An Unusual Trifluoromethyl Elimination Reaction from the 4,4-Bis(trifluoromethyl)-5-hydroxyimidazoline Ring System

Article abstract of DOI:10.1021/jo961723x

A facile detrifluoromethylation was observed when 4,4-bis(trifluoromethyl)-5-hydroxyimidazoline 5 was treated with a variety of bases to afford the biologically interesting 4-(trifluoromethyl)- imidazole analogs (9 and 10). A unique mechanism was proposed for this transformation, supported by isolating and trapping the hypothesized intermediates. Heating of 5 with Et₄NCN in DMSO provided 19, which was clearly derived from the proposed intermediate 17. Finally, imidazole 9 was converted into the N-[2-phenyl-4-(trifluoromethyl)-]1H-imidazol-5-yl]-N-methylbenzamide analogs, which were potential acyl CoA:cholesterol acyltransferase (ACAT) inhibitors.

Full text of DOI:10.1021/jo961723x

2550
J . Org. Chem. 1997, 62, 2550-2554
An Un u su a l Tr iflu or om eth yl Elim in a tion Rea ction fr om th e
4,4-Bis(tr iflu or om eth yl)-5-h yd r oxyim id a zolin e Rin g System
Hui-Yin Li,*,1 Indawati DeLucca, Spencer Drummond, and George A. Boswell*,2
The DuPont Merck Pharmaceutical Company, Chemical Sciences Division,
Experimental Station, Wilmington, Delaware 19880-0500, and The DuPont Merck Pharmaceutical
Company, Chemical Process R&D, Chambers Works, Deepwater, New J ersey 08023-0999
Received September 9, 1996X
A facile detrifluoromethylation was observed when 4,4-bis(trifluoromethyl)-5-hydroxyimidazoline
5 was treated with a variety of bases to afford the biologically interesting 4-(trifluoromethyl)-
imidazole analogs (9 and 10). A unique mechanism was proposed for this transformation, supported
by isolating and trapping the hypothesized intermediates. Heating of 5 with Et4NCN in DMSO
provided 19, which was clearly derived from the proposed intermediate 17. Finally, imidazole 9
was converted into the N-[2-phenyl-4-(trifluoromethyl)-1H-imidazol-5-yl]-N-methylbenzamide ana-
logs, which were potential acyl CoA:cholesterol acyltransferase (ACAT) inhibitors.
In tr od u ction
supported by isolating and trapping the hypothesized
intermediates.
Recently, we reported the synthesis of a series of 4,4-
bis(trifluoromethyl)imidazolines (1) as potent acyl CoA:
cholesterol acyltransferase (ACAT) inhibitors and/or
cholesterol biosynthesis inhibitors.3-7 These activities
may be useful in the development of new agents for the
treatment of hypercholesterolemia and atherosclerosis.
During our efforts to synthesize 5-ester substituted 4,4-
bis(trifluoromethyl)imidazoline analogs (2) as part of the
structure-activity relationship (SAR) study,6 we realized
that the alcohol 5 was very labile to bases. One of the
reactions we observed was an apparent detrifluoro-
methylation reaction, which converted the 4,4-bis(tri-
fluoromethyl)imidazoline ring system to the 4-(trifluoro-
methyl)imidazole ring system. It is known that the
trifluoromethyl group is one of the most stable functional
groups and almost all the 4,4-bis(trifluoromethyl)imid-
azoline derivatives we have synthesized3-7 so far appear
to be very stable, both chemically and thermally. We
disclose herein the reactions of the alcohol 5 with a
variety of bases to give the biologically interesting
4-(trifluoromethyl)imidazole analogs.8-15 A reaction mech-
anism was proposed for this transformation, which was
Resu lts a n d Discu ssion s
The alcohol 5 was prepared as shown in Scheme 1.
Treatment of the amidine 3 with wet alumina afforded
the lactam 4 in surprisingly quantitative yield.16 Alter-
natively, lactam 4 could be prepared from acylimine 6,
which was readily prepared from hexafluoroacetone and
p-fluorobenzamide.17 Addition of KCN to 6 afforded 7
in 65% yield.18 The compound 7 existed as an equilib-
rium mixture between the cyano form and the cis and
1
trans imidates as observed by the H NMR spectrum.19
Subsequently, 7 was converted to the lactam 8 with H2O2/
NaOH in aqueous methanol20 in one step with moderate
yield. Methylation of 8 with CH3I/NaH produced 4 in
76% yield. Dibal-H reduction of lactam 4 provided
imidazoline alcohol 5 in quantitative yield.
Treatment of the alcohol 5 with sodium hydroxide or
potassium hydroxide in DMSO afforded the imidazole 9
in moderate yields (Table 1). The structure of 9 was
confirmed by X-ray crystal structure analysis (Figure 1).
When non-hydroxide bases, such as n-Bu4NF or K2CO3,
were used, 5-fluoroimidazole 10 was also isolated as a
minor product accompanying the major product 9.
There are few cases in which a trifluoromethyl group
is eliminated.21,22 The transformation of 5 to 9 and 10 is
a very unusual apparent detrifluoromethylation reaction
with a net loss of CF3OH or CF2HOH. We propose here
that the transformation of 5 to 9 goes through an
X Abstract published in Advance ACS Abstracts, March 15, 1997.
(1) Current address: The DuPont Merck Pharmaceutical Co.,
Chemical Process R&D, Chambers Works, Deepwater, NJ 08023-0999.
(2) Current address: 226 Sequoia Circle, Blairsden, CA 96103.
(3) Li, H.-Y.; DeLucca, I.; Drummond, S.; Boswell, G. A. Heterocycles
1996, 43, 937.
(4) Boswell, G. A.; Li, H.-Y.; DeLucca, I.; Billheimer, J . T.; Drum-
mond, S.; Gillies, P. J .; Robinson, C. Bioorg. Med. Chem. Lett. 1996, 6,
885.
(5) Li, H.-Y.; Drummond, S.; DeLucca, I.; Boswell, G. A. Tetrahedron
1996, 52, 11153.
(6) Li, H.-Y.; DeLucca, I.; Drummond, S.; Boswell, G. A. Bioorg. Med.
Chem., in press.
(7) Li, H.-Y.; DeLucca, I.; Drummond, S.; Boswell, G. A. Tetrahedron,
in press.
(14) Kamitori, Y.; Hojo, M.; Masuda, R.; Ohara, S.; Kawasaki, K.;
Kawamura, Y.; Tanaka, M. J . Heterocycl. Chem. 1990, 27, 487.
(15) Patents: US 5155126 (CA 118:73687); US 5179113 (CA 118:
247648); WO 9533730 (CA 124:232445).
(8) Burger, K.; Wucherpfennig, U.; Brunner, E. In Advances in
Heterocyclic Chemistry; Katritzky, A. R., Ed.; Academic Press: San
Diego, 1994; Vol. 60, pp 1-64.
(9) Burger, K.; Sewald, N.; Schierlinger, C. Brunner, E. in Chemistry
of Organic Fluorine Compounds II; ACS Monograph 187; Hudlicky,
M., Pavlath, A. E., Eds.; American Chemical Society: Washington, DC,
1995; pp 840-887.
(10) Scriabine, A.; Ludden, C. T.; Morgan, G.; Baldwin, J . J .
Experientia 1979, 35, 1634.
(11) Scriabine, A.; Ludden, C. T.; Watson, L. S.; Stavorski, J . M.;
Morgan, G.; Baldwin, J . J . Experientia 1979, 35, 653.
(12) Kamitori, Y.; Hojo, M.; Masuda, R.; Kawamura, Y.; Fang, X.
Heterocycles 1990, 31, 2103.
(16) For reviews on reactions at alumina surfaces, see: (a) Posner,
G. H. Angew. Chem. Int Ed. Engl. 1978, 17, 487. (b) Rawal, V. H.; I.
Seiji; Florjancic, A. S.; Fabre, A. In Encyclopedia of Reagents for
Organic Synthesis; Paquette, L. A., Ed.; J ohn Wiley & Sons: New York,
1995; Vol 1, pp 141.
(17) Steglich, W.; Burger, K.; Durr, M.; Burgis, E. Chem. Ber. 1974,
107, 1488.
(18) Patent DE 3704100 (CA 109:185489).
(19) Burger, K.; Huber, E.; Kahl, T.; Partscht, H.; Ganzer, M.
Synthesis 1988, 44.
(20) Nomoto, Y.; Takai, H.; Ohna, T.; Kubo, K. Chem. Pharm. Bull.
1991, 39, 352.
(21) Burger, K.; Kahl, T. J . Fluorine Chem. 1987, 36, 329.
(22) Kobayashi, Y.; Kumadaki, I.; Taguchi, S.; Hanzawa, Y. Chem.
Pharm. Bull. 1972, 20, 1047.
(13) Moazzam, M.; Parrick, J . Indian J . Chem., Sect. B 1988, 27B,
1051.
S0022-3263(96)01723-9 CCC: $14.00 © 1997 American Chemical Society

An Unusual Trifluoromethyl Elimination Reaction
J . Org. Chem., Vol. 62, No. 8, 1997 2551
Sch em e 1
Ta ble 1. Ba se-P r om oted Con ver sion of 5 to 9 a n d 10
reaction conditions
% yield of
productsd
temp time
no.
basea
solventc (°C)
(h)
9
10
1
2
3
4
5
6
7
8
9
NaOH (powder)
NaOH (powder)
NaOH (50% aqueous) DMSO
KOH (powder)
CsF
DMSO
DMSO
120
23
120
23
120
120
120
120
70
2
16
2
16
2
16
16
16
16
4
51
47
39
55
62e
DMSO
DMSO
DMSO
DMSO
DMSO
THF
6
KF
50 28
NaF
LiF
20 trace
11 trace
45e 13e
Bu4NFb
10 K2CO3
DMSO
120
60
7
a
10 equiv of bases were used. b 15 equiv was used. c All solvents
d
were anhydrous and purchased from Aldrich Chemical Co. Yields
were determined by HPLC except when indicated. e Isolated yields.
F igu r e 1. X-ray crystal structures of 5 and 9 (from Chem 3D
based on their PDB files).
unprecedented difluorooxetane intermediate 14, which
loses carbonyl difluoride to form imidazole 9. Difluoro-
oxetane 14 could be formed through a ring-opening and
ring-closure process through intermediates 12 or 13, as
shown in Scheme 2. Although R-hydroxylamines and
N-acylhydroxylamines were known to exist in an equi-
group in the X-ray crystal structure (Figure 1). We also
considered the possibility of hydrolysis of vinyl fluoride
13 to carboxylic acid, which might undergo decarboxyl-
ation. This possibility was excluded by using CsF or
K2CO3 as a base because very little water was presented
in these reaction mixtures.
The ring-opened intermediates 12 or 15 could also be
used to explain the formation of 5-fluoroimidazole 10.
Hydrolysis of formamide 15 should provide 16, which
could lose HF to give vinyl fluoride 17. Subsequent ring
closure of 17 followed by the fluoride elimination should
provide the product 10.30,31 Burger reported32 an analo-
librium between aldehydes and amines or amides,23,24
a
few exceptions with carbonyl/R-carbon cleavage were also
reported.8,25,26 We believe that the gem-trifluoromethyl
groups facilitated this carbonyl/R-carbon cleavage (i.e. 5
f 15) both sterically and electronically.
It is unlikely that 14 was formed by an intramolecular
displacement of fluoride from one of the trifluoromethyl
groups by oxygen anion,27-29 despite the fact that the
hydroxyl group was very close to its cis-trifluoromethyl
(23) Morzycki, J . W.; Rodewald, W. J . Heterocycles 1981, 16, 1097.
(24) Nagasaka, T.; Yamamoto, H.; Hayashi, H.; Watanabe, M.;
Hamaguchi, F. Heterocycles 1989, 29, 155.
(25) Schweizer, E. E.; Lee, K. J . J . Org. Chem. 1984, 49, 4848.
(26) Schlecker, R.; Seebach, D.; Lubosch, W. Helv. Chim. Acta 1978,
61, 512.
(27) Kobayashi, Y.; Kumadaki, I.; Taguchi, S.; Hanzawa, Y. Tetra-
hedron Lett. 1970, 3901.
(28) Kobayashi, Y.; Kumadaki, I.; Taguchi, S. Chem. Pharm. Bull.
1971, 19, 624.
(29) Kobayashi, Y.; Kumadaki, I.; Taguchi, S.; Hanzawa, Y. J . Org.
Chem. 1974, 39, 1836.

2552 J . Org. Chem., Vol. 62, No. 8, 1997
Li et al.
Sch em e 2
Sch em e 3
gous synthesis of 2-aryl-4-(trifluoromethyl)-5-fluoroimid-
azole by the reduction of the N-arylbenzamidines and
hexafluoroacetone adducts with stannous chloride to
produce intermediates like 18, which provided similar
5-fluoroimidazole analogs.
Compound 5 was stable upon heating (120 °C, 4 h) in
the absence of base. Methyl ether of 5 did not react upon
treatment with n-tetrabutylammonium fluoride under
reflux. These experiments suggested that deprotonation
of the hydroxyl group was crucial for ring opening. We
proposed that further transformations require a base that
could deprotonate 15 and 16. Thus, if a base could only
deprotonate 5, but not 15 and 16, the ring-opened
compound 15 should be the reaction product. Heating
of 5 with weaker bases, such as Et3N, allowed us to
isolate and characterize 15 (Scheme 3) in variable
isolated yields. Treatment of 15 with n-tetrabutyl-
ammonium fluoride afforded a mixture of 9 and 10, as
expected.
Compounds resembling 17 have rarely been encoun-
tered. It is known, however, that vinyl fluoride can be
displaced by a variety of nuclophiles, presumably through
an addition and elimination mechanism.30,33 Heating of
5 with Et4NCN in DMSO at 70-90 °C provided 19, which
was clearly derived from 17, as a major product (70%)
along with small amount of 9. Compound 19 was very
stable with a unique and interesting structure.34
“Elimination” of a trifluoromethyl group of the gem-
bis(trifluoromethyl) compounds such as 5 by a novel ring-
opening and ring-closing mechanism provided a unique
way to synthesize regioselectively trifluoromethyl-sub-
stituted heterocycles, which possessed very interesting
biological activities. 4-(Trifluoromethyl)imidazole 9 was
then converted to the amide analogs 22 and 23 (Scheme
4). Treatment of 9 with n-BuLi followed by 4-fluorobenz-
aldehyde gave alcohol 20, which was subsequently oxi-
dized by PCC to the ketone 21. Schmidt rearrangement
of 21 afforded two amides, 22 and 23. For direct
comparison with our previously synthesized imidazoline
series of ACAT inhibitors, 23 was methylated to produce
24 in 95% yield. Both 23 and 24 showed moderate
inhibition in our ACAT in vitro assay, which was
comparable to the imidazoline series.3-6
(30) Hudlicky, M. Chemistry of Organic Flurine Compounds, 2nd
ed.; Ellis Horwood Limited: Chichester, England, 1992; pp 285-297.
(31) Vij, A.; Zheng, Y. Y.; Kirchmeier, R. L.; Shreeve, J . M. Inorg.
Chem. 1994, 33, 3281.
(32) Ottlinger, R.; Burger, K.; Goth, H.; Firl, J . Tetrahedron Lett.
1978, 5003.
(33) J in, F.; J iang, B.; Xu, Y. Tetrahedron Lett. 1992, 33, 1221.
(34) Lorente, A.; Balcazar, J . L.; Florencio, F. J . Chem. Soc. Perkin
Trans. 1 1992, 3377.
Exp er im en ta l Section 35
P r epa r a tion of 2-(4-Flu or op h en yl)-4,5-dih yd r o-1-m eth -
yl-4,4-bis(tr iflu or om eth yl)-4H-im id a zol-5-on e (4). A solu-
tion of N-[4,4-bis(trifluoromethyl)-2-(4-fluorophenyl)-4,5-dihydro-
(35) For a summary of general experimental methods, see ref 5.

An Unusual Trifluoromethyl Elimination Reaction
J . Org. Chem., Vol. 62, No. 8, 1997 2553
Sch em e 4
1-methyl-1H-imidazol-5-ylidene]-4-(fluorophenyl)benzamide (3)3
(1.1 g, 2.3 mmol) in diethyl ether was eluted to the center of
a basic alumina (III) column with diethyl ether at room
temperature. After 2 h, the material was eluted from the
column with ethyl acetate and the crude product was purified
by column chromatography with hexane-ethyl acetate (10:1)
to give the title compound 4 in quantitative yield (0.80 g, 100%)
as a white solid: mp 59-61 °C; IR (KBr) 1767, 1618 cm-1; 1H
NMR (300 MHz, CDCl3) δ 3.28 (s, 3H, NCH3), 7.27 (t, J ) 8.8
Hz, 2H), 7.78 (dd, J ) 5.1, 8.8 Hz, 2H); 19F NMR (CDCl3,
CFCl3) δ -72.17 (s, 6F, 2 × CF3), -105.12 (m, 1F); MS m/ e
329 (M + H)+; HRMS for C12H7F7N2O (M+) calcd 328.0447,
found 328.0454. Anal. Calcd for C12H7F7N2O C, 43.92; H, 2.15;
N, 8.54; F, 40.52. Found: C, 43.91; H, 1.80; N, 8.48; F, 40.36.
P r ep a r a tion of N-[1-Cya n o-2,2,2-tr iflu or o-1-(tr iflu o-
r om et h yl)et h yl]-4-flu or ob en za m id e a n d 2-(4-F lu or o-
p h en yl)-4,4-bis(tr iflu or om eth yl)-5(4H)-oxa zolim in e (7).
To a solution of 4-fluoro-N-[2,2,2-trifluoro-1-(trifluoromethyl)-
ethylidene]benzamide (6)18,19 (72.7 g, 0.25 mol) in anhydrous
diethyl ether (145 mL) was added KCN (22.0 g, 0.34 mol) at 0
°C in portions. After stirring at room temperature overnight,
the reaction mixture was worked up to give the title compound
(7) (53.2 g, 65%) as a crystalline solid. This product exists as
an equilibrium of three compounds in chloroform: mp 127-
128 °C; IR (KBr) 3268, 1677 cm-1; 1H NMR (300 MHz, CDCl3)
δ 6.38 (s, 0.21H, NH), 7.19-7.26 (m, 2H), 7.84 (dd, J ) 5.3,
8.7 Hz, 0.42H), 8.10 (dd, J ) 5.3, 8.7 Hz, 0.84H), 8.17 (dd, J )
5.3, 8.7 Hz, 0.74H), 8.74 (s, 0.42H, NH), 9.28 (s, 0.37H, NH);
19F NMR (CDCl3, CFCl3) δ -73.02 (s, 1.2F, CF3), -73.52 (s,
2.5F, CF3), -73.58 (s, 2.3F, CF3), -102.11 (m, 0.38F), -102.32
(m, 0.42F), -104.01 (m, 0.20F); MS m/ e 315 (M + H)+; HRMS
for C11H6F7N2O (M + H)+ calcd 315.0368, found 315.0368.
Anal. Calcd for C11H5F7N2O C, 42.06; H, 1.60; N, 8.92.
Found: C, 41.94; H, 1.73; N, 8.89.
P r epa r a tion of 2-(4-Flu or op h en yl)-4,5-dih yd r o-1-m eth -
yl-4,4-bis(tr iflu or om eth yl)-4H-im id a zol-5-on e (4). Sodium
hydride (60% suspension in mineral oil, 1.73 g, 26 mmol) was
suspended in anhydrous dimethylformamide (25 mL). To this
suspension was added a solution of 8 (5.77 g, 18.4 mmol) in
anhydrous DMF (25 mL) dropwise at 0 °C. The resulting
reaction mixture was allowed to stir at room temperature for
30 min before iodomethane (3.65 g, 26 mmol) was added
dropwise. After being stirred at room temperature for 2 h,
the reaction mixture was poured into water and extracted with
ethyl acetate (3 × 30 mL). The combined organic layers were
washed successively with water and saturated aqueous sodium
chloride, dried over anhydrous magnesium sulfate, and con-
centrated in vacuo. The residue was crystallized in hexane/
ethyl acetate to give the title compound (4, 4.6 g, 76%), which
was identical with the authentic sample obtained above.
P r epa r a tion of 2-(4-Flu or op h en yl)-4,5-dih yd r o-1-m eth -
yl-4,4-bis(tr iflu or om eth yl)-1H-im id a zol-5-ol (5). To a so-
lution of 2-(4-fluorophenyl)-3,5-dihydro-3-methyl-4,4-bis-(tri-
fluoromethyl)-4H-imidazol-4-one (4) (1.21 g, 3.69 mmol) in
anhydrous THF (40 mL) was added a DIBAL-H solution (1.0
M in THF, 5 mL, 5 mmol) over 10 min. After being refluxed
for 2 h under nitrogen, the reaction mixture was quenched
with methanol (0.5 mL) and water (300 mL). The mixture was
extracted with diethyl ether (2 × 50 mL) and then ethyl acetate
(2 × 50 mL). The combined organic layers were washed with
saturated aqueous sodium chloride solution, dried over anhy-
drous sodium sulfate, filtered, and concentrated in vacuo to
give the title compound (5) as a white crystalline solid (1.209
g, 100%): mp 180-195 °C; IR (KBr) 1606, 1564 cm-1; 1H NMR
(300 MHz, CDCl3) δ 2.97 (d, J ) 9.5 Hz, 1H), 3.02 (s, 3H,
NCH3), 5.48 (d, J ) 9.5 Hz, 1H), 7.16 (t, J ) 8.7 Hz, 2H), 7.62
(dd, J ) 5.3, 8.7 Hz, 2H); 19F NMR (CDCl3, CFCl3) δ -68.83
(q, J ) 9.5 Hz, 3F, CF3), -76.65 (q, J ) 9.5 Hz, 3F, CF3),
-107.98 (m, 1F); HRMS for C12H9F7N2O (M+) calcd 330.0603,
found 330.0603.
P r ep a r a tion of 2-(4-F lu or op h en yl)-4,5-d ih yd r o-4,4-bis-
(tr iflu or om eth yl)-4H-im id a zol-5-on e (8). To a solution of
7 (10.0 g, 31.9 mmol) in 10% NaOH (30 mL) and MeOH (30
mL) was added 30% H2O2 (30 mL) dropwise over 10 min at 0
°C. The reaction mixture was stirred at room temperature
for another 2 h and neutralized with 1 N HCl to pH 7. The
mixture was concentrated in vacuo to remove most of the
methanol. After dilution with water (100 mL), the aqueous
mixture was extracted with ethyl acetate (3 × 50 mL). The
combined organic layers were washed with saturated aqueous
sodium sulfite twice and saturated aqueous sodium chloride
twice, dried over anhydrous sodium sulfate, filtered, and
concentrated in vacuo. The residue was crystallized from ethyl
acetate and hexane to give the title compound (8, 4.7 g, 47%)
as a white crystalline solid: mp 152-154 °C; IR (KBr) 3302,
Gen er a l P r oced u r e for Rea ction of 2-(4-F lu or op h en -
yl)-4,5-d ih yd r o-1-m e t h yl-4,4-b is(t r iflu or om e t h yl)-1H -
im id a zol-5-ol (5) w ith Ba ses. Compound 5 (1 equiv) and a
base (5-10 equiv) were mixed in anhydrous DMSO, and the
reaction mixture was heated at 120 °C for 4-24 h. After
cooling to room temperature, the reaction was quenched with
water and extracted with diethyl ether or ethyl acetate. The
combined organic layers were washed successively with satu-
rated aqueous ammonium chloride solution and saturated
aqueous sodium chloride solution, dried over anhydrous
sodium sulfate, and concentrated in vacuo. The residue was
purified by flash column chromatography.
P r ep a r a tion of 2-(4-F lu or op h en yl)-1-m eth yl-4-(tr iflu o-
r om eth yl)-1H-im id a zole (9). This compound was obtained
from 5 (50 mg, 0.15 mmol) and CsF (229 mg, 1.5 mmol)
following the general procedure described above in 62% as a
white crystalline solid: mp 86-87.2 °C; IR (KBr) 3126, 2960,
1
1771, 1628 cm-1; H NMR (300 MHz, CDCl3) δ 10.09 (s, 1H,
NH), 8.07 (dd, J ) 5.3, 8.7 Hz, 2H), 7.28 (t, J ) 8.4 Hz, 2H);
19F NMR (CDCl3, CFCl3) δ -71.86 (s, 6F), -102.85 (m, 1F);
HRMS for C11H6F7N2O (M + H)+ calcd 315.0368, found
315.0346. Anal. Calcd for C11H5F7N2O C, 42.06; H, 1.60; N,
8.92. Found: C, 43.91; H, 1.21; N, 9.12.
1610, 1580 cm-1
;
1H NMR (300 MHz, CDCl3) δ 3.75 (s, 3H,
NCH3), 7.19 (t, J ) 8.5 Hz, 2H), 7.30 (s, 1H), 7.61 (dd, J ) 5.5,

2554 J . Org. Chem., Vol. 62, No. 8, 1997
Li et al.
8.5 Hz, 2H); 19F NMR (CDCl3, CFCl3) δ -63.279 (s, 3F, CF3),
-111.363 (m, 1F); HRMS for C11H9F4N2 (M + H)+ calcd
245.0702, found 245.0706. Anal. Calcd for C11H8F4N2 C,
54.11; H, 3.30; N, 11.47. Found: C, 53.93; H, 3.13; N, 11.33.
The residue was dissolved in CH2Cl2 (5 mL) and reacted with
PCC (1.1 g, 5.1 mmol). The resulting reaction mixture was
stirred at room temperature for overnight, diethyl ether (30
mL) was added, and the solvent was decanted. The solid was
washed with diethyl ether twice. The combined diethyl
ethereal solution was purified by a short Florisil column. The
solvent was removed under reduced pressure to give a residue
(21): 1H NMR (300 MHz, CDCl3) δ 3.73 (s, 3H, NCH3), 7.21
(t, J ) 8.7 Hz, 2H), 7.23 (t, J ) 8.7 Hz, 2H), 7.68 (dd, J ) 5.3,
8.7 Hz, 2H), 7.96 (dd, J ) 5.3, 8.7 Hz, 2H); 19F NMR (CDCl3,
CFCl3) δ -59.71 (s, 3F, CF3), -102.83 (m, 1F), -109.83 (m,
1F). The residue was dissolved in benzene (10 mL) and concd
H2SO4 (4 mL). To this solution, was added NaN3 (264 mg, 4
mmol) in portions at <5 °C. The reaction mixture was stirred
at 0 °C for 2 h and then room temperature for 2 days. After
the reaction mixture was quenched with ice, the mixture was
extracted with ethyl acetate (3 × 30 mL). The combined
organic layers were washed with water, dried over anhydrous
sodium sulfate, filtered, and concentrated in vacuo. The
residue was purified by flash column chromatography to give
compounds 22 (96 mg, 27%) and 23 (248 mg, 70%). For 22:
P r ep a r a tion of 2-(4-F lu or op h en yl)-1-m eth yl-4-(tr iflu o-
r om et h yl)-1H -im id a zole (9) a n d 5-F lu or o-2-(4-flu or o-
p h en yl)-1-m eth yl-4-(tr iflu or om eth yl)-1H-im id a zole (10).
To a solution of 5 (108 mg, 0.33 mol) in anhydrous THF (5
mL) was added tetrabutylammonium fluoride (1.0 M solution
in THF, 5 mL, 5 mmol) and the reaction mixture was refluxed
for 16 h. After cooling to room temperature, the reaction was
quenched with water (50 mL) and extracted with diethyl ether
(2 × 20 mL). The combined organic layers were washed with
saturated aqueous sodium chloride solution, dried over anhy-
drous sodium sulfate, filtered, and concentrated in vacuo. The
residue was purified by flash column chromatography to afford
three fractions: I (12 mg), II (11 mg, 13%), and III 36 mg (9,
45%). Fraction II was the title compound (10): IR (KBr) 2964,
1
1644 cm-1; H NMR (300 MHz, CDCl3) δ 3.56 (d, J ) 0.8 Hz,
NCH3), 7.11 (t, J ) 8.7 Hz, 2H), 7.53 (dd, J ) 4.9, 8.7 Hz, 2H);
19F NMR (CDCl3, CFCl3) δ -62.08 (d, J ) 10.3 Hz, 3F),
-110.67 (m, 1F), -141.50 (q, J ) 10.3 Hz, 1F), HRMS for
C11H8F5N2 (M+) calcd 263.0608, found 263.0605.
mp 183-184 °C; IR (KBr) 3251, 1672, 1612, 1510 cm-1 1H
;
NMR (300 MHz, CDCl3) δ 3.84 (s, 3H, NCH3), 7.08 (t, J ) 8.4
Hz, 2H), 7.19 (t, J ) 8.4 Hz, 2H), 7.53-7.62 (m, 4H), 8.11 (br
s, 1H, NH); 19F NMR (CDCl3, CFCl3) δ -59.348 (s, 3F, CF3),
-109.853 (m, 1F), -116.548 (m, 1F); HRMS for C18H12F5N3O
(M+) calcd 381.0901, found 381.0904; For 23: mp 114-116 °C;
IR (KBr) 3258, 1672, 1666 cm-1; 1H NMR (300 MHz, CDCl3) δ
3.60 (s, 3H, NCH3), 7.19 (t, J ) 8.7 Hz, 2H), 7.23 (t, J ) 8.3
Hz, 2H), 7.66 (m, 3H), 7.95 (dd, J ) 5.3, 8.7 Hz, 2H); 19F NMR
(CDCl3, CFCl3) δ -61.855 (s, 3F, CF3), -105.493 (m, 1F),
-111.02 (m, 1F); HRMS for C18H12F5N3O (M+) calcd 381.0901,
found 381.0900.
P r ep a r a tion of 4-F lu or o-N-for m yl-N-m eth yl-N′-[2,2,2-
t r iflu o r o -1-(t r iflu o r o m e t h y l)e t h y l]b e n ze n e c a r b o x -
im id a m id e (15). The mixture of 5 (246 mg, 0.75 mmol) and
Et3N (2 mL, 27 mmol) in anhydrous DMSO (3 mL) was heated
at 100 °C for 24 h. After cooling to room temperature, the
reaction was quenched with water (40 mL) and extracted with
diethyl ether (3 × 40 mL). The combined organic layers were
washed successively with saturated aqueous ammonium chlo-
ride solution and saturated aqueous sodium chloride solution,
dried over anhydrous sodium sulfate, and concentrated in
vacuo. The residue was purified by flash column chromatog-
raphy to give the recovered starting material 5 (160 mg) and
the title compound 15 as a viscous oil (12 mg, 14%): IR (KBr)
P r ep a r a tion of 4-F lu or o-N-[2-(4-flu or op h en yl)-1-m eth -
yl-4-(tr iflu or om eth yl)-1H-im id a zol-5-yl]-N-m eth ylben z-
a m id e (24). To a suspension of sodium hydride (60% suspen-
sion in mineral oil, 29 mg, 0.72 mg) in anhydrous dimethyl-
formamide (5 mL) was added in portions 23 (230 mg, 0.6 mmol)
and the mixture was allowed to stir at room temperature for
30 min. Iodomethane (103 mg, 0.72 mmol) was added drop-
wise and the reaction mixture was allowed to stir at room
temperature for 2 h. The reaction mixture was poured into
water and extracted with ethyl acetate (3 × 30 mL). The
combined organic layers were washed successively with water
and saturated aqueous sodium chloride, dried over anhydrous
magnesium sulfate, and concentrated in vacuo to give the title
compound (24, 226 mg, 95%): mp 123-125 °C; IR (KBr) 2924,
1
1720, 1708, 1630 cm-1; H NMR (300 MHz, CDCl3) δ 8.41 (s,
1H), 7.27 (m, 4H), 4.06 (m, 1H), 3.35 (s, 3H, NCH3); 19F NMR
(CDCl3, CFCl3) δ -107.40 (m, 1F), -71.65 (d, J ) 6.9 Hz, 6F);
HRMS for C12H8F7N2O (M + H)+ calcd 329.0525, found
329.0529.
P r ep a r a t ion of N′-[2,2-Dicya n o-1-(t r iflu or om et h yl)-
eth en yl]-4-flu or o-N-m eth ylben zen ecar boxim idam ide (19).
To a solution of 5 (1.53 g 4.56 mmol) in anhydrous DMSO (15
mL) was added Et4NCN36 (3.02 g, 18 mmol) at 70 °C over 2 h.
After it was stirred at 70 °C for another 14 h and then cooled
to rt, the reaction mixture was poured into water (300 mL)
and extracted with diethyl ether (3 × 150 mL). The combined
organic layers were washed with water, dried over anhydrous
sodium sulfate, filtered, and concentrated in vacuo. The
residue was purified by flash column chromatography to give
the compound 9 (142 mg, 13%) and the title compound (19,
947 mg, 70%) as a crystalline solid: mp >250 °C; IR (KBr)
1
1671 cm-1; H NMR (300 MHz, CDCl3) δ 3.42 (s, 3H, NCH3),
3.44 (s, 3H, NCH3), 6.97 (t, J ) 8.4 Hz, 2H), 7.16 (t, J ) 8.4
Hz, 2H), 7.37 (m, 2H), 7.48 (m, 2H); 19F NMR (CDCl3, CFCl3)
δ -63.194 (s, 3F, CF3), -108.034 (m, 1F), -110.289 (m, 1F);
HRMS for C19H14F5N3O (M+) calcd 395.1057, found 395.1072.
1
3350, 2373, 1617 cm-1; H NMR (300 MHz, CDCl3) δ 3.31 (d,
J ) 7.5 Hz, 3H, NCH3), 7.34 (m, 2H), 7.74 (br s, 1H, NH), 8.57
(m, 2H); 19F NMR (CDCl3, CFCl3) δ -69.450 (s, 3F, CF3),
-109.554 (m, 1F); HRMS for C13H9F4N4 (M + H)+ calcd
297.0763, found 297.0771.
Ack n ow led gm en t. We thank Prof. E. Taylor of
Princeton University, Prof. H. Rapoport of the Univer-
sity of California, Berkeley, and Dr. B. Smart and Mr.
F. Davidson of Du Pont CR&D, for their very helpful
discussions. We thank J oe Calabrese for obtaining the
X-ray crystal structures and DuPont Merck Physical
Sciences group for obtaining most of the NMR, IR, and
MS data. We also want to thank Drs. J . T. Billheimer
and P. J . Gillies for obtaining IC50 data for the ACAT
in vitro assay.
P r ep a r a t ion of N,2-Bis(4-flu or op h en yl)-1-m et h yl-4-
(tr iflu or om eth yl)-1H-im id a zole-5-ca r boxa m id e (22) a n d
4-F lu or o-N -[2-(4-flu or op h e n yl)-1-m e t h yl-4-(t r iflu or o-
m eth yl)-1H-im id a zol-5-yl]ben za m id e (23). To a solution
of 9 (525 mg 2.15 mmol) in anhydrous THF (20 mL) was added
a solution of n-BuLi (1.6 M in hexane, 1.47 mL, 2.3 mmol)
dropwise at -70 °C. After the reaction mixture was stirred
at -78 °C for 2 h, a solution of 4-fluorobenzaldehyde (267 mg,
2.15 mmol) in THF (5 mL) was added slowly. The resulting
reaction mixture was stirred at -78 °C for 1 h and then at 23
°C for another 1 h. The reaction was quenched with aqueous
saturated ammonium chloride solution (40 mL) and the
mixture was extracted with ethyl acetate (3 × 30 mL). The
combined organic layers were washed with water, dried over
anhydrous sodium sulfate, filtered, and concentrated in vacuo.
Su p p or tin g In for m a tion Ava ila ble: 1H NMR and 19F
NMR spectra for compounds 4, 5, 7-10, 15, 19, 21, and 22-
24 and the X-ray crystal structure data for 5 and 9 (36 pages).
This material is contained in libraries on microfiche, im-
mediately follows this article in the microfilm version of the
journal, and can be ordered from the ACS; see any current
masthead page for ordering information.
(36) The purity of this material is 94% from Aldrich Chemical Co.
J O961723X