Synlett 2009(8): 1346-1350  
DOI: 10.1055/s-0028-1088130
LETTER
© Georg Thieme Verlag Stuttgart ˙ New York

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

Nagarapu Srinivas, Vijay K. Marrapu, Kalpana Bhandari*
Division of Medicinal and Process Chemistry, Central Drug Research Institute, Lucknow 226 001, India
Fax: +91(522)2623405; e-Mail: bhandarikalpana@rediffmail.com;
Further Information

Publication History

Received 23 January 2009
Publication Date:
08 April 2009 (online)

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.

    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 
15

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]+.

16

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. 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. ESI-MS: m/z (%) = 249 (100) [M + 1]+.

19

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