Jul-Aug 2006
Dibenzo-fused Seven-membered Nitrogen Heterocycles
1033
General Procedure for Hydrogenation:
Aminophenoxy)benzoate (8).
Methyl 2-(2-
The synthesis differs from an earlier route by initially
forming the ether, amine or methylene linkage between
two functionalized aromatic rings followed by closure of
the lactam in a second step. This avoids the necessity of
exposing the lactam bond to harsh basic conditions and
results in higher overall yields with fewer side products.
The products are isolated directly following workup and
do not require extensive purification.
To a solution of 0.50 g (1.83 mmoles) of 2 in 150 mL of
methanol was added 125 mg of 5% palladium-on-carbon and the
mixture was shaken in a stainless steel reaction vessel under 3
atmospheres of hydrogen for 3 hours at 30°. [Caution: Though
we never experienced any problems, addition of 5% palladium-
on-carbon to methanol can cause fires. This operation should be
performed under a nitrogen atmosphere.] The crude product
was concentrated, diluted with ether and filtered through a plug
of Celite topped with a layer of anhydrous magnesium sulfate to
remove the catalyst. Following removal of the ether, the crude
amino ester was triturated with 2% ether in hexanes to give 0.39
g (86%) of 8 as a light yellow solid, mp 56-57°. This material
was spectroscopically pure and was used without further
purification. The spectral data were: ir: 3454, 3365, 1718 cm-1;
1H nmr: ꢀ 7.84 (dd, 1H, J = 7.6, 1.9), 7.38 (ddd, 1 H, J = 8.5, 7.4,
1.9), 7.06 (td, 1H, J = 7.6, 1.1), 6.98 (ddd, 1H, J = 7.9, 7.4, 1.6),
6.90 (dd, 1H, J = 8.5, 1.1), 6.88 (dd, 1H, J = 7.9, 1.6), 6.80 (dd,
1H, J = 7.9, 1.6), 6.70 (ddd, 1H, J = 7.9, 7.4, 1.6), 4.04 (br s,
2H), 3.88 (s, 3H); 13C nmr: ꢀ 166.6, 156.8, 142.8, 138.9, 133.4,
131.5, 125.2, 122.4, 121.5, 120.4, 118.3, 117.4, 116.5, 52.1; ms:
m/z 243 (M+).
EXPERIMENTAL
All reactions were run under dry nitrogen in oven-dried
glassware. Reactions were monitored by thin layer
chromatography on silica gel GF plates (Analtech no. 21521)
with ultraviolet detection. Melting points were uncorrected.
Infrared spectra were run as thin films on sodium chloride disks
1
and referenced to polystyrene. Unless otherwise noted, H and
13C nuclear magnetic resonance spectra were measured in
deuteriochloroform at 300 MHz and 75 MHz, respectively,
using tetramethylsilane as an internal standard; coupling
constants (J) are given in Hertz. Mass spectra (electron
impact/direct probe) were obtained at 70 electron volts.
Anal. Calcd. for C14H13NO3: C, 69.14; H, 5.35; N, 5.76.
Found: C, 69.36; H, 5.38; N, 5.62.
Methyl 2-(2-Nitrophenoxy)benzoate (2).
This compound was prepared from methyl salicylate and 2-
fluoro-1-nitrobenzene on a 10-mmole scale according to the
general method reported by Bunce and Easton [10]. The yield
was 2.45 g (90%) as a white solid, mp 48-49° (ether-hexanes);
lit mp 49-50° (no solvent given) [16]. ir: 1727, 1528, 1351 cm-1;
1H nmr: ꢀ 8.00 (dd, 1H, J = 7.9, 1.6), 7.96 (dd, 1H, J = 8.2, 1.6),
7.57 (td, 1H, J = 7.9, 1.9), 7.45 (ddd, 1H, J = 8.5, 7.6, 1.6), 7.31
(tt, 1H, J = 7.9, 0.5), 7.15 (tm, 1H, J = 7.6), 7.12 (dd, 1H, J =
8.2, 0.5), 6.80 (dd, 1H, J = 8.5, 1.1), 3.75 (s, 3H); 13C nmr: ꢀ
165.2, 154.1, 151.5, 148.7, 134.1 (2), 132.5, 125.7, 125.3, 123.4,
122.5, 122.1, 118.4, 52.3; ms: m/z 273 (M+).
Methyl 2-[(2-Aminophenyl)amino]benzoate (9).
This compound (0.41 g, 92%) was isolated as a light tan solid,
mp 102-103°, lit mp 102-103° (ethanol-water) [17]; ir: 3454,
1
3324, 1682 cm-1; H nmr: ꢀ 8.95 (br s, 1H), 7.94 (dd, 1H, J =
7.6, 1.4), 7.26 (ddd, 1H, J = 8.7, 7.6, 1.6), 7.12 (dd, 1H, J = 7.6,
1.4), 7.08 (td, 1H, J = 7.4, 1.6), 6.84-6.60 (complex, 4H), 3.90
(s, 3H), 3.81 (br s, 2H); 13C nmr: ꢀ 169.0, 149.5, 143.3, 134.4,
131.4, 127.7, 127.1, 125.9, 118.8, 116.4, 115.9, 113.7, 110.9,
51.7; ms: m/z 242 (M+).
Anal. Calcd. for C14H14N2O2: C, 69.42; H, 5.79; N, 11.57.
Found: C, 69.32; H, 5.83; N, 11.34.
Anal. Calcd. for C14H11NO5: C, 61.54; H, 4.03; N, 5.13.
Found: C, 61.72; H, 4.09; N, 5.01.
2-[(2-Aminophenyl)methyl]benzoic Acid (10).
Methyl 2-[(2-Nitrophenyl)amino]benzoate (4).
This compound (0.40 g, 91%) was isolated as a white solid,
mp 124-125°, lit mp 126-127° (80% aqueous ethanol) [18]; ir:
3638-1741, 1701 cm-1; 1H nmr (DMSO-d6): ꢀ 9.1-6.0 (br s, 3H),
7.81 (dd, 1H, J = 7.9, 1.6), 7.43 (td, 1H, J = 7.6, 1.6), 7.30 (td,
1H, J = 7.6, 1.1), 7.12 (d, 1H, J = 7.4), 6.90 (td, 1H, J = 7.9, 1.6),
6.63 (m, 2H), 6.44 (td, 1H, J = 7.4, 1.1), 4.12 (s, 2H); 13C nmr
(DMSO-d6): ꢀ 169.3, 146.2, 140.7, 131.5, 131.3, 130.6, 130.0,
129.5, 126.7, 126.0, 124.0, 116.0, 114.4, 40.3; ms: m/z 227 (M+).
Anal. Calcd. for C14H13NO2: C, 74.01; H, 5.73; N, 6.17.
Found: C, 73.79; H, 5.67; N, 6.11.
This compound was prepared on a 25-mmole scale according
to the method of Black and Rothnie [11]. The yield was 6.15 g
(90%) as bright orange crystals, mp 159-160° (aqueous acetone);
lit mp 152-153° (aqueous acetone) [11]. ir: 3298, 1696, 1500,
1344 cm-1; 1H nmr: ꢀ 11.1 (br s, 1H), 8.16 (dd, 1H, J = 8.5, 1.1),
8.03 (ddd, 1H, J = 7.9, 1.6, 0.5), 7.60 (dd, 1H, J = 8.5, 1.4), 7.52
(dd, 1H, J = 8.5, 1.4), 7.44, (tm, 2H, J = 7.9), 7.05 (ddd, 1H, J =
8.5, 7.1, 1.4), 6.94 (ddd, 1H, J = 8.5, 7.1, 1.4), 3.96 (s, 3H); 13C
nmr: ꢀ 167.4, 147.7, 142.2, 139.0, 134.6, 133.3, 132.0, 126.6,
121.8, 119.9, 119.0, 118.6, 118.5, 52.3; ms: m/z 272 (M+).
Anal. Calcd. for C14H12N2O4: C, 61.76; H, 4.41; N, 10.29.
Found: C, 61.92; H, 4.49; N, 10.12.
General Procedure for Lactam Closure in High-Boiling
Solvents.
p-Xylene: Solutions of 0.50 mmoles of 8, 9 and 10 in 5 mL
of p-xylene were heated under reflux for 24 hours. The mixtures
were cooled, the solvent was removed under high vacuum, and
the residues were triturated with ether-hexanes. This yielded 11,
12 and 13 in 72%, 45% and 69%, respectively, as dark brown
solids.
2-[(2-Nitrophenyl)methyl]benzoic Acid (7).
This compound was prepared via compound 6 on a 10-mmole
scale according to the method of Bunce and Schammerhorn
[12]. The resulting solid was triturated with cold ether and
filtered to give 1.18 g (47%, three steps) of 7 as a light yellow
solid. The physical and spectral properties matched those
reported previously [12].
Acetic Acid: Solutions of 0.50 mmoles of 8, 9 and 10 in 5
mL of glacial acetic acid were heated at reflux for 30-60