Download PDF
Synlett 2009(11): 1842-1846  
DOI: 10.1055/s-0029-1217361
LETTER
© Georg Thieme Verlag Stuttgart ˙ New York

Unexpected Formation of Fluorine-Containing Multiply Substituted Dispirocyclohexanes from the Reaction of Ethyl-4,4,4-trifluoro-1,3-dioxobutanoate and 2-Arylideneindane-1,3-diones

Baifan Daia, Liping Song*a,b, Pengyuan Wanga, Hai Yia, Weiguo Caoa, Guifang Jinb, Shizheng Zhu*b, Min Shaoc
a Department of Chemistry, School of Science, Shanghai University, 99 Shangda Road, Shanghai 200444, P. R. of China
Fax: +86(21)66132797; e-Mail: lpsong@shu.edu.cn;
b Key Laboratory of Organofluorine Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 354 Fenglin Lu, Shanghai 200032, P. R. of China
c Instrumental Analysis and Research Center, Shanghai University, Shanghai 200444, P. R. of China
Further Information

Publication History

Received 16 February 2009
Publication Date:
12 June 2009 (online)

    Permissions and Reprints All articles of this category

Abstract

In the presence of a catalytic amount of piperidine ­(10 mol%), reaction of ethyl 4,4,4-trifluoro-3-oxobutanoate 3 and ­2-arylidene-indane-1,3-diones 4 gave the unexpected fluorine-­containing multiply substituted dispirocyclohexanes 5 in good yields. The structures of compounds 5 were fully confirmed by spectroscopic methods and elemental analysis. A representative compound 5a was further confirmed by XRD analysis. A plausible reaction mechanism for the formation of compounds 5 was presented.

Key words

fluorine-containing - spiro compound - polysubstitution - 2-arylidene-indan-1,3-dione - ethyl 4,4,4-trifluoro-3-oxobutanoate

    References and Notes

  • 1a Gross U. Rüdiger S. Organo-Fluorine Compounds, In Methods of Organic Chemistry (Houben-Weyl)   Vol. E10a:  Baasner B. Hagemann H. Tatlow JC. Thieme; Stuttgart: 1999.  p.18-26  
    Google Scholar
  • 1b Smart BE. J. Fluorine Chem.  2001,  109:  3 
    Google Scholar
  • 2a Banks RE. Smart BE. Tatlow JC. Organofluorine Chemistry: Principles and Commercial Applications   Plenum Press; New York: 1994. 
    Google Scholar
  • 2b Hiyama T. Organofluorine Compounds: Chemistry and Properties   Springer; Berlin: 2000. 
    Google Scholar
  • 3 Burger’s Medicinal Chemistry and Drug Discovery   Vol. 1:  Abraham DJ. John Wiley and Sons; New York: 2003. 
    Google Scholar
  • 4a Ismail FMD. J. Fluorine Chem.  2002,  118:  27 
    Google Scholar
  • 4b Organofluorine Compounds in Medicinal Chemistry and Biomedical Applications   Filler R. Kobayashi Y. Yagulpolskii LM. Elsevier; Amsterdam: 1993. 
    Google Scholar
  • 4c Welch JT. Ewarakrishnan SE. Fluorine in Bioorganic Chemistry   John Wiley; New York: 1991. 
    Google Scholar
  • 4d Becker A. Inventory of Industrial Fluoro-Biochemicals   Eyrolles; Paris: 1996. 
    Google Scholar
  • 5a Kozikowski AP. Acc. Chem. Res.  1984,  17:  410 
    Google Scholar
  • 5b Howe RK. Shelton BR. J. Org. Chem.  1990,  55:  4603 
    Google Scholar
  • 5c De Amici M. De Michelli C. Sani VM. Tetrahedron  1990,  46:  1975 
    Google Scholar
  • 5d Caroll WA. Grieco PA. J. Am. Chem. Soc.  1993,  115:  1164 
    Google Scholar
  • 5e Early WG. Oh T. Overman LE. Tetrahedron Lett.  1988,  29:  3785 
    Google Scholar
  • 5f Ban Y. Taga N. Oishi T. Chem. Pharm. Bull.  1976,  24:  736 
    Google Scholar
  • 5g Ban Y. Seto M. Oishi T. Chem. Pharm. Bull.  1975,  23:  2605 
    Google Scholar
  • 5h Ban Y. Taga N. Oishi T. Tetrahedron Lett.  1974,  15:  187 
    Google Scholar
  • 5i Van Tamelen EE. Yardley JP. Miyano M. Hinshaw WB. J. Am. Chem. Soc.  1969,  91:  7333 
    Google Scholar
  • 5j Kobayashi J. Tsuda M. Ageme K. Shigemori H. Ishibashi M. Sasaki T. Mikami Y. Tetrahedron  1991,  47:  6617 
    Google Scholar
  • 5k James DM. Kunze HB. Faulkner JD.
    J. Nat. Prod.  1991,  54:  1137 
    Google Scholar
  • 5l Sinclair A. Stockman RA. Nat. Prod. Rep.  2007,  24:  298 
    Google Scholar
  • 5m Xu S. Arimoto H. Uemura D. Angew. Chem. Int. Ed.  2007,  46:  5746 
    Google Scholar
  • 5n Clive DLJ. Yu M. Wang J. Yeh VSC. Kang S. Chem. Rev.  2005,  105:  4483 
    Google Scholar
  • 5o Yashin NV. Averina EB. Grishin YK. Kuznetsova TS. Zefirov NS. Synthesis  2006,  279 
    Google Scholar
  • 5p Bernard AM. Frongia A. Guillot R. Piras PP. Secci F. Spiga M. Org. Lett.  2007,  9:  541 
    Google Scholar
  • 5q Salim H. Piva O. Tetrahedron Lett.  2008,  49:  2994 
    Google Scholar
  • 6a Berger STA. Lemek T. Mayr H. ARKIVOC  2008,  (x):  37 
    Google Scholar
  • 6b Mosher WA. Brenne JL. J. Org. Chem.  1971,  36:  3383 
    Google Scholar
  • 6c Zalukaevs LP. Anokhina I. J. Gen. Chem. USSR.  1964,  34:  834 ; Zh. Obshch. Khim. 1964, 34, 840
    Google Scholar
  • 6d Soliman FM. Said MM. Maigali SS. Heteroat. Chem.  1997,  8:  157 
    Google Scholar
  • 7a Babu ARS. Raghunathan R. J. Heterocycl. Chem.  2006,  43:  1357 
    Google Scholar
  • 7b Babu ARS. Raghunathan R. Gayatri G. Sastry GN. J. Heterocycl. Chem.  2006,  43:  1367 
    Google Scholar
  • 7c Babu ARS. Raghunathan R. Synth. Commun.  2007,  37:  451 
    Google Scholar
  • 7d Babu ARS. Raghunathan R. Tetrahedron Lett.  2006,  47:  9221 
    Google Scholar
  • 7e Babu ARS. Raghunathan R. Tetrahedron  2007,  63:  8010 
    Google Scholar
  • 8a Ramachary DB. Anebouselvy K. Chowdari NS. Barbas CF. J. Org. Chem.  2004,  69:  5838 
    Google Scholar
  • 8b Ramachary DB. Chowdari NS. Barbas CF. Synlett  2003,  1910 
    Google Scholar
  • 9 Dhawan SN. Sharma M. Bajaj S. Sharma K. Sharma S. Heterocycles  2007,  71:  1509 
    CrossrefGoogle Scholar
  • 10 Harig M. Kuck D. Eur. J. Org. Chem.  2006,  1647 
    CrossrefGoogle Scholar
  • 11a Zalukaevs LP. Anokhina I. J. Gen. Chem. USSR.  1964,  34:  834 ; Zh. Obshch. Khim. 1964, 34, 840
    Google Scholar
  • 11b Zimaity T. Afsah ES. Hammouda M. Indian J. Chem., Sect. B: Org. Chem. Incl. Med. Chem.  1979,  17:  578 
    Google Scholar
  • 11c Zalukaevs LP. Vnenkovskaya DG. Zh. Org. Khim.  1966,  2:  672 
    Google Scholar
  • 11d Stankevich EI. Yanags GY. J. Gen. Chem. USSR.  1962,  32:  1123 ; Zh. Obshch. Khim. 1962, 32, 1146
    Google Scholar
  • 11e Pati HN. Das U. De Clercq E. Balzarini J. Dimmock JR. J. Enzym. Inhib. Med. Chem.  2007,  22:  37 
    Google Scholar
  • 12a Tu SJ. Jiang B. Zhang JY. Zhang Y. Jia RH. Li CM. Zhou DX. Cao LJ. Shao QQ. Synlett  2007,  480 
    Google Scholar
  • 12b Pabolkova EA. Trukhin EV. Kasem YA. Berestovitskaya VM. Russ. J. Gen. Chem.  2006,  76:  1349 
    Google Scholar
  • 12c Kozlov NG. Tarasevich VA. Vasilovskii DA. Baselaeva LI. Russ. J. Gen. Chem.  2006,  42:  107 
    Google Scholar
  • 12d Pizzirani D. Roberti M. Recanatini M. Tetrahedron Lett.  2007,  48:  7120 
    Google Scholar
  • 12e Chen Y. Tu SJ. Jiang B. Shi T. J. Heterocycl. Chem.  2007,  44:  1201 
    Google Scholar
  • 12f Shi DQ. Ni SN. Yang F. Shi JW. Duo GL. Li XY. Wang XS. Ji SJ. J. Heterocycl. Chem.  2008,  45:  963 
    Google Scholar
  • 12g Tu SJ. Jiang B. Zhang JY. Jia RH. Zhang Y. Yao CS. Org. Biomol. Chem.  2006,  4:  3980 
    Google Scholar
  • 12h Li M. Yang WL. Wen LR. Li FQ. Eur. J. Org. Chem.  2008,  2751 
    Google Scholar
  • 13a Song SD. Song LP. Dai BF. Yi H. Jin GF. Zhu SZ. Shao M. Tetrahedron  2008,  64:  5728 
    Google Scholar
  • 13b Li XF. Song LP. Xing CH. Zhao JW. Zhu SZ. Tetrahedron  2006,  62:  2255 
    Google Scholar
  • 13c Li DM. Song LP. Li XF. Xing CH. Peng WM. Zhu SZ. Eur. J. Org. Chem.  2007,  3520 
    Google Scholar
  • 13d Li DM. Song LP. Song SD. Zhu SZ. J. Fluorine Chem.  2007,  128:  952 
    Google Scholar
  • 14 Wu DY. Ren ZJ. Cao WG. Tong WQ. Synth. Commun.  2005,  35:  3157 
    CrossrefGoogle Scholar
15

A Typical Experimental Procedure for the Preparation of 5a To a mixture of ethyl 4,4,4-trifluoro-3-oxobutanoate (184.0 mg, 1.0 mmol) and 2-benzylidene-indane-1,3-dione (468.0 mg, 2.0 mmol) in MeCN (3.0 mL) was added a catalytic amount of pipreridine (8.5 mg, 0.1 mmol). The resulting mixture was stirred at r.t. until the reaction was completed
(8 h, monitored by TLC). The solvent was removed under reduced pressure. And then the residue was purified by column chromatography on silica gel using PE-EtOAc [6:1 (v/v)] as eluent to afford 5a as a colorless solid in 78% yield.

16

Spectroscopic Data for Products 5 Compound 5a: colorless solid (509.0 mg), mp 211-214 ˚C. ¹H NMR (500 MHz, CDCl3): δ = 0.89 (t, J = 7.0 Hz, 3 H, OCH2CH 3), 3.84 (qd, J 1 = 7.0 Hz, J 2 = 3.5 Hz, 2 H, OCH 2CH3), 4.51 (d, J = 12.5 Hz, 1 H, CH), 4.56 (s, 1 H, CH), 5.19 (d, J = 12.5 Hz 1 H, CH), 5.65 (s, 1 H, OH), 6.37 (br, 1 H, ArH), 6.59-7.06 (m, 8 H, ArH), 7.32-7.42 (m, 4 H, ArH), 7.54-7.56 (m, 3 H ArH), 7.66-7.69 (m, 1 H, ArH), 7.93-7.95 (m, 1 H, ArH). ¹9F NMR (470 MHz, CDCl3): δ = -71.63 (s, 3 F, CF3). IR (KBr): 3402, 3062, 2981, 2932, 1745, 1711, 1594, 1247, 1184 cm-¹. ESI-MS: m/z = 653 [M + H]+, 670 [M + NH4]+. Anal. Calcd for C38H27F3O7: C, 69.94; H, 4.17. Found: C, 70.06; H, 4.06.
Compound 5b: colorless solid (510.0 mg), mp 227-229 ˚C. ¹H NMR (500 MHz, CDCl3): δ = 0.91 (t, J = 7.0 Hz, 3 H, OCH2CH 3), 1.78 (s, 3 H, ArCH3), 2.04 (s, 3 H, ArCH3), 3.84 (qd, J 1 = 7.0 Hz, J 2 = 3.5 Hz, 2 H, OCH 2CH3), 4.47 (d, J = 12.5 Hz, 1 H, CH), 4.51 (s, 1 H, CH), 5.15 (d, J = 12.5 Hz, 1 H, CH), 5.63 (s, 1 H, OH), 6.15 (br, 1 H, ArH), 6.50-6.70 (m, 4 H, ArH), 6.82-6.86 (m, 2 H, ArH), 7.24-7.36 (m, 2 H, ArH), 7.39-7.43 (m, 2 H, ArH), 7.66-7.69 (m, 4 H, ArH), 7.92-7.93 (m, 1 H, ArH). ¹9F NMR (470 MHz, CDCl3): δ = -71.65 (s, 3 F, CF3). IR (KBr): 3408, 3029, 2986, 1741, 1712, 1247 cm-¹. ESI-MS: m/z = 681 [M + H]+, 698 [M + NH4]+. Anal. Calcd for C40H31F3O7: C, 70.58; H, 4.59. Found: C, 70.33; H, 4.77.
Compound 5c: colorless solid (617.0 mg), mp 246-247 ˚C. ¹H NMR (500 MHz, CDCl3): δ = 0.96 (t, J = 7.0 Hz, 3 H, OCH2CH 3), 3.89 (qd, J 1 = 7.0 Hz, J 2 = 3.5 Hz, 2 H, OCH 2CH3), 4.69 (d, J = 12.5 Hz, 1 H, CH), 4.71 (s, 1 H, CH), 5.20 (d, J = 12.5 Hz, 1 H, CH), 5.45 (s, 1 H, OH), 6.84-7.28 (m, 4 H, ArH), 7.43-7.53 (m, 3 H, ArH), 7.58-7.71 (m, 5 H, ArH), 7.76-7.80 (m, 2 H, ArH), 7.97-8.00 (m, 2 H, ArH). ¹9F NMR (470 MHz, CDCl3): δ = -71.67 (s, 3 F, CF3). IR (KBr): 3420, 3058, 2979, 2934, 1746, 1710, 1595, 1248, 1188 cm-¹. ESI-MS: 743 [M + H]+, 760 [M + NH4]+. HRMS (MALDI/DHB): m/z calcd for [C38H25F3N2O11 + H]+: 743.1483; found: 743.1501; m/z calcd for [C38H25F3N2O11 + Na]+: 765.1303; found:765.1309.
Compound 5d: colorless solid (584.0 mg), mp 243-244 ˚C. ¹H NMR (500 MHz, CDCl3): δ = 0.95 (t, J = 7.0 Hz, 3 H, OCH2CH 3), 3.87 (qd, J 1 = 7.0 Hz, J 2 = 3.5 Hz, 2 H, OCH 2CH3), 4.49 (d, J = 12.5 Hz, 1 H, CH), 4.53 (s, 1 H, CH), 5.11 (d, J = 12.5 Hz, 1 H, CH), 5.52 (s, 1 H, OH), 6.36-7.07 (m, 7 H, ArH), 7.33-7.51 (m, 4 H, ArH), 7.60-7.72 (m, 3 H, ArH), 7.72-7.75 (m, 1 H, ArH), 7.94-7.96 (m, 1 H, ArH). ¹9F NMR (470 MHz, CDCl3): δ = -71.70 (s, 3 F, CF3). IR (KBr): 3408, 3071, 2986, 2937, 1739, 1713, 1593, 1243, 1196 cm-¹. ESI-MS: m/z = 721, 723, 725 [M + H]+, 738, 740, 742 [M + NH4]+. Anal. Calcd for C38H25Cl2F3O7: C, 63.26; H, 3.49. Found: C, 62.87; H, 3.58.
Compound 5e: colorless solid (551.0 mg), mp 222-223 ˚C. ¹H NMR (500 MHz, CDCl3): δ = 0.92 (t, J = 7.0 Hz, 3 H, OCH2CH 3), 3.86 (qd, J 1 = 7.0 Hz, J 2 = 3.5 Hz, 2 H, OCH 2CH3), 4.49 (d, J = 12.5 Hz, 1 H, CH), 4.54 (s, 1 H, CH), 5.11 (d, J = 12.5 Hz, 1 H, CH ), 5.55 (s, 1 H, OH), 6.09 (br, 1 H, ArH) 6.49-6.93 (m, 6 H, ArH), 7.37-7.49 (m, 4 H, ArH), 7.56-7.60 (m, 3 H, ArH), 7.70-7.73 (m, 1 H, ArH), 7.93-7.95 (m, 1 H, ArH). ¹9F NMR (470 MHz, CDCl3): δ = -71.71 (s, 3 F, CF3), -112.61 (m, 1 F, ArF), -114.13 (m, 1 F, ArF). IR (KBr): 3397, 3087, 2983, 2938, 1743, 1711, 1511, 1247, 1190 cm-¹. ESI-MS: m/z = 689 [M + H]+. Anal. Calcd for C38H25F5O7: C, 66.28; H, 3.66. Found: C, 66.04; H, 3.49.

Compound 5f: colorless solid (620.0 mg), mp 241-243 ˚C. ¹H NMR (500 MHz, CDCl3): δ = 0.94 (br, 3 H, OCH2CH 3), 3.87 (br, 2 H, OCH 2CH3), 4.51 (br, 2 H, CH), 5.13 (br, 1 H, CH), 5.58 (s, 1 H, OH), 6.34-7.01 (m, 7 H, ArH), 7.43-8.00 (m, 9 H, ArH). ¹9F NMR (470 MHz, CDCl3): δ = -71.63 (s, 3 F, CF3). IR (KBr): 3440, 3055, 2984, 1744, 1710, 1593, 1249, 1235, 1176 cm-¹. ESI-MS: m/z = 721, 723, 725 [M + H]+, 738, 740, 742 [M + NH4]+. Anal. Calcd for C38H25Cl2F3O7: C, 63.26; H, 3.49. Found: C, 62.91; H, 3.37.
Compound 5g: colorless solid (743 mg), mp 265-266 ˚C. ¹H NMR (500 MHz, CDCl3): δ = 0.95 (br, 3 H, OCH2CH 3), 3.88 (br, 2 H, OCH 2CH3), 4.48 (br, 2 H, CH), 5.13 (br, 1 H, CH), 5.58 (s, 1 H, OH), 6.61-7.13 (m, 7 H, ArH), 7.35-7.76 (m, 8 H, ArH), 7.95-8.02 (m, 1 H, ArH). ¹9F NMR (470 MHz, CDCl3): δ = -71.61 (s, 3 F, CF3). IR (KBr): 3441, 3072, 2983, 1744, 1711, 1592, 1250, 1178 cm-¹. ESI-MS: m/z = 809, 811, 813 [M + H]+, 826, 828, 830 [M + NH4]+. HRMS (MALDI/DHB): m/z calcd for [C38H25Br2F3O7 + Na]+: 830.9811; found: 830.9817.

17

In particular, in the cases of compounds 5f and 5g, the ¹H NMR spectrum showed broad signals due to decreased rotational flexibility of the highly puckered structures.

18

CCDC 720376 contains the supplementary crystallographic data for this paper. These data can be obtained free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by emailing data_request@ccdc.cam.ac.uk, or by contacting The Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44 (1223)336033.