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

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

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 [e-mail], or by contacting The Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: [phone].