A Mild and Efficient Bisaldolization of Ketones and its Application towards Spirocyclic 1,3-Dioxanes and Novel 1,3,5-Trioxocanes

Abstract

Bisaldolization of aryl alkyl ketones as well as cyclic ­ketones with paraformaldehyde in the presence of a catalytic amount of l-proline and low concentration of aqueous sodium ­hydroxide has been developed in excellent yields. Further, these bisaldols are elaborated to the corresponding spirocyclic dioxanes and novel spirocyclic trioxocanes in the presence of p-toluene sulfonic acid. The structures and preferred conformations of these eight-membered spirocyclic 1,3,5-trioxocanes are discussed.

Key words

aqueous media - bisaldol - Mannich adduct - Mannich-aldol - l-proline - spirocylic dioxane - trioxocane

References and Notes

• 1 Rychnovsky SD. Chem. Rev.  1995,  95:  2021 
• 2a Cordova A. Janda KD. J. Am. Chem. Soc.  2001,  123:  8248 
• 2b Horva G. Huszthy P. Szarvas S. Szokan G. Redd JT. Bradshaw JS. Izatt RM. Ind. Eng. Chem. Res.  2000,  39:  3576 
• 3a Weissermel K. Arpe HJ. Polyhydric Alcohols, In Industrial Organic Chemistry   3rd ed.:  VCH; New York: 1997.  p.210 
• 3b Holm VS. Salmi T. Arvela PM. Paatero E. Lindfors LP. Org. Process Res. Dev.  2001,  5:  368 
• 4 Jan EV. Acta. Chem. Scand. Ser. B  1974,  28:  509 
• 5a Notz W. Tanaka F. Barbas III CF. Acc. Chem. Res.  2004,  37:  580 
• 5b Cordova A. Barbas III CF. Tetrahedron Lett.  2003,  44:  1923 
• 5c Casas J. Sunden H. Cordova A. Tetrahedron Lett.  2004,  45:  6117 
• 6 Ibrahem I. Casas J. Cordova A. Angew. Chem. Int. Ed.  2004,  43:  6528 
• 7a Erkkila A. Pihko PM. J. Org. Chem.  2006,  71:  2538 
• 7b Wang W. Mei Y. Li H. Wang J. Org. Lett.  2005,  7:  601 
• 8 Srinivas N. Bhandari K. Tetrahedron Lett.  2008,  49:  7070 
• 9a Srinivas N. Palne S. Nishi Gupta S. Bhandari K. Bioorg. Med. Chem. Lett.  2009,  19:  324 
• 9b Bhandari K. Srinivas N. Shiva Keshava GB. Shukla PK. Eur. J. Med. Chem.  2009,  437 
• 10 Bachman GB. Heisey LV. J. Am. Chem. Soc.   1946,  68:  2496 
• 11a Li CJ. Chan TH. Organic Reactions in Aqueous Media   John Wiley and Sons; New York: 1997. 
• 11b Organic Synthesis in Water   Grieco PA. Blackie Academic and Professional; London: 1998. 
• 11c Blackmond DG. Armstrong A. Coombe V. Wells A. Angew. Chem. Int. Ed.  2007,  46:  3798 
• 12 Kagan ES. Ardashev BI. Chem. Heterocycl. Compd.  1967,  3:  701 
• 13a Emer E. Galletti P. Giacomini D. Tetrahedron  2008,  64:  11205 
• 13b Zhao JF. He L. Jiang J. Tang Z. Cun LF. Gong LZ. Tetrahedron Lett.  2008,  49:  3372 
• 14 Kim KS. Ahn YH. Tetrahedron: Asymmetry  1998,  9:  3601 
• 17a Singh C. Pandey S. Saxena G. Srivastava N. Sharma M. J. Org. Chem.  2006,  71:  9057 
• 17b Ushigoe Y. Torao Y. Masuyama A. Nojima M. J. Org. Chem.  1997,  62:  4949 
• 17c McCullough KJ. Masuyama A. Morgan KM. Nojima M. Okada Y. Satake S. Takeda S. J. Chem. Soc., Perkin Trans. 1  1998,  2353 
• 17d Martin A. Martin IP. Quintanal LM. Suarez E. Org. Lett.  2007,  9:  1785 
• 18a Polshettiwar V. Varma RS. J. Org. Chem.  2007,  72:  7420 
• 18b Hiraguri Y. Tokiwa Y. Macromolecules  1997,  30:  3691 

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General Procedure for the Preparation of Bisaldols 1a-8a (e.g., 2a)
A solution of a-tetralone (1.0 mmol), paraformaldehyde (4.0 mmol), and l-proline (40 mol%) in H₂O (0.5 mL) was stirred at r.t. for 34 h. To this added 0.53 M NaOH (0.3 mL) solution slowly. After completion of the reaction (monitored by TLC) the reaction mixture was extracted with EtOAc (3 × 4 mL). The combined organic extracts were washed with distilled H₂O (5 × 3 mL), dried over Na₂SO₄, and removal of the solvent under reduced pressure furnished the crude product, which was filtered through SiO₂ column (EtOAc-hexane = 1:2, v/v) to give 2a (96%) as a white solid; mp 98-99 ˚C. ^¹H NMR (300 MHz, CDCl₃): δ = 1.98 (t, J = 6.4 Hz, 2 H), 3.01 (t, J = 6.4 Hz, 2 H), 3.62 (br s, 2 H), 3.71-3.95 (dd, J = 11.3 Hz, 4 H), 6.69 (m, 2 H), 6.84 (d, J = 8.8 Hz, 1 H), 7.97 (d, J = 8.8 Hz, 1 H). ^¹³C NMR (75 MHz, CDCl₃): δ = 24.9, 26.4, 51.2, 64 (2 C), 126.8, 127.6, 128.9, 131.6, 134.1, 143.8, 203.1. ESI-MS: m/z (%) = 207 (100) [M + 1]⁺.

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General Procedure for the Preparation of 9-16b (e.g., 10a,b)
A mixture of 2,2-bishydroxymethyl-3,4-dihydro-2H-naphthalen-1-one (2a, 1.0 mmol), paraformaldehyde (4.0 mmol), and catalytic amount of PTSA (0.05 equiv) in CH₂Cl₂ (6 mL) was stirred at ambient temperature for 11 h. After completion of reaction (monitored by TLC), the reaction mixture was filtered through sintered funnel. The filtrate was washed with 1% aq NaHCO₃ solution (2 × 2 mL), followed by H₂O (3 × 2 mL), and dried over anhyd Na₂SO₄. Removal of the solvent under vacuum afforded the crude mixture of corresponding spirocyclic 1,3-dioxane 10a and 1,3,5-trioxocane 10b in quantitative amount. The above mixture was subjected to Florisil column (EtOAc-hexane = 1:20, v/v) to give pure products (10a and 10b in a 1:1.2 ratio).
Compound 10a: mp 46-47 ˚C. ^¹H NMR (300 MHz, CDCl₃): δ= 2.92 (t, J = 6.9 Hz, 2 H), 3.66 (d, J = 11.6 Hz, 2 H), 3.98-4.07 (dd, J = 11.6 Hz, 2 H), 4.69 (d, J = 5.8 Hz, 2 H), 5.24 (d, J = 5.8 Hz, 2 H), 7.18 (m, 1 H), 7.31 (m, 2 H), 7.63 (d, J = 6.4 Hz, 1 H). ^¹³C NMR (75 MHz, CDCl₃): δ = 24.8, 27.5, 45.9, 70.6 (2 C), 94.3, 126.8, 127.7, 128.9, 131.7, 133.9, 143.2, 198.1. IR (KBr): 3222, 2361, 1708, 1221, 1165, 762, 667 cm^-¹. ESI-MS: m/z (%) = 219 (77) [M + 1]⁺.
Compound 10b: oil. ^¹H NMR (300 MHz, CDCl₃): δ = 2.26 (t, J = 6.4 Hz, 2 H), 3.04 (t, J = 6.4 Hz, 2 H), 3.82-4.21 (dd, J = 12.0 Hz, 4 H), 4.8 (d, J = 6.7 Hz, 2 H), 4.96 (d, J = 6.4 Hz, 2 H), 7.34 (m, 2 H), 7.52 (m, 1 H), 8.03 (d, J = 7.8 Hz, 1 H). ^¹³C NMR (75 MHz, CDCl₃): δ = 24.8 (2 C), 28.7, 29.6, 49.6, 69.9, 95.9, 126.7, 127.8, 128.7, 131.4, 133.5, 143.2, 199.4. IR (neat): 3027, 2367, 1709, 1217, 1161, 767 cm^-¹. ESI-MS: m/z (%) = 249 (100) [M + 1]⁺.

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Experimental procedures, characterization and 1D, 2D NMR spectra are available as supplementary data.