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

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 
• 1b Gershonov E. Granoth R. Tzehoval E. Gaoni Y. Fridkin M. J. Med. Chem.  1996,  39:  4833 
• 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 
• 2b Jiménez-Osés G. Corzana F. Busto JH. Pérez-Fernández M. Peregrina JM. Avenoza A. J. Org. Chem.  2006,  71:  1869 
• 3 Robins LI. Dixon SM. Wilson DK. Kurth MJ. Bioorg. Med. Chem.  2006,  14:  7728 
• 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 
• 5 Gaoni Y. Chapman AG. Parvez N. Pook PC.-K. Jane DE. Watkins JC. J. Med. Chem.  1994,  37:  4288 
• 6 Allan RD. Hanrahan JR. Hambley TW. Johnston GAR. Mewett KN. Mitrovic AD. J. Med. Chem.  1990,  33:  2905 
• 7 Kabalka GW. Yao M.-L. J. Org. Chem.  2004,  69:  8280 
• 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 
• 8b Shoup TM. Goodman MM. J. Labelled Compd. Radiopharm.  1999,  42:  215 
• 8c Goodman MM. inventors; WO 2007001940 A2  20070104. 
• 9a O’Hagan D. Rzepa HS. Chem. Commun.  1997,  645 
• 9b Kirsch P. In Modern Fluoroorganic Chemistry   Wiley-VCH; Weinheim: 2004. 
• 10 Gallucci RR. Going R. J. Org. Chem.  1981,  46:  2532 
• 11a Perkin WH. Ber. Dtsch. Chem. Ges.  1883,  16:  1787 
• 11b Perkin WH. Ber. Dtsch. Chem. Ges.  1884,  17:  54 
• 11c Pigou PE. Schiesser CH. J. Org. Chem.  1988,  53:  3841 
• 12a Bergs H. inventors; DE  566094.  ; Chem. Abstr. 1933, 27: 1001
• 12b Bucherer HR. Barsch H. J. Prakt. Chem.  1934,  140:  151 
• 13 Dmowski W. Houben-Weyl Methods of Organic Chemistry   Vol. E10a:  Baasner B. Hagemann H. Tatlow JC. Thieme; Stuttgart: 1999.  p.321 

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].