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Synlett 2009(11): 1827-1829  
DOI: 10.1055/s-0029-1217355
LETTER
© Georg Thieme Verlag Stuttgart ˙ New York

Trifluoromethyl-Substituted Analogues of 1-Aminocyclobutane-1-carboxylic Acid

Dmytro S. Radchenkoa,b, Pavel K. Mykhailiuk*a, Andrii V. Bezdudnyb,c, Igor V. Komarova,b
a Department of Chemistry, Kyiv National Taras Shevchenko University, Volodymyrska Street 64, 01033 Kiev, Ukraine
Fax: +380(44)2351273; e-Mail: pashamk@gmx.de;
b Enamine Ltd., Oleksandra Matrosova Street 23, 01103 Kiev, Ukraine
c The Institute of Organic Chemistry, The National Academy of Sciences of Ukraine, Murmanska Street 5, 02660 Kiev-94, Ukraine
Further Information

Publication History

Received 6 March 2009
Publication Date:
12 June 2009 (online)

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Abstract

Trifluoromethyl-substituted analogues of the 1-amino-cyclobutane-1-carboxylic acid - 1-amino-3-(trifluoromethyl) ­cyclo­butanecarboxylic and 1-amino-3,3-bis(trifluoromethyl)cyclobutanecarboxylic acids - have been synthesized from 1,3-dibromoacetone dimethyl ketal. The key step of the syntheses is a transformation of the acid moiety into the trifluoromethyl group using SF4 and HF.

Key words

fluorine - amino acids - conformational restriction - ­cyclobutane - alkylation

    References and Notes

  • 1a Tsang JW. Schmied B. Nyfeler R. Goodman M. J. Med. Chem.  1984,  27:  1663 
    Google Scholar
  • 1b Gershonov E. Granoth R. Tzehoval E. Gaoni Y. Fridkin M. J. Med. Chem.  1996,  39:  4833 
    Google Scholar
  • 2a Gatos M. Formaggio F. Crisma M. Toniolo C. Bonora GM. Benedetti Z. Di Blasio B. Iacovino R. Santini A. Saviano M. Kamphuis J. J. Pept. Sci.  1997,  3:  110 
    Google Scholar
  • 2b Jiménez-Osés G. Corzana F. Busto JH. Pérez-Fernández M. Peregrina JM. Avenoza A. J. Org. Chem.  2006,  71:  1869 
    Google Scholar
  • 3 Robins LI. Dixon SM. Wilson DK. Kurth MJ. Bioorg. Med. Chem.  2006,  14:  7728 
    CrossrefGoogle Scholar
  • 4 Wrobleski ML. Reichard GA. Paliwal S. Shah S. Tsui H.-C. Duffy RA. Lachowicz JE. Morgan CA. Varty GB. Shih N.-Y. Bioorg. Med. Chem. Lett.  2006,  16:  3859 
    CrossrefGoogle Scholar
  • 5 Gaoni Y. Chapman AG. Parvez N. Pook PC.-K. Jane DE. Watkins JC. J. Med. Chem.  1994,  37:  4288 
    CrossrefGoogle Scholar
  • 6 Allan RD. Hanrahan JR. Hambley TW. Johnston GAR. Mewett KN. Mitrovic AD. J. Med. Chem.  1990,  33:  2905 
    CrossrefGoogle Scholar
  • 7 Kabalka GW. Yao M.-L. J. Org. Chem.  2004,  69:  8280 
    CrossrefGoogle Scholar
  • 8a Martarello L. McConathy J. Camp VM. Malveaux EJ. Simpson NE. Simpson CP. Olson JJ. Bowers GD. Goodman MM. J. Med. Chem.  2002,  45:  2250 
    Google Scholar
  • 8b Shoup TM. Goodman MM. J. Labelled Compd. Radiopharm.  1999,  42:  215 
    Google Scholar
  • 8c Goodman MM. inventors; WO 2007001940 A2  20070104. 
  • 9a O’Hagan D. Rzepa HS. Chem. Commun.  1997,  645 
    Google Scholar
  • 9b Kirsch P. In Modern Fluoroorganic Chemistry   Wiley-VCH; Weinheim: 2004. 
    Google Scholar
  • 10 Gallucci RR. Going R. J. Org. Chem.  1981,  46:  2532 
    CrossrefGoogle Scholar
  • 11a Perkin WH. Ber. Dtsch. Chem. Ges.  1883,  16:  1787 
    Google Scholar
  • 11b Perkin WH. Ber. Dtsch. Chem. Ges.  1884,  17:  54 
    Google Scholar
  • 11c Pigou PE. Schiesser CH. J. Org. Chem.  1988,  53:  3841 
    Google Scholar
  • 12a Bergs H. inventors; DE  566094.  ; Chem. Abstr. 1933, 27: 1001
  • 12b Bucherer HR. Barsch H. J. Prakt. Chem.  1934,  140:  151 
    Google Scholar
  • 13 Dmowski W. Houben-Weyl Methods of Organic Chemistry   Vol. E10a:  Baasner B. Hagemann H. Tatlow JC. Thieme; Stuttgart: 1999.  p.321 
    Google Scholar
14

Spectral and Analytical Data for New Compounds
Diisopropyl 3-Oxo-1,1-cyclobutanedicarboxylate (10) ¹H NMR (400 MHz, CDCl3): δ = 5.10 [m, J = 6.4 Hz, 2 H, CH(CH3)2], 3.58 (s, 4 H, CH2), 1.26 [d, J = 6.4 Hz, 12 H, CH(CH 3)2]. ¹³C NMR (100 MHz, CDCl3): δ = 200.95 (s, CH2 CO), 169.64 (s, COO), 69.66 [s, CH(CH3)2], 54.98 (s, CH2CO), 43.54 [s, C(COOi-Pr)2], 21.14 [s, CH(CH3)2]. MS: m/z = 243 [M + 1].
Diisopropyl 6,8-Dioxo-5,7-diazaspiro[3.4]octane-2,2-dicarboxylate (11) Mp 142-143 ˚C. ¹H NMR (400 MHz, CDCl3): δ = 8.75 (br s, 1 H, NH), 6.69 (s, 1 H, NH), 5.03 [m, 2 H, CH(CH3)2], 3.14 (d, J = 13.6 Hz, 2 H, CH2), 2.63 (d, J = 13.6 Hz, 2 H, CH2), 1.18 [2 overlapped d, J = 6.4 Hz, 12 H, CH(CH 3)2]. ¹³C NMR (100 MHz, CDCl3): δ = 175.70 (s, CCONH), 172.22 (s, COO), 169.20 (s, COO), 156.08 (s, NHCONH), 70.64 [s, CH(CH3)2], 69.55 [s, CH(CH3)2], 58.16 (s, NHCCO), 46.72 (s, CH2), 41.98 [s, C(COOi-Pr)2], 39.14 (s, CH2), 21.68 [s, CH(CH3)2], 21.63 [s, CH(CH3)2]. MS: m/z = 313 [M + 1].
2,2-Bis(trifluoromethyl)-5,7-diazaspiro[3.4]octane-6,8-dione (13) Mp >230 ˚C. ¹H NMR [500 MHz, (CD3)2SO]: δ = 10.88 (s, 1 H, NH), 8.59 (s, 1 H, NH), 3.14 (d, J = 12.0 Hz, 2 H, CH2), 2.69 (d, J = 12.0 Hz, 2 H, CH2). ¹9F NMR [377 MHz, (CD3)2SO]: δ = -71.72 (q, 4 J F-F = 7.4 Hz, CF3), -73.13 (q, 4 J F-F = 7.4 Hz, CF3). ¹³C NMR [125 MHz, (CD3)2SO]: δ = 176.23 (s, CCONH), 157.14 (s, NHCONH), 126.87 (q, ¹ J C-F = 280.0 Hz, CF3), 125.15 (q, ¹ J C-F = 277.5 Hz, CF3), 55.52 (s, NHCCO), 42.73 [m, C(CF3)2], 33.79 (s, CH2). MS: m/z = 277 [M + 1].
1-Amino-3,3-bis(trifluoromethyl)cyclobutanaminium Chloride (6) Mp >230 ˚C. ¹H NMR [400 MHz, (CD3)2SO]: δ = 3.21 (d, J = 16.0 Hz, 2 H, CH2), 3.07 (d, J = 16.0 Hz, 2 H, CH2). ¹9F NMR [377 MHz, (CD3)2SO]: δ = -67.21 (q, 4 J F-F = 7.4 Hz, CF3), -67.49 (q, 4 J F-F = 7.4 Hz, CF3). ¹³C NMR [100 MHz, (CD3)2SO]: δ = 173.35 (s, COOH), 125.15 (q, ¹ J C-F = 273.0 Hz, CF3), 124.65 (q, ¹ J C-F = 272.4 Hz, CF3), 53.35 (s, NHCCO), 40.39 [m, C(CF3)2], 31.81 (s, CH2). MS: m/z = 252 [M - Cl].
cis -2-(Trifluoromethyl)-5,7-diazaspiro[3.4]octane-6,8-dione (16a) Mp >230 ˚C. ¹H NMR [400 MHz, (CD3)2SO]: δ = 10.76 (s, 1 H, NH), 8.41 (s, 1 H, NH), 3.05 (m, 1 H, CHCF3), 2.58 (pseudo t, J = 10.0 Hz, 2 H, CH2), 2.35 (pseudo t, J = 10.0 Hz, 2 H, CH2). ¹9F NMR [377 MHz, (CD3)2SO]: δ = -72.46 (d, ³ J H-F = 11.3 Hz, CF3). ¹³C NMR [100 MHz, (CD3)2SO]: δ = 178.26 (s, CCONH), 156.34 (s, NHCONH), 127.02
(q, ¹ J C-F = 274.0 Hz, CF3), 56.73 (s, NHCCO), 32.46 (q, ³ J C-F = 3.0 Hz, CH2), 28.86 (q, ² J C-F = 32.0 Hz, CHCF3).
MS: m/z = 209 [M + 1].
cis -1-Carboxy-3-(trifluoromethyl)cyclobutanaminium Chloride (7) Mp >230 ˚C. ¹H NMR (400 MHz, D2O): δ = 3.26 (m, 1 H, CHCF3), 2.64 (pseudo t, J = 12.8, 8.8 Hz, 2 H, CH2), 2.48 (pseudo t, J = 10.0 Hz, 2 H, CH2). ¹9F NMR (377 MHz, D2O): δ = -76.53 (d, ³ J H-F = 7.5 Hz, CF3). ¹³C NMR (100 MHz, D2O): δ = 174.40 (s, COOH), 125.10 (q, ¹ J C-F = 273.0 Hz, CF3), 52.26 (s, NHCCO), 29.39 (q, ² J C-F = 32.0 Hz, CHCF3), 28.80 (q, ³ J C-F = 3.0 Hz, CH2). MS: m/z = 184 [M -Cl].