936 J . Org. Chem., Vol. 63, No. 4, 1998
Akhavan-Tafti et al.
Calcd for C23H15F6NO6S: C, 50.46; H, 2.76; N, 2.56. Found:
C, 50.39; H, 2.91; N, 2.55.
rophenol (260 mg) was added to the solution, which was stirred
at room temperature until the reaction was complete. The
pyridine was removed under reduced pressure and the prod-
ucts separated by preparative TLC. Compound 2b was
isolated as the minor isomer. Compound 2b: 1H NMR (CDCl3)
δ 4.03 (s, 3H), 4.04 (s, 3H), 6.86-6.88 (d, 1H), 7.04-7.24 (m,
2H), 7.33-7.37 (dd, 1H), 7.49-7.50 (d, 1H), 7.71-7.77 (m, 1H),
7.81-7.83 (m, 1H), 8.08-8.11 (d, 1H).
2′,3′,6′-Tr iflu or op h en yl 1,6-Dim eth oxy-10-m eth yla cr i-
d in iu m -9-ca r boxyla te Tr iflu or om eth a n esu lfon a te (3b).
N-Methylacridinium ester 3b (45 mg) obtained by the standard
procedure was used without purification in the next step.
2′,3′,6′-Tr iflu or op h en yl 1,6-Dim eth oxy-10-m eth yla cr i-
d a n -9-ca r boxyla te (4b). Following the standard protocol, 12
mg of the acridan ester was isolated: 1H NMR (CDCl3) δ 3.39
(s, 3H), 3.84 (s, 3H), 3.90 (s, 3H), 5.90 (s, 1H), 6.50-7.43 (m,
8H).
2′,3′,6′-Tr iflu or op h en yl Acr id in e-9-ca r boxyla te (2c).
The commercially available acridine-9-carboxylic acid (0.5 g)
was refluxed with 5 mL of SOCl2 for 3 h, the solution
evaporated, and the acid chloride reacted with 0.365 g of 2,3,6-
trifluorophenol and 0.53 g of pyridine using the general
procedure described above to produce ester 2c: 1H NMR
(CDCl3) δ 7.08-7.28 (m, 2H) 7.71-8.42 (m, 8H); 19F NMR
(CDCl3) δ -146.13 (m), -139.85 (m), -129.82 (m). Anal.
Calcd for C20H10F3NO2: C, 67.99; H, 2.85; N, 3.96. Found: C,
67.91; H, 2.92; N, 3.97.
2′,3′,6′-Tr iflu or op h en yl 10-Meth yla cr id a n -9-ca r boxy-
la te (4c). Because of the low reactivity of 2c with methyl
triflate, an alternate procedure was used to prepare 4c. Ester
2c was reduced with zinc and NH4Cl in 2-propanol. The crude
product was then methylated in CH2Cl2 with methyl triflate
as described above. Ester 4c was purified by chromatography
on silica gel with 25% CH2Cl2/hexane: 1H NMR (CDCl3) δ 3.44
(s, 3H), 5.29 (s, 1H), 6.76-6.84 (m, 2 H) 6.99-7.39 (m, 8H);
19F NMR (CDCl3) δ -147.57, -141.15, -131.19. HRMS (EI)
m/z calcd for C21H14NO2F3 (M+) 369.0976, found 369.0966; MS
(EI) m/z (rel int): 369 (5), 194 (100), 179 (17). Anal. Calcd
for C21H14F3NO2: C, 68.29; H, 3.82; N, 3.79. Found: C, 68.18;
H, 3.76; N, 3.80.
Gen er a l P r oced u r e for Red u ction of N-Meth yla cr i-
din iu m car boxylic Ester s. 2′,3′,6′-Tr iflu or oph en yl 3-Meth -
oxy-10-m eth yla cr id a n -9-ca r boxyla te (4a ). Compound 3a
(0.035 g) was suspended in absolute ethanol (15 mL) and the
solution was refluxed for 10 min to obtain a clear solution.
Excess NH4Cl (4.0 g), was added by portions to the solution
followed by zinc (4.0 g) causing immediate decolorization of
the solution. The colorless solution was refluxed for 30 min.
The cooled solution was filtered and the precipitate washed
with ethanol (3 × 20 mL). The solution was concentrated to
obtain an off-white solid which was redissolved in CH2Cl2 and
washed with water (3 × 50 mL). The crude material obtained
after evaporation of CH2Cl2 was chromatographed on silica gel
(ethyl acetate/hexane) to yield 4a as a white solid: 1H NMR
(CDCl3) δ 3.422 (s, 3H), 3.847 (s, 3H), 5.25 (s, 1H), 6.54-7.39
(m, 9H); 19F NMR (CDCl3) δ -147.55 (m), -141.18 (m),
-131.15 (m). HRMS (EI) m/z calcd for C22H16NO3F3 (M+)
399.1082, found 399.1084; MS (EI) m/z (rel int) 399.1 (5), 224.1
(100), 209 (7), 181 (17), 166 (8), 148 (4). Anal. Calcd for
C
22H16F3NO3: C, 66.16; H, 4.04; N, 3.51. Found: C, 65.92; H,
4.03; N, 3.47.
3-Meth oxya ceta n ilid e. Acetic anhydride (20 mL) was
added to a solution of m-anisidine (20 g) in 20 mL of acetic
acid at 0 °C. The solution was stirred overnight at room
temperature and then poured into 100 g of ice and 100 mL of
water. The light pink solid was filtered and air-dried, yielding
21.5 g of the product: 1H NMR (CDCl3) δ 2.18 (s, 3H), 3.81 (s,
3H), 6.65-6.68 (d, 1H), 6.94-6.97 (d, 1H), 7.15 (br s, 1H),
7.18-7.28 (m, 2H); 13C NMR (CDCl3) δ 24.43, 55.15, 105.77,
109.84, 112.12, 129.51, 139.19, 159.95, 168.91.
Bis(3-m eth oxyp h en yl)a m in e. 3-Methoxyacetanilide (20
g) was condensed with 3-bromoanisole (38.3 mL) in the
presence of 18.4 g of K2CO3 and 2.3 g of CuI at 220 °C for 17
days. After 8 days, 2.76 g of K2CO3, 3.45 g of CuI, and 10 mL
of bromoanisole were added. After 12 days, an additional 1.9
g of K2CO3 and 2.3 g of CuI were added. TLC (30% ethyl
acetate/hexane) indicated complete conversion of the acet-
anilide to the diphenylamine compound. The excess bro-
moanisole was distilled away under vacuum and the product
used without further purification. The acetanilide compound
was dissolved in 100 mL of absolute ethanol containing 13.46
g of KOH. The mixture was refluxed for 1.5 h. The cooled
mixture was concentrated, dissolved in ether, and washed with
3 × 100 mL of water. The organic layer was dried and
concentrated to a brown oil. The diphenylamine product (33
g) was isolated by column chromatography using 40% ethyl
acetate/hexane: 1H NMR (CDCl3) δ 3.77 (s, 6H), 6.48-6.51
(dd, 2H), 6.65-6.68 (m, 4H), 7.16 (t, 2H); 13C NMR (CDCl3) δ
55.18, 103.71, 106.41, 110.57, 130.06, 144.20, 160.62.
1,6-Dim eth oxya cr id in e-9-ca r boxylic Acid (1b). A solu-
tion of 10 g of bis(3-methoxyphenyl)amine in 50 mL of CH2Cl2
was added dropwise over 35 min to a warm solution of 4.95
mL of oxalyl chloride in 50 mL of CH2Cl2. The solution was
refluxed for 1 h, after which time the volatiles were evaporated,
and the residue was redissolved in 200 mL of CH2Cl2. The
ice-cooled solution was treated with 20.36 g of AlCl3 added in
portions. Reflux was started after 25 min. The volatiles were
removed after 3 h and the black residue quenched with a
mixture of 250 g of ice and 250 mL of 0.5 N HCl. The orange
isatin compound was filtered and air-dried: 1H NMR (CDCl3)
δ 3.85, 3.87 (2 s, 6H), 6.38 (d, 1H), 6.60-6.64 (dd, 1H), 6.93-
7.01 (m, 3H), 7.46 (t, 1H), 7.68 (d, 1H). Without further
purification, the isatin was refluxed with 200 mL of 10% KOH
for 22 h, cooled, evaporated, and neutralized with 200 mL of
5 N HCl and 300 g of ice. The product, isolated by filtration
as a yellow solid, contained a mixture of 1,6-dimethoxyacri-
dine-9-carboxylic acid and 3,6-dimethoxyacridine-9-carboxylic
acid, which were separated after conversion to the 2,3,6-
trifluorophenyl esters.
2′,6′-Diflu or op h en yl Acr id in e-9-ca r boxyla te (2d ). Acri-
dine-9-carboxylic acid (0.5 g) was refluxed with 10 mL of SOCl2
for 3 h, the solution evaporated and the acid chloride reacted
with 0.32 g of 2,6-difluorophenol and 0.44 g of pyridine using
the general procedure described above to produce ester 2d :
1H NMR (CDCl3) δ 7.13-7.39 (m, 3H), 7.68-8.35 (m, 8H); 19
F
NMR (CDCl3) δ -125.33 (s). Anal. Calcd for C20H11F2NO2:
C, 71.64; H, 3.31; N, 4.18. Found: C, 71.42; H, 3.30; N, 4.14.
2′,6′-Diflu or op h en yl 10-Meth yla cr id in iu m -9-ca r boxy-
la te (3d ). Compound 2d (0.40 g) was dissolved in CH2Cl2 (5
mL) under argon and methyl trifluoromethanesulfonate (0.945
mL) was added. The solution was stirred overnight at room
temperature to yield a thick yellow precipitate. This precipi-
tate was filtered, washed with ether, and dried to obtain 3d
as yellow crystals: 1H NMR (acetone-d6) δ 5.28 (s, 3H), 7.44-
7.68 (m, 3H), 8.32-9.13 (m, 8H); 19F NMR (acetone-d6) δ
-125.57 (m), -77.73 (s). Anal. Calcd for C22H14F5NO5S: C,
52.91; H, 2.83; N, 2.80. Found: C, 53.23; H, 2.94; N, 2.82.
2′,6′-Diflu or op h en yl 10-Meth yla cr id a n -9-ca r boxyla te
(4d ). Compound 3d (0.10 g) was reduced with 0.65 g of Zn
and 0.535 g of NH4Cl in 15 mL of ethanol according to the
general procedure described above to produce acridan 4d as a
white solid: 1H NMR (CDCl3) δ 3.49 (s, 3H), 5.29 (s, 1H), 6.82-
7.10 (m, 7 H) 7.29-7.41(m, 4H); 19F NMR (CDCl3) δ -126.65
(m). HRMS (EI) m/z calcd for C21H15NO2F2 (M+) 351.1071,
found 351.1074; MS (EI) m/z (rel int): 351 (5), 194 (100), 179
(16). Anal. Calcd for C21H15F2NO2: C, 71.79; H, 4.30; N, 3.99.
Found: C, 71.68; H, 4.24; N, 3.96.
5-Met h oxy-2-m et h yla cet a n ilid e. 5-Methoxy-2-methyl-
aniline (9.77 g, Aldrich) was converted to the acetamide
derivative by reaction with 8.7 mL of acetic anhydride, 8.2 mL
of acetic acid, and 43 mg of zinc at reflux for 7 h. The reaction
mixture was poured into 250 mL of ice water and stirred. The
light brown solid was filtered and air-dried yielding 6.37 g of
the product: mp 95-95.7 °C; 1H NMR (CDCl3) δ 2.19 (s, 3H),
2′,3′,6′-Tr iflu or op h en yl 1,6-Dim eth oxya cr id in e-9-ca r -
boxyla te (2b). A mixture of the 3,6- and 1,6-dimethoxyacridi-
necarboxylic acids (100 mg) in pyridine was reacted wtih
p-toluenesulfonyl chloride (280 mg) for 1 h. 2,3,6-Trifluo-