3-Trifluoromethyl- and 3-difluoromethyl-thalidomides

Article abstract of DOI:10.1016/j.tet.2003.11.027

Syntheses of racemic 3-trifluoromethyl- and 3-difluoromethyl-thalidomide starting from 2-(tert-butyloxycarbonylimino)-3,3,3-trifluoropropionate or -3,3-difluoropropionate as fluorine-containing building blocks are described.

Full text of DOI:10.1016/j.tet.2003.11.027

Tetrahedron 60 (2004) 271–274
3-Trifluoromethyl- and 3-difluoromethyl-thalidomides
Sergej N. Osipov,a Pavel Tsouker,b Lothar Hennigb and Klaus Burgerb
,
*
aA.N. Nesmeyanov Institute of Organoelement Compounds, Russian Academy of Sciences, Vavilov street 28, GSP-1, RUS 117813 Moscow,
Russian Federation
bDepartment of Organic Chemistry, University of Leipzig, Johannisallee 29, D-04103 Leipzig, Germany
Received 29 April 2003; revised 26 June 2003; accepted 12 November 2003
Dedicated to Professor Dr. H.-D. Jakubke on the occasion of his 70th birthday
Abstract—Syntheses of racemic 3-trifluoromethyl- and 3-difluoromethyl-thalidomide starting from 2-(tert-butyloxycarbonylimino)-3,3,3-
trifluoropropionate or -3,3-difluoropropionate as fluorine-containing building blocks are described.
q 2003 Published by Elsevier Ltd.
1. Introduction
2. Results and discussion
Thalidomide (1) [2-(2,6-dioxo-3-piperidyl)isoindoline-1,3-
dione], a sedativum without the side effects of barbiturates,
was introduced into the market by Chemie Gru¨nenthal in
1956 with the trade name Conterganw.1–3 Thalidomide was
withdrawn from the market in 1962,4 when its use was
linked to severe birth defects.3,5 Unexpected teratogenic
side effects produced one of the most notorious medicinal
disasters of modern medicinal history.
Introduction of fluorine and/or fluoroalkyl groups into
strategical positions of target molecules may considerably
modify chemical properties, biological activity and
selectivity.17 Numerous fluoro- and fluoroalkyl-substituted
pharmaceuticals, agrochemicals, dyes and polymers have
been successfully commercialized.18 The number of patents
concerning fluorinated compounds shows growing
tendency. Thus, one can anticipate that fluoro-modified
compounds will continue to play a significant role in
medicinal and agricultural chemistry as well as in material
science.19
However, the unique and broad physiological properties
discovered during recent years, prompted a reevaluation of
its therapeutic potential.6 Thus, thalidomide is currently
applied for treatment of painful inflammations associated
with leprosy (recently approved in the USA),7 rheumatoid
arthritis8 and graft-versus host disease.9 Furthermore,
promising results in the case of treatment of AIDS,10
Crohn’s disease,11 Behcet’s syndrom12 and cancer related
pathologic angiogenesis13 have been disclosed. Recently,
thalidomide was effective in the treatment of high-risk,
refractory multiple myeloma.14
In an effort to improve the biological profile of thalidomide
we synthesized new fluoroanalogues of thalidomide by
replacing C(3)–H by a trifluoromethyl and a difluoromethyl
group, respectively. Key step of the synthesis is the
construction of the methyl 2-fluoroalkyl-2-(tert-butoxy-
carbonylamino)-5-aminopent-3-inoates 2, which we already
used as intermediates for the synthesis of a-trifluoromethyl
and a-difluoromethyl ornithine20 and arginine.21 Com-
pounds 2a and 2b are readily obtained in very good yields
via addition of bis(trimethylsilyl)propargylamine to the
highly electrophilic Boc-protected imines 122 (Scheme 1).
Overproduction of TNF-a is associated with these patho-
logical disorders.15 The effectivity of thalidomide in these
diseases has mostly been attributed to its specific inhibitory
activity on TNF-a production. Therefore, based on
thalidomide as a lead structure several analogues have
been developed.16 We now report on concise syntheses of
racemic 3-trifluoromethyl- and 3-difluoromethyl-thalido-
mides.
The unsaturated ornithine derivatives 2a,b obtained
were subjected to catalytic hydrogenation to give the
Keywords: 2-Fluoroalkyl-2,5-diaminopent-3-inoates; 3-Fluoroalkyl-3-
aminopiperidin-2-ones; 3-Fluoroalkyl-3-aminopiperidin-2,6-diones.
*
Corresponding author. Fax: þ49-341-9736599;
e-mail address: burger@organik.chemie.uni-leipzig.de
Scheme 1.
0040–4020/$ - see front matter q 2003 Published by Elsevier Ltd.
doi:10.1016/j.tet.2003.11.027

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S. N. Osipov et al. / Tetrahedron 60 (2004) 271–274
Scheme 2.
Boc-protected 2-fluoroalkyl-ornithine methylesters which
spontaneously cyclize to give the Boc-protected 3-amino-3-
fluoroalkylpiperidin-2-ones (3).23 Compounds 3 are formed
as racemic mixtures. Then the Boc group of 3 was removed
on treatment with TFA at room temperature to furnish 4.
The amino group was diacylated with o-phthaloyl
dichloride in the presence of DMAP (4!5)24 (Scheme 2).
positive ion detection. For flash chromatography, silica gel
(32–63 mm) was used with solvent systems given in text.
Organic solvents were dried and distilled prior to use.
3.1.1. 3-Trifluoromethyl-3-(tert-butoxycarbonylamino)-
piperidin-2-one (3a). A mixture of 2a21,22 (4.00 g,
12.9 mmol) and 10% Pd/C (0.80 g) in methanol (70 mL)
was stirred under an atmosphere of hydrogen for 48 h. The
catalyst was filtered off, and the filtrate was concentrated
under reduced pressure. The remaining solid was washed
with a hot mixture of ethyl acetate/hexanes (1:10), to give
3a (3.09 g, 85%). The product was purified by column
chromatography (eluent: ethyl acetate/hexanes, 1:1); mp
Finally, oxidation of 5 was performed using a catalytic
amount of RuO2 in the presence of excess sodium
metaperiodate in a two phase system25 to give the
fluoroalkyl-substituted thalidomides 6a and 6b in 65 and
53% yield, respectively (Scheme 3).
1
136 8C; IR (KBr): n¼3295, 3264, 1684, 1172 cm21; H
NMR (CDCl3): d¼1.48 (s, 9H, OCMe3), 1.98 (m, 2H, CH2),
2.56 (m, 1H, CH2), 2.73 (m, 1H, CH2), 3.45 (m, 2H, NCH2),
5.63 (s, 1H, NH), 6.28 (s br, 1H, NH); 13C NMR (CDCl3):
d¼19.18 (CH2), 27.39 (CH2), 28.47 (3£CH3), 43.36
2
(NCH2), 60.93 (q, JCF¼27.5 Hz, CCF3), 81.03 (OCMe3),
1
125.35 (d, JCF¼287.9 Hz, CF3), 154.31 (CvO), 166.20
(CvO); 19F NMR (CDCl3): d¼5.03 (s, 3F, CF3); HRMS
[MþNa]þ. Found: m/z¼305.10816; C11H17F3N2NaO3
requires m/z¼305.10835.
Scheme 3.
3.1.2. 3-Difluoromethyl-3-(tert-butoxycarbonylamino)-
piperidin-2-one (3b). Applying the above protocol 2b21,22
(3.30 g, 11.3 mmol) was converted into 3b (2.71 g, 91%);
mp 158 8C; IR (KBr): n¼3389, 3203, 1662, 1063 cm21; 1H
NMR (CDCl3): d¼1.41 (s, 9H, OCMe3), 1.95 (m, 2H, CH2),
2.28 (m, 1H, CH2), 2.42 (m, 1H, CH2), 3.32 (m, 1H, NCH2).
3.47 (m, 1H, NCH2), 5.26 (s, 1H, NH), 6.04 (t, 1H,
2JHF¼57.1 Hz, CF2H), 6.35 (s br, 1H, NH). 13C NMR
(CDCl3): d¼26.98 (CH2), 28.39 (CH2), 42.17 (NCH2),
59.50 (t, 2JCF¼24.0 Hz, CCF2H), 80.79 (OCMe3), 116.42 (t,
1JCF¼249.5 Hz, CF2H), 154.39 (CvO), 167.88 (d,
3JCF¼5.3 Hz, CvO); 19F NMR (CDCl3): d¼256.50
Biological tests of compounds 5a,b and 6a,b are under
current investigation.
3. Experimental
3.1. General
Melting points were determined on a Boetius heating table.
IR spectra were obtained with a FTIR spectrometer (Genesis
ATI Mattson/Unicam). 1H NMR spectra were recorded with
VARIAN Gemini 2000 spectrometers at 200 and 300 MHz.
Chemical shifts were reported in ppm relative to tetra-
methylsilane (TMS, d¼0 ppm); J values are given in Hertz
(Hz). 13C NMR spectroscopy was performed at 50 and
75 MHz. 19F spectra were recorded at 188 and 282 MHz
with trifluoroacetic acid (TFA, d¼0 ppm) as external
standard. HRMS spectra were performed at ESI-Mass
Spectrometer: 7 T, Bruker Daltronics APEX II ESI-FT-
ICR-MS in acetone/methanol solution; ESI ionisation and
2
2
(ddABX 1F, JFF¼282.3 Hz, JFH¼57.1 Hz, CF2H);
,
2
2
248.31 (ddABX,
1F, JFF¼282.3 Hz, JFH¼57.1 Hz,
CF2H); HRMS [MþNa]þ. Found m/z¼287.11777; C11H18-
F2NaN2O3 requires m/z¼287.11777.
3.1.3. 3-Trifluoromethyl-3-aminopiperidin-2-one (4a).
TFA (10 mL) was added to a solution of 3a (3.00 g,
10.6 mmol) in CH2Cl2 (50 mL) at 0 8C. The mixture was
stirred for 6 h at rt. The volatiles were removed under

S. N. Osipov et al. / Tetrahedron 60 (2004) 271–274
273
reduced pressure. The remaining solid was dissolved in
ethyl acetate (100 mL), then the solution was treated with a
saturated solution of NaHCO3 (50 mL). The organic phase
was separated, the aqueous layer was extracted with ethyl
acetate (2£30 mL). The combined organic phase was dried
over MgSO4 and evaporated in vacuo to give 4a (1.45 g,
75%); mp 115 8C; IR (KBr): n¼3394, 3319, 1671,
CCF2H), 114.36 (t, 1JCF¼247.3 Hz, CF2H), 123.58, 131.62,
134.55 (C-arom), 165.93 (CvO), 167.87 (2£CvO); 19F
2
NMR (CDCl3): d¼244.9 (dd, 1F, JFF¼279.0 Hz,
2
2JFF¼54.9 Hz, CF2H), 246.7 (dd, 1F, JFF¼279.0 Hz,
2JFF¼53.4 Hz, CF2H); HRMS [MþNa]þ. Found m/z¼
317.07047; C14H12F2NaN2O3 requires m/z¼317.07082.
1141 cm21
;
1H NMR (CDCl3): d¼1.95 (m, 5H, CH2,
3.1.7. 3-Trifluoromethyl-3-(phthalimido)piperidin-2,6-
dione (6a). A mixture of 5a (0.10 g, 0.32 mmol) and
15 mg of ruthenium dioxide hydrate in CH2Cl2 (10 mL) was
stirred at rt with 10 equiv. of 10% aqueous solution of
NaIO4 for 3 days. The layers were separated; the aqueous
layer was extracted with CH2Cl2 (3£15 mL). To the
combined organic layer methanol (0.1 mL) was added to
destroy the excess of the oxidant. The mixture was filtered
and the filtrate was washed with 5 mL of 10% aqueous
Na2S2O3. The solvent was removed under reduced pressure
and the remaining solid was purified by column chroma-
tography to give analytically pure 6a (68 mg, 65%); mp
198 8C; IR (KBr): n¼3436, 3426, 3223, 1743, 1352,
NH2), 2.25 (m, 1H, CH2), 3.41 (m, 2H, NCH2), 6.37 (s br,
1H, NH); 13C NMR (CDCl3): d¼18.75 (CH2), 29.66 (d,
3JCF¼1.7 Hz, CH2), 42.40 (NCH2), 58.92 (q, 2JCF¼26.3 Hz,
1
CCF3), 125.45 (q, JCF¼286.3 Hz, CF3), 169.00 (CvO);
19F NMR (CDCl3): d¼20.15 (s, 3F, CF3); MS: HRMS
[2MþNa]þ. Found m/z¼387.12210; C12H18F6NaN4O2
requires m/z¼387.12262.
3.1.4. 3-Difluoromethyl-3-aminopiperidin-2-one (4b).
Applying the above protocol 3b (1.20 g, 4.45 mmol) was
transformed into 4b (0.51 g, 68%); mp 147 8C; IR (KBr):
n¼3389, 3204, 1665, 1063 cm21
;
1H NMR (CDCl3):
d¼1.98 (m, 6H, 2£CH2, NH2), 3.39 (m, 2H, NCH2), 6.00
1218 cm21
;
1H NMR (CDCl3): d¼2.28 (m, 1H, CH2),
2
(t, 1H, JHF¼57.8 Hz, CF2H), 6.57 (s br, 1H, NH); 13C
2.65 (m, 1H, CH2), 2.85 (m, 1H, CH2), 3.71 (m, 1H, CH2),
7.85 (m, 4H arom), 7.97 (s, 1H, NH); 13C NMR (d6-
acetone): d¼22.74 (CH2), 28.37 (CH2), 64.01 (q,
3
NMR (CDCl3): d¼18.90 (CH2), 26.52 (d, JCF¼4.5 Hz,
2
CH2), 42.55 (NCH2), 58.14 (t, JCF¼22.6 Hz, CCF2H),
117.85 (t, 1JCF¼271.5 Hz, CF2H), 171.28 (d, 3JCF¼7.4 Hz,
CvO); 19F NMR (CDCl3): d¼262.85 (dd ABX, 1F,
2JFF¼277.8 Hz, 2JFH¼57.8 Hz, CF2H); 245.81 ppm
2JCF¼28.5 Hz, CCF3), 124.46, 125.05 (q, JCF¼285.7 Hz,
1
CF3), 132.00, 136.03 (C arom), 163.92 (CvO), 168.02
(2£CvO), 171.25 (CvO); 19F NMR (CDCl3): d¼3.43 (s,
3F, CF3). HRMS [2MþNa]þ. Found m/z¼675.09233;
C28H18F6NaN4O8 requires m/z¼675.09265.
2
2
(ddABX
,
1F, JFF¼277.8 Hz, JFH¼57.8 Hz, CF2H).
HRMS [2MþNa]þ. Found m/z¼351.14097; C12H20F4-
NaN4O2 requires m/z¼351.14146.
3.1.8. 3-Difluoromethyl-3-(phthalimido)piperidin-2,6-
dione (6b). Applying the above protocol 5b (25 mg,
0.294 mmol) was transformed into 6b (14 mg, 65%); mp
3.1.5. 3-Trifluoromethyl-3-(phthalimido)piperidin-2-one
(5a). To a solution of 4a (0.20 g, 1.1 mmol) and DMAP
(0.27 g, 2.2 mmol) in CHCl3 (50 mL) was added at 0 8C
under argon a solution of o-phthaloyl dichloride (0.24 g,
1.18 mmol) in CHCl3 (10 mL). The temperature was
allowed to rise to rt, then after refluxing for 72 h, the
mixture was washed with 1 N HCl (50 mL), then the organic
phase was dried with MgSO4 and concentrated in vacuo.
The crude phthalimido derivative was purified by column
chromatography on silica gel (eluent: ethyl acetate/hexanes,
1:1) to afford analytically pure 5a (0.17 g, 50%); mp 203 8C;
209 8C; IR (KBr): n¼3434, 2363, 1722, 1375, 1067 cm21
;
1H NMR (d6-acetone): d¼2.55 (m, 1H, CH2), 2.81 (m, 2H,
2
CH2), 2.92 (m, 1H, CH2), 7.04 (dd, JHF¼55.0 Hz, CF2H),
7.95 (m, 4H, arom), 10.25 (s. br, 1H, NH); 13C NMR (d6-
DMSO): d¼19.64 (CH2), 27.78 (CH2), 62.61 (t,
1
2JCF¼24.8 Hz, CCF2H), 114.70 (t, JCF¼271.0 Hz, CF2H),
123.84, 130.87, 135.00 (C arom), 164.01 (CvO), 167.34
(2£CvO), 171.98 (CvO); 19F NMR (d6-acetone):
2
2
d¼245.5 (dd, 1F, JFH¼55.0 Hz, JFF¼284.0 Hz, CF2H),
IR (KBr): n¼3402, 1733, 1339, 1334 cm21
;
1H NMR
249.3 (dd, 1F, JFH¼55.0 Hz, JFF¼284.0 Hz, CF2H).
HRMS [MþNa]þ. Found m/z¼331.05046; C14H10F2NaN2-
O4 requires 331.05008.
2
2
(CDCl3): d¼1.88 (m, 1H, CH2), 2.08 (m, 1H, CH2), 2.41 (m,
1H, CH2), 2.82 (m, 1H, CH2), 3.44 (m, 2H, NCH2), 6.37 (s,
1H, NH), 7.81 (m, 4H arom); 13C NMR (d6-acetone):
3
d¼19.47 (CH2), 28.64 (d, JCF¼1.8 Hz, CH2), 41.61
2
(NCH2), 65.54 (q, JCF¼28.0 Hz, CCF3), 125.35 (q,
1JCF¼285.6 Hz, CF3), 124.78, 132.80, 136.38 (C-arom),
164.14 (CvO), 168.25 (2£CvO); 19F NMR (CDCl3):
d¼10.38 (s, 3F, CF3); HRMS [MþNa]þ. Found
Acknowledgements
This work was supported by Stiftung Volkswagenwerk,
Hannover, and the Fonds der Chemischen Industrie.
m/z¼335.06112;
C14H11F3NaN2O3
requires
m/z¼
335.06140.
3.1.6. 3-Difluoromethyl-3-(phthalimido)piperidin-2-one
(5b). Applying the above described protocol 4b (0.24 g,
1.46 mmol) was transformed into 5b (0.27 g, 63%); mp
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