Synthesis of the trifluoromethylated retinoial aromatic amide - 4-[1-(5,6,7,8-tetrahydro-3-trifluoromethyl-5,5,8,8-tetramethyl-2-naphthalenyl) carbamoyl]benzoic acid

Article abstract of DOI:10.1016/S0022-1139(99)00070-6

A new methodology was developed for the preparation of an o-trifluoromethylated arylamine. The condensation of 2-amino-3-trifluoromethyl-5,6,7,8-tetrahydro-5,5,8,8-tetramethylnaphthalene and terephthalic acid monomethyl ester chloride gave the trifluoromethylated retinoial aromatic amide. The key step in the synthesis is the introduction of the aryl trifluoromethyl group.

Full text of DOI:10.1016/S0022-1139(99)00070-6

Journal of Fluorine Chemistry 96 (1999) 159±161
Synthesis of the tri¯uoromethylated retinoial aromatic
amideÐ4-[1-(5,6,7,8-tetrahydro-3-tri¯uoromethyl-5,5,8,8-
tetramethyl-2-naphthalenyl)carbamoyl]benzoic acid
Feng-Ling Qing*, Junfa Fan
Laboratory of Organo¯uorine Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 354 Fenglin Lu, Shanghai 200032, China
Received 30 November 1998; accepted 5 March 1999
Abstract
A new methodology was developed for the preparation of an o-tri¯uoromethylated arylamine. The condensation of 2-amino-3-
tri¯uoromethyl-5,6,7,8-tetrahydro-5,5,8,8-tetramethylnaphthalene and terephthalic acid monomethyl ester chloride gave the tri¯uoro-
methylated retinoial aromatic amide. The key step in the synthesis is the introduction of the aryl tri¯uoromethyl group. # 1999 Elsevier
Science S.A. All rights reserved.
Keywords: Retinoids; Tri¯uoromethylation
1. Introduction
Retinoids, natural and synthetic analogs of Vitamin A, are
potent molecules that can affect a variety of fundamental
biological processes including cell differentiation and pro-
liferation and apoptosis [1,2]. Recent evidence has shown
that retinoids exert their functions through at least two
classes of nuclear receptors: RAR (a,b,g) and RXR
(a,b,g) [3]. Current research efforts in this ®eld have focused
on searching for receptor-speci®c ligands in order to eluci-
date the biological functions of each receptor. Several
classes of molecules that are speci®c for the RAR [4] or
RXR [5] families of receptors have been described. Among
them, aromatic amide, 4-[(5,6,7,8-tetrahydro-5,5,8,8-tetra-
methyl-2-naphthalenyl)carbamoyl]benzoic acid (Am 80, 1)
binds strongly to two subtypes, RARa and RARb, but not to
RARg [6].
Due of its high lipophilicity, and powerful electron-with-
drawing effect, the tri¯uoromethyl group is an increasingly
popular aromatic substituent in compounds synthesized for
improving their biological activity [7]. From this perspec-
tive, we became interested in the incorporation of the
tri¯uoromethyl substituted into retinoid 1, The synthesis
of compound 2 is described below:
2. Results
Disconnection of the amide bond divides the target
molecule 2 into two precursors o-tri¯uoromethylated
arylamine 3 and terephthalic acid monomethyl ester
chloride 4. Compound 4 is commercially available. Thus,
we turned our attention to prepare the key precursor o-
tri¯uoromethyl arylamine 3. Compound 3 was synthesized
as outlined in Scheme 1. The bromo compound 5, was
prepared by reaction of bromobenzene with 2,5-dichloro-
2,5-dimethylhexane in the presence of aluminum chloride.
Nitration of 5 at 608C gave the nitro product 6 in 75% yield.
Reaction of 6 with FSO2CF2CO2Me and CuI in DMF/
HMPA [8] afforded the tri¯uoromethylated product 7 in
85% yield. Reduction of 7 with Fe/HCl gave the o-tri¯uor-
omethylated arylamine 3 in 95% yield. The condensation of
3 and terephthalic acid monomethyl ester chloride 4 in the
presence of pyridine provided the amide 8, which on hydro-
lysis produced the tri¯uoromethylated retinoial aromatic
amide 2.
*Corresponding author. Fax: +86-2164166128.
0022-1139/99/$ ± see front matter # 1999 Elsevier Science S.A. All rights reserved.
PII: S 0 0 2 2 - 1 1 3 9 ( 9 9 ) 0 0 0 7 0 - 6

160
F.-L. Qing, J. Fan / Journal of Fluorine Chemistry 96 (1999) 159±161
Scheme 1.
3. Experimental
(CDCl3) ꢀ: 1.25(s, 6H), 1.28 (s, 6H), 1.70 (s, 4H), 7.60 (s,
1H), 7.82 (s, 1H); MS (m/e): 313 (16.8), 311 (17.1), 298
Melting points are uncorrected. 19F NMR spectra
(56.4 Hz) were recorded on a Varian-360A instrument using
CF3CO2H as an external standard, up®eld positive. 1H NMR
and 13C NMR spectra were recorded on a 300 MHz spectro-
meter with tetramethylsilane as the internal standard. All
chemical shifts are expressed in ppm. The mass spectra were
recorded on a Finnigan-MAT-8430 mass spectrometer. IR
spectra were recorded as KBr discs on a Shimadzu IR-440
Spectrometer. Light petroleum ether refers to the fraction
with distillation range 60±908C.
(100), 296 (95.5), 256 (42.5), 141 (28.4); IR: 3458, 3371,
1
2963, 2928, 1635, 1329, 1273, 1144, 1097, 900, 701 cm
;
Anal. Calc. for C14H18BrNO2: C, 53.86; H, 5.81; N, 4.48;
Found: C, 54.00; H, 5.78; N, 4.01%.
3.2. 2-Nitro-3-trifluoromethyl-5,6,7,8-tetrahydro-5,5,8,8-
tetramethylnaphthalene (7)
A mixture of FSO2CF2CO2Me (3 ml, 27 mmol), CuI
(5.0 g, 27 mmol), HMPA (4.8 ml, 27 mmol) and
6
(1.14 g, 3.7 mmol) in DMF (5 ml) was stirred for 5 h at
708C. The reaction mixture was then cooled to room
temperature, 5 ml of saturated aq. NH4Cl were added and
the mixture was extracted with Et2O (3 Â 20 ml). The
organic layer was washed successively with saturated aq.
NaHCO3 and brine, and dried over Na2SO4. The solvent was
removed in vacuo. Flash chromatography with petroleum
ether afforded compound 7 (950 mg, 85%), m.p. 89±918C;
19F NMR (CDCl3) ꢀ: 18.0 (s); 1H NMR (CDCl3) ꢀ: 1.35(s,
12 H), 1.77 (s, 4H), 7.73 (s, 1H), 7.86 (s, 1H); MS (m/e): 302
(7.0), 312 (3.8), 287 (16.4), 286 (100.0), 282 (23.7), 244
(18.4); IR: 2969, 2940, 1535, 1362, 1296, 1162, 1142, 1083,
910 cm 1; Anal. Calc. for C15H18F3NO2: C, 59.79; H, 6.02;
N, 4.65; Found: C, 59.73; H, 5.92; N, 4.84%.
3.1. 2-Bromo-3-nitro-5,6,7,8-tetrahydro-5,5,8,8-
tetramethylnaphthalene (6)
Under 108C, 4 ml concentrated H2SO4 was added
dropwise to 2-bromo-5,6,7,8-tetrahydro-5,5,8,8-tetra-
methylnaphthalene (5, 4.0 g, 15 mmol). The mixture was
vigorously stirred to dissolve compound 5, then 5 ml of
concentrated HNO3/H2SO4 (1 : 1) was slowly added to the
mixture while keeping the reaction temperature at about
658C. After the reaction was complete (TLC analysis), the
reaction mixture was poured into 40 ml iced water, the
yellow solids were ®ltered and washed with water to give
1
3.5 g (75%) of 6 after drying, m.p. 121±1238C; H NMR

F.-L. Qing, J. Fan / Journal of Fluorine Chemistry 96 (1999) 159±161
161
3.3. 2-Amino-3-trifluoromethyl-5,6,7,8-tetrahydro-5,5,8,8-
tetramethylnaphthalene (3)
3.5. 4-[1-(5,6,7,8-tetrahydro-3-trifluoromethyl-5,5,8,8-
tetramethyl-2-naphthalenyl)carbamoyl]benzoic acid
(2)
A mixture of 7 (2.5 g, 8.3 mmol), concentrated HCl (2ml)
and menthol (100 ml) was stirred at re¯ux, then iron powder
(34.0 g) was added in portions to the reaction mixture for 1 h
at re¯ux. After the reaction was complete (TLC analysis),
the reaction mixture was cooled to room temperature and
then ®ltered. The ®ltrate was concentrated at reduced pres-
sure until a volume of about 10 ml remained. 10 ml of water
were added and the mixture was extracted with Et2O
(2 Â 20 ml). The organic layer was washed with water
and brine, and dried over Na2SO4. The solvent was removed
in vacuo to give 3 (2.1 g, 95%), m.p. 61±628C; 19F NMR
(CDCl3) ꢀ: 16.0 (s); 1H NMR (CDCl3) ꢀ: 1.24 (s, 6H), 1.25
(s, 6H), 1.65 (s, 4H), 3.94 (br, 2H), 6.67 (s, 1H), 7.34 (s, 1H);
13C NMR (CDCl3) ꢀ: 31.7, 31.9, 33.7, 34.4, 35.0, 35.1,
112.4, 112.8, 115.0, 123.5, 124.7, 127.1, 135.2, 141.7,
150.4; MS (m/e): 271 (21.7), 257 (20.2), 256 (100.0),
A mixture of 8 (86 mg, 0.2 mmol), ethanol (10 ml) and
2N NaOH (1.5 ml, 0.3 mmol) was stirred at re¯ux. After the
reaction was complete (TLC analysis), the reaction mixture
was cooled to room temperature and acidi®ed with 2 N HCl.
The mixture was then extracted with ethyl acetate and the
solution was washed with water, brine, and dried over
Na2SO4. The solvent was removed in vacuo. Flash chro-
matography with petroleum ether/ethyl acetate (1 : 1)
afforded compound 2 (80 mg, 95%), m.p. 235±2388C;
19F NMR (CDCl3) d: -18.5 (s); 1H NMR (CDCl3) ꢀ:
1.31(s, 6 H), 1.35 (s, 6H), 1.73 (s, 4H), 7.58 (s, 1H), 7.
98 (d, J ˆ 8.2 Hz, 2H), 8.14 (s, 1H), 8.27 (d, J ˆ 8.2 Hz,
2H); MS (m/e): 419 (26.1), 404 (100.0), 384 (24.2), 342
(18.6), 149 (68.3); IR: 3482, 3217, 2964, 1694, 1625, 1581,
1
1523, 1407, 1320, 1278, 1155, 1102, 1079, 906, 722 cm
.
227 (11.2); IR: 3485, 3371, 2963, 2928, 1635, 1329,
1
1273, 1144, 1097, 900 cm
;
C15H20F3N: 271.1549, Found: 271.1518.
HRMS Calc. for
Acknowledgements
We thank the National Natural Science Foundation of
China and Shanghai Municipal Scienti®c Committee for
funding this work.
3.4. Methyl,4-[1-(5,6,7,8-tetrahydro-3-trifluoromethyl-
5,5,8,8-tetramethyl-2-
naphthalenyl)carbamoyl]benzoate (8)
A mixture of 3 (27 mg, 0.1 mmol), 4 (20 mg, 0.1 mmol),
pyridine (0.1 ml, 0.1 mmol) and anhydrous benzene (15 ml)
was stirred at room temperature. After the reaction was
complete (TLC analysis), 5 ml of water were added and the
mixture was extracted with ethyl acetate (2 Â 20 ml). The
organic layer was washed successively with 2N HCl, water,
1N NaHCO3 and brine, and dried over Na2SO4. The solvent
was removed in vacuo. Flash chromatography with petro-
leum ether/ethyl acetate (10 : 1) afforded compound 8
(42 mg, 96%), m.p. 218±2208C; 19F NMR (CDCl3)
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ꢀ: -18.3 (s); H NMR (CDCl3) ꢀ: 1.30(s, 6 H), 1.35 (s,
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