 5.04-5.11 (m, 2 H), 5.67-5.76 (m, 1 H). 13C NMR (100 MHz, CDCl3): δ = 13.8, 22.2, 27.1, 37.1, 40.6, 44.0, 74.2, 119.0, 133.9, 205.1. IR (CHCl3): 2956, 1698, 1425, 1304 cm-1. HRMS (EI): m/z calcd for C11H19OS2 [M + H]+: 231.0877; found: 231.0876.
3-[(2-Benzoyl)-1,3-dithiolanyl]- N -methoxy- N -methyl-propionamide (20) Yield 70%; R f = 0.45 (hexane-EtOAc, 9:1), colorless syrup. 1H NMR (300 MHz, CDCl3): δ = 2.58-2.67 (m, 4 H), 3.11 (s, 3 H), 3.58 (s, 3 H), 3.46-3.56 (m, 4 H), 7.25-7.38 (m, 3 H), 7.88-8.05 (m, 2 H). 13C NMR (75 MHz, CDCl3): δ = 29.5, 32.1, 35.8, 39.5, 60.9, 75.8, 127.9, 129.2, 131.9, 135.6, 172.8, 196.2. IR (CHCl3): 2816, 1689, 1676, 1492, 1347 cm-1. Anal. Calcd for C15H19NO3S2: C, 55.36, H, 5.88, N, 4.30, S, 19.71. Found: C, 55.49; H, 5.63; N, 4.31; S, 19.10.
2-[Butoxy(phenyl)methylene]-1,3-dithiolane (26)
Yield 68%; R f = 0.6 (hexane-EtOAc, 9.5:0.5), colorless syrup. 1H NMR (400 MHz, CDCl3): δ = 0.87 (t, 3 H, J = 7.2 Hz), 1.36-1.42 (m, 2 H), 1.57-1.60 (m, 2 H), 3.27-3.29 (m, 4 H), 3.58 (t, 2 H, J = 6.4 Hz), 7.17-7.19 (m, 1 H), 7.27-7.30 (m, 1 H), 7.39-7.41 (m, 2 H). 13C NMR (100 MHz, CDCl3): δ = 13.7, 19.3, 32.0, 36.4, 38.9, 70.4, 123.9, 127.3, 128.1, 135.2, 141.9. IR (CHCl3): 2927, 1541, 1489, 1457, 1276, 1094 cm-1. HRMS (EI): m/z calcd for C14H18OS2 [M + H]+: 267.0877; found: 267.0878.



Ethyl 2-[1-(1,3-Dithiolan-2-ylidene)oct-2-ynyloxy]acetate (27)
Yield 65%; R f = 0.3 (hexane-EtOAc, 8.5:1.5), yellow colored syrup. 1H NMR (400 MHz, CDCl3): d = 0.84 (t, 3 H, J = 7.2 Hz), 1.25-1.31 (m, 7 H), 1.33-1.40 (m, 2 H), 2.34 (t, 2 H, J = 7.2 Hz), 3.29-3.33 (m, 4 H), 4.18 (q, 2 H, J = 7.2 Hz), 4.62 (s, 2 H). 13C NMR (100 MHz, CDCl3): δ = 13.9, 14.1, 19.6, 22.1, 28.1, 30.9, 37.7, 38.6, 60.9, 66.2, 73.1, 101.2, 125.1, 128.1, 169.3. IR (CHCl3): 2924, 1719, 1586, 1187 cm-1. HRMS (EI): m/z calcd for C15H23O3S2 [M + H]+: 315.1089; found: 315.1098.
6-(2-Methyl-1,3-dithiolan-2-yl)-2,3,4,5-tetrahydropyridine (32) Yield 80%; R f = 0.3 (hexane-EtOAc, 8:2), yellow solid, mp 55-57 °C. 1H NMR (400 MHz, CDCl3): d = 1.56-1.59 (m, 2 H), 1.67-1.71 (m, 2 H), 1.92 (s, 3 H), 2.50-2.55 (m, 2 H), 3.37-3.39 (m, 4 H), 3.64-3.67 (m, 2 H). 13C NMR (100 MHz, CDCl3): δ = 19.9, 21.7, 25.6, 31.2, 40.6, 49.6, 71.2, 170.7. IR (CHCl3): 2922, 1645, 1472, 1304 cm-1. HRMS (EI): m/z calcd for C9H16NS2 [M + H]+: 202.0724; found: 202.0728.