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

Sivaraman Balasubramaniam; Indrapal Singh Aidhen

doi:10.1055/s-2007-973882

LETTER

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;

Abstract

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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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References

References and Notes

<A NAME="RG00307ST-1">1</A> For a review, see: Krongauz ES. Russ. Chem. Rev. 1977, 46: 59

<A NAME="RG00307ST-2">2</A> Khan FA. Prabhudas B. Dash J. Sahu N. J. Am. Chem. Soc. 2000, 122: 9558 ; and references cited therein

<A NAME="RG00307ST-3">3</A> Mitchell RB. Iyer VS. Tetrahedron Lett. 1993, 34: 3683

<A NAME="RG00307ST-4">4</A> Westerhoff UT. Zhou M. Synlett 1994, 975

<A NAME="RG00307ST-5">5</A> Sibi MP. Sharma R. Paulson KL. Tetrahedron Lett. 1992, 33: 1941

<A NAME="RG00307ST-6">6</A> In an isolated single example, methyl 2-methyl-1,3-dithiolane carboxylate has been used in the proposed way. See: Heuet F. Pellet M. Conia JM. Tetrahedron Lett. 1976, 39: 3579

<A NAME="RG00307ST-7A">7a</A> Abbaspour Tehrani K. Boeykens M. Tyvorskii VI. Kulinkovich O. De Kimpe N. Tetrahedron 2000, 56: 6541 ; and references cited therein

<A NAME="RG00307ST-7B">7b</A> De Kimpe N. Stanoeva E. Boeykens M. Synthesis 1994, 427

For reviews on Weinreb amide chemistry, see:

<A NAME="RG00307ST-8A">8a</A> Singh J. Satyamurthi N. Aidhen IS. J. Prakt. Chem. 2000, 342: 340

<A NAME="RG00307ST-8B">8b</A> Mentzel M. Hoffmann HMR. J. Prakt. Chem. 1997, 339: 517

<A NAME="RG00307ST-8C">8c</A> Sibi MP. Org. Prep. Proced. Int. 1993, 25: 15

<A NAME="RG00307ST-9">9</A> Mickel SJ. Niederer D. Daeffler R. Osani A. Kuesters E. Schmid E. Schaer K. Gamboni R. Chen W. Loeser E. Kinder FR. Konigsberger K. Prasad K. Ramsey TM. Repic O. Wang R.-M. Florence G. Lyothier I. Paterson I. Org. Process Res. Dev. 2004, 8: 122

<A NAME="RG00307ST-10">10</A> Abramski W. Belzecki C. Chmielewski M. Bull. Acad. Sci. Chem. 1985, 33: 451

<A NAME="RG00307ST-11">11</A> Juaristi E. Tapia J. Mendez R. Tetrahedron 1986, 42: 1253

<A NAME="RG00307ST-12">12</A> Raghuram T. Vijaysaradhi S. Aidhen IS. Singh J. Synth. Commun. 1999, 29: 3215

<A NAME="RG00307ST-13">13</A> Vedejs E. Arnost MJ. Dolphin JM. Eustache J. J. Org. Chem. 1980, 45: 2601

<A NAME="RG00307ST-14">14</A> Fujisawa T. Kojima E. Itoh T. Sato T. Chem. Lett. 1985, 11: 751

<A NAME="RG00307ST-15">15</A> Trost BM. Hiroi K. Jungheim LN. J. Org. Chem. 1980, 45: 1839

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.

<A NAME="RG00307ST-17">17</A> Huet F. Pellet M. Lechevallier A. Conia JM. J. Chem. Res., Synop. 1982, 9: 246

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.

<A NAME="RG00307ST-19A">19a</A> Adams A. De Kimpe N. Chem. Rev. 2006, 106: 2299

<A NAME="RG00307ST-19B">19b</A> De Kimpe N. Stevens C. J. Org. Chem. 1993, 58: 2904

<A NAME="RG00307ST-19C">19c</A> De Kimpe N. Keppens M. J. Agric. Food Chem. 1996, 44: 1515

<A NAME="RG00307ST-19D">19d</A> Harrison TJ. Dake GR. J. Org. Chem. 2005, 70: 10872

<A NAME="RG00307ST-20">20</A> Snider BB. Lu Q. J. Org. Chem. 1996, 61: 2839 ; THP refers to tetrahydropyranyl ether protection