ortho-Arylation and One-Pot Cyclization to Phenanthridines
chromatography (EtOAc/hexanes 1/9 to 1/6) gave 230 mg (91%)
138.3, 131.0, 130.4, 127.9, 126.9, 122.1, 120.8 (q, JC-F ) 257.1
Hz), 120.0, 20.5 (signal for one carbon could not be detected); FT-
IR (neat, cm-1) ν 3370, 1603, 1250, 1216, 1152. Anal. Calcd for
C21H15F6NO2: C, 59.02; H, 3.54; N, 3.28. Found: C, 59.29; H,
3.56; N, 3.38.
General Procedure for in situ Cyclization of Arylated
Anilides: First, a standard procedure for ortho-arylation of anilides
was performed without isolation of product. The reaction mixture
was cooled to room temperature, and trifluoroacetic anhydride
(TFAA, 2.0-3.0 equiv) was added. The vial was placed in an oil
bath (110 °C) for 0.5-3 h. The conversion was monitored by GC.
After completion of reaction, ether was added to reaction mixture
and the reaction mixture was filtered through a pad of Celite. Filtrate
was washed twice with aqueous NaHCO3. Organic layer was dried
over MgSO4. Solvent was removed by evaporation in vacuum, and
residue was purified by flash chromatography.
3-Bromo-6-methoxymethyl-7,9-dimethylphenanthridine: 3-Bro-
mo-N-(2-methoxyacetyl)aniline (171 mg, 0.7 mmol), Pd(OAc)2 (7.8
mg, 0.035 mmol), AgOAc (152 mg, 0.91 mmol), and 3,5-
dimethyliodobenzene (487 mg, 2.1 mmol) were dissolved in TFA
(0.5 mL). Resulting solution was heated for 2.5 h at 120 °C. After
cooling to room temperature, trifluoroacetic anhydride (200 µL,
1.4 mmol) was added and reaction mixture was heated for 1.5 h at
110 °C. Filtration of the reaction mixture, basic extraction, and
purification by flash chromatography (EtOAc/hexanes 1/10 to 1/5)
gave 172 mg (74%) of crystalline material: mp 141-142 °C (EtOH/
water); Rf ) 0.45 (EtOAc/hexanes 1/4); 1H NMR (300 MHz, CDCl3,
ppm) δ 8.39 (d, 1H, J ) 8.9 Hz), 8.30 (d, 1H, J ) 2.0 Hz), 8.28
(s, 1H), 7.70 (dd, 1H, J ) 8.9, 2.0 Hz), 7.38 (s, 1H), 5.11 (s, 2H),
3.48 (s, 3H), 3.01 (s, 3H), 2.58 (s, 3H); 13C NMR (75 MHz, CDCl3,
ppm) δ 158.0, 143.8, 140.7, 137.2, 134.9, 134.0, 132.3, 130.2,
124.0, 123.6, 123.4, 122.2, 120.4, 78.4, 58.6, 23.8, 22.0; FT-IR
(neat, cm-1) ν 1619, 1596, 1568, 1097. Anal. Calcd for C17H16-
BrNO: C, 61.83; H, 4.88; N, 4.24. Found: C, 61.27; H, 4.81; N,
4.16.
of crystalline material: mp 152-153 °C (EtOAc/hexanes), Rf )
1
0.45 (EtOAc/hexanes 1/4); H NMR (300 MHz, CDCl3, ppm) δ
8.61 (s, 1H), 7.54-7.48 (m, 2H), 7.31-7.25 (m, 3H), 7.22 (br s,
1H), 7.09 (d, 1H, J ) 8.0 Hz), 2.25 (q, 2H, J ) 7.5 Hz), 1.37 (s,
9H), 1.12 (t, 3H, J ) 7.5 Hz); 13C NMR (75 MHz, CDCl3, ppm)
δ 172.0, 151.7, 136.2, 134.2, 131.4, 130.5, 129.0, 127.2, 126.4,
124.0, 122.1, 35.0, 31.5, 31.0, 9.5; FT-IR (neat, cm-1) ν 3250, 1655.
Anal. Calcd for C19H22BrNO: C, 63.34; H, 6.15; N, 3.89. Found:
C, 63.58; H, 6.20; N, 3.81.
4-Methyl-2,6-di-(3-trifluoromethoxyphenyl)-N-propionyl-
aniline: 4-Methyl-N-propionylaniline (114 mg, 0.70 mmol), Pd-
(OAc)2 (7.8 mg, 0.035 mmol), AgO2CCF3 (356 mg, 1.61 mmol),
and 3-trifluoromethoxyiodobenzene (806 mg, 2.8 mmol) were
dissolved in TFA (0.5 mL). Resulting solution was heated for 5.5
h at 120 °C. Purification by flash chromatography (EtOAc/hexanes
1/6) gave 266 mg (79%) of crystalline material: mp 156-157 °C
1
(EtOAc/hexanes), Rf ) 0.26 (EtOAc/hexanes 1/4); H NMR (300
MHz, CDCl3, ppm) δ 7.43 (dd, 2H, J ) 7.7, 7.7 Hz), 7.36-7.30
(m, 2H), 7.25-7.18 (m, 6H), 6.48 (s, 1H), 2.43 (s, 3H), 1.93 (q,
2H, J ) 7.6 Hz), 0.83 (t, 3H, J ) 7.6 Hz); 13C NMR (75 MHz,
CDCl3, ppm) δ 173.3, 149.1, 141.8, 139.7, 138.1, 131.1, 128.9,
128.8, 127.6, 121.6, 120.7 (q, JC-F ) 257.4 Hz), 120.0, 29.6, 21.2,
9.5; FT-IR (neat, cm-1) ν 3220, 1652. Anal. Calcd for C24H19F6-
NO3: C, 59.63; H, 3.96; N, 2.90. Found: C, 59.39; H, 3.95; N,
2.92.
4-Methyl-N-propionyl-2-(3-trifluoromethoxyphenyl)aniline:
4-Methyl-N-propionylaniline (114 mg, 0.70 mmol), Pd(OAc)2 (7.8
mg, 0.035 mmol), AgOAc (152 mg, 0.91 mmol), and 3-trifluo-
romethoxyiodobenzene (605 mg, 2.8 mmol) were dissolved in a
1:1 mixture of TFA and AcOH (0.5 mL). Resulting solution was
heated for 6 h at 120 °C. Purification by flash chromatography
(EtOAc/hexanes 1/6 to 1/2) gave 120 mg (53%) of crystalline
material: mp 98.5-99.4 °C (EtOAc/hexanes); Rf ) 0.15 (EtOAc/
1
hexanes 1/4); H NMR (300 MHz, CDCl3, ppm) δ 8.07 (d, 1H, J
) 8.2 Hz), 7.54-7.47 (m, 1H), 7.34-7.18 (m, 4H), 7.06 (s, 1H),
6.94 (br s, 1H), 2.36 (s, 3H), 2.24 (q, 2H, J ) 7.6 Hz), 1.12 (t, 3H,
J ) 7.6 Hz); 13C NMR (75 MHz, CDCl3, ppm) δ 172.2, 149.6,
140.7, 134.7, 132.1, 131.8, 130.7, 130.5, 129.7, 127.9, 123.2, 121.9,
120.6 (q, JC-F ) 257.3 Hz), 120.4, 30.6, 21.0, 9.6; FT-IR (neat,
cm-1) ν 3229, 1654. Anal. Calcd for C17H16F3NO2: C, 63.15; H,
4.99; N, 4.33. Found: C, 63.08; H, 4.98; N, 4.28.
3-Chloro-8-methyl-6-(5-phthalimidopentyl)phenanthridine:
3-Chloro-N-(ω-phthalimidocaproyl)aniline (259 mg, 0.7 mmol), Pd-
(OAc)2 (7.8 mg, 0.035 mmol), AgOAc (175 mg, 1.05 mmol), and
4-methyliodobenzene (458 mg, 2.1 mmol) were dissolved in TFA
(0.5 mL). The solution was heated for 3 h at 120 °C. After cooling
to room temperature, trifluoroacetic anhydride (300 µL, 2.1 mmol)
was added and reaction mixture was heated for 40 min at 110 °C.
Filtration, basic extraction, and purification by flash chromatography
(EtOAc/hexanes 1/4 to 1/1) gave 250 mg (80%) of crystalline
material: mp 164-165 °C (EtOH/EtOAc); Rf ) 0.23 (EtOAc/
5-Bromo-2-(4-tert-butylphenyl)aniline: 5-Bromo-2-(4-tert-bu-
tylphenyl)-N-propionylaniline (80 mg, 0.22 mmol) and sodium
hydroxide (44 mg, 1.11 mmol) were dissolved in EtOH (0.5 mL)
and heated for 2 h at 90 °C in a closed vessel. After heating was
finished, water was added to reaction mixture and the resulting
solution was extracted with ether three times. Organic layer was
dried over MgSO4. Evaporation of solvent gave 67 mg (>99%) of
crystalline material: mp 166-167 °C (EtOAc/hexanes); Rf ) 0.62
(EtOAc/hexanes 1/4); 1H NMR (300 MHz, CDCl3, ppm) δ 7.48-
7.42 (m, 2H), 7.36-7.31 (m, 2H), 6.96 (d, 1H, J ) 7.7 Hz), 6.93-
6.87 (m, 2H), 3.80 (br s, 2H), 1.35 (s, 9H); 13C NMR (75 MHz,
CDCl3, ppm) δ 150.7, 145.3, 135.7, 131.9, 128.8, 126.7, 126.1,
122.0, 121.6, 118.2, 34.8, 31.6; FT-IR (neat, cm-1) ν 3382, 1615,
1484. Anal. Calcd for C16H18BrN: C, 63.17; H, 5.96; N, 4.60.
Found: C, 63.32; H, 6.03; N, 4.50.
4-Methyl-2,6-di-(3-trifluoromethoxyphenyl)aniline: 4-Methyl-
N-propionyl-2-(3-trifluoromethoxyphenyl)aniline (80 mg, 0.16 mmol)
and sodium hydroxide (46 mg, 1.16 mmol) were dissolved in EtOH
(0.3 mL) and heated for 37 h at 130 °C in a closed vessel. After
heating was finished, water was added to reaction mixture and the
resulting solution was extracted with ether three times. Organic
layer was dried over MgSO4. Evaporation of solvent and purification
by flash chromatography (EtOAc/hexanes 1/8) gave 60 mg (85%)
of crystalline material: mp 60-61 °C (hexanes); Rf ) 0.64 (EtOAc/
hexanes 1/4); 1H NMR (300 MHz, CDCl3, ppm) δ 7.51-7.41 (m,
4H), 7.38 (br s, 2H), 7.24-7.18 (m, 2H), 6.96 (s, 2H), 3.66 (br s,
2H), 2.31 (s, 3H); 13C NMR (75 MHz, CDCl3, ppm) δ 149.9, 141.9,
1
hexanes 1/4); H NMR (300 MHz, CDCl3, ppm) δ 8.45 (d, 1H, J
) 8.5 Hz), 8.40 (d, 1H, J ) 8.8 Hz), 8.06 (d, 1H, J ) 2.2 Hz),
8.01 (s, 1H), 7.87-7.80 (m, 2H), 7.74-7.68 (m, 2H), 7.66 (dd,
1H, J ) 8.5, 1.6 Hz), 7.53 (dd, 1H, J ) 8.8, 2.2 Hz), 3.73 (t, 2H,
J ) 7.2 Hz), 3.36-3.28 (m, 2H), 2.62 (s, 3H), 2.04-1.91 (m, 2H),
1.86-1.74 (m, 2H), 1.65-1.52 (m, 2H); 13C NMR (75 MHz,
CDCl3, ppm) δ 168.6, 163.0, 144.3, 137.7, 134.0, 133.7, 132.5,
132.3, 130.4, 128.9, 126.8, 126.0, 125.4, 123.3, 123.2, 122.43,
122.37, 38.1, 36.1, 28.7, 27.2, 22.1 (one aliphatic carbon signal
could not be detected); FT-IR (neat, cm-1) ν 1774, 1718, 1396,
1371. Anal. Calcd for C27H23ClN2O2: C, 73.21; H, 5.23; N, 6.32.
Found: C, 72.95; H, 5.24; N, 6.17.
Acknowledgment. We thank the Welch Foundation (Grant
No. E-1571) for supporting this research. We thank Dr. James
Korp for collecting and solving the X-ray structures.
Supporting Information Available: Detailed experimental
procedures and characterization data for new compounds. This
material is available free of charge via the Internet at http://
pubs.acs.org.
JO701387M
J. Org. Chem, Vol. 72, No. 20, 2007 7725