Metalation of o- and p-Anisidine
J . Org. Chem., Vol. 61, No. 16, 1996 5433
Calcd for C13H17NO4 (251.28): C, 62.14; H, 6.82. Found: C,
62.33; H, 7.08.
a column filled with more silica (500 mL) using a 1:4 (v/v)
mixture of ethyl acetate and hexane. White platelets were
obtained: mp 200-203 °C dec (from dichloromethane/hexane
1:3); yield 44%; 1H-NMR (CDCl3, 400 MHz) δ 7.52 (2 H, s,
broad), 6.88 (2 H, d, J ) 2.4), 6.82 (2 H, d, J ) 8.8), 6.33 (2 H,
s, broad), 6.28 (1 H, d, J ) 4.0), 3.79 (6 H, s), 3.43 (1 H, d, J
) 4.4), 1.48 (18 H, s); MS m/z 174 (49, M+), 457 (80), 274 (100).
Anal. Calcd for C25H34N2O7 (474.55): C, 63.28; H, 7.22.
Found: C, 63.21, H, 7.13.
4-[2-[(ter t-Bu toxyca r bon yl)a m in o]-3-m eth oxyp h en yl]-
1,4-d ih yd r o-8-m eth oxy-2H-3,1-ben zoxa zin -2-on e (3). As
described for the preparation of benzoate 2, tert-butyl (2-
methoxyphenyl)carbamate15 (5.6 g, 25 mmol) was treated with
tert-butyllithium. At -50 °C, methyl formate (0.74 mL, 0.72
g, 12 mmol) was added dropwise, in the course of 10 min. After
6 h at -50 °C, the mixture was poured into water (0.10 L).
Extraction with diethyl ether (2 × 75 mL) and dichloro-
methane (50 mL), evaporation, and chromatography on a silica
gel support using a 2:3 (v/v) mixture of ethyl acetate and
hexane as the eluent afforded pale yellow platelets; mp 175-
177 °C dec (from dichloromethane/hexane 1:3); yield 40%; 1H-
NMR δ 7.42 (1 H, s), 7.16 (1 H, t, J ) 8.1), 6.96 (1 H, t, J )
8.0), 6.92 (1 H, dd, J ) 8.1, 1.2), 6.84 (1 H, d, J ) 8.0), 6.72 (1
H, s), 6.71 (1 H, d, broad), 6.64 (1 H, d, broad), 6.17 (1 H, s,
broad), 3.90 (3 H, s), 3.86 (3 H, s), 1.45 (9 H, s); MS m/z 401
(3, M+), 3.45 (100), 301 (59), 240 (43). Anal. Calcd for
C21H24N2O6 (400.43): C, 62.99; H, 6.04. Found: C, 63.11; H,
6.19. When methyl formate had been replaced by tert-butyl
(2-formyl-6-methoxyphenyl)carbamate, the heterocyclic prod-
uct 3 was isolated in 50% yield.
Meth yl 2-[(ter t-bu toxyca r bon yl)a m in o]-5-m eth oxyben -
zoa te (6). The tert-butyllithium-promoted metalation of tert-
butyl (4-methoxyphenyl)carbamate, the trapping with carbon
dioxides and the workup were carried out as described for the
preparation of the isomer 2 (see section 1). After treatment
with diazomethane a pale yellow solid was isolated. According
to gas chromatography (30 m, DB-1701, 220 °C), the crude
product was composed of the regioisomers 5 and 6 in the ratio
of 12:88, 86% yield. Pure ester 6 was obtained after recrys-
tallization (from dichloromethane/hexane 1:3) in form of white
needles: mp 54-56 °C; yield 55%; 1H-NMR δ 9.98 (1 H, s,
broad), 8.35 (1 H, d, J ) 9.3), 7.48 (1 H, d, J ) 3.1), 7.10 (1 H,
dd, J ) 9.3, 3.1), 3.92 (3 H, s), 3.80 (3 H, s), 1.52 (9 H, s); MS
m/z 281 (24, M+), 225 (38, 181 (100). Anal. Calcd for C14H19
-
NO5 (281.31): C, 59.78; H, 6.81. Found: C, 59.71; H, 6.99.
Bis-4,4-[2-[(ter t-b u t oxyca r b on yl)a m in o]-3-m et h oxy-
p h e n yl]-1,4-d ih yd r o-8-m e t h oxy-2H -3,1-b e n zoxa zin -2-
on e (4). An analogous reaction, employing ethyl chloroformate
(0.78 mL, 8.1 mmol), gave pale yellow platelets: mp 196-200
°C dec (from dichloromethane/hexane 1:3); yield 29%; 1H-NMR
(CDCl3; 25 °C) δ 7.40 (1 H, s), 7.18 (1 H, s, broad), 7.06 (1 H,
t, J ) 8.1), 6.95 (1 H, t, J ) 8.0), 6.9 (2 H, m), 6.87 (1 H, d, J
) 8.1), 6.72 (1 H, s, broad), 6.39 (1 H, s, broad), 6.22 (1 H, s,
broad), 3.89 (3 H, s), 3.84 (3 H, s), 3.80 (3 H, s), 1.24 (9 H, s),
1.18 (9 H, s); 1H-NMR (D3CSOCD3; 25 °C) δ 7.21 (1 H, s,
broad), 7.1 (4 H, m), 6.90 (1 H, t, J ) 8.0), 6.76 (1 H, s, broad),
6.45 (1 H, s, broad), 6.07 (1 H, s, broad), 3.82 (3 H, s), 3.75 (3
H, s), 3.72 (3 H, s), 1.20 (9 H, s), 1.13 (9 H, s); 1H-NMR
(D3CSOCD3; 100 °C) δ 7.1 (5 H, m), 6.92 (1 H, t, J ) 7.9), 6.47
(1 H, d, J ) 7.8), 6.38 (2 H, s, broad), 3.87 (3 H, s), 3.78 (6 H,
s), 1.23 (18 H, s) MS m/z 622 (22, M+), 580 (8), 522 (12), 461
(41), 405 (21), 79 (100). Anal. Calcd for C33H39N3O9 (621.69):
C, 63.76; H, 6.32. Found: C, 63.96; H, 6.34. Coalescence of
the signals at 3.75 and 3.72 (both 3 H) occurred at 326.0 K,
that of the signals at 1.20 and 1.13 (both 9 H), at 337.5 K.
Applying the standard equations,16 gave an activation barrier
of 17.1 (( 0.1) kcal/mol.
(2) Rea ction s In volvin g N-BOC-P r otected p-An isid in e.
Meth yl 5-[(ter t-Bu toxyca r bon yl)a m in o]-2-m eth oxyben -
zoa te (5). The metalation of tert-butyl (4-methoxyphenyl)-
carbamate17 (5.6 g, 25 mmol) was accomplished with butyl-
lithium in the presence of potassium tert-butoxide, the
intermediate was intercepted with carbon dioxide, and the
mixture was worked up as described for the preparation of
isomer 1 (see section 1). After treatment of the residue with
diazomethane, colorless needles were obtained: mp 111.0-
112.5 °C (from dichloromethane/hexane 1:3); yield 68%. Ac-
cording to gas chromatography (30 m, DB-1701, 220 °C), 5 was
contaminated by its regioisomer 6 in the ratio 94:6: 1H-NMR
δ 7.74 (1 H, d, J ) 2.7), 7.56 (1 H, d, broad), 6.92 (1 H, d, J )
9.0), 6.46 (1 H, s, broad), 3.88 (6 H, s), 1.51 (9 H, s); MS m/z
281 (13, M+), 225 (100), 181 (27). Anal. Calcd for C14H19NO5
(281.31): C, 59.78, H, 6.81. Found: C, 59.79, H, 6.79.
Di-(ter t-bu tyl) 3,3′-Hyd r oxym eth ylen ebis[(4-m eth oxy-
p h en yl)ca r ba m a te] (7). In an analogous reaction as the one
described in the preceding paragraph, carbon dioxide was
replaced by methyl formate (0.74 mL, 0.72 g, 12 mmol). After
neutralization, the product was extracted with diethyl ether
(3 × 50 mL), absorbed on silica gel (25 mL), and eluted from
Di-(ter t-bu tyl 2,3′-Hyd r oxym eth ylen ebis[(4-m eth oxy-
p h en yl)ca r ba m a te] (8) a n d Di(ter t-bu tyl 2,2′-Hyd r oxy-
m eth ylen ebis[(4-m eth oxyph en yl)car bam ate] (9). The car-
bon dioxide was replaced by methyl formate in a reaction
analogously conducted as the one described in the preceding
paragraph. The crude product contained 8 and 9 as the minor
and main component, respectively. The separation was
achieved by chromatography using silica gel (500 mL) as the
support and a 1:4 (v/v) mixture of ethyl acetate and hexane
as the eluent. Biscarbamate 8: white platelets; mp 66-70
°C dec; yield 10%; 1H-NMR δ 7.6 (3 H, m), 6.88 (1 H, s, broad),
6.87 (1 H, d, J ) 8.9), 6.83 (1 H, dd, J ) 8.9, 3.0), 6.73 (1 H, d,
J ) 2.8), 6.35 (1 H, s, broad), 6.06 (1 H, d, J ) 3.6), 3.85 (3 H,
s), 3.74 (3 H, s), 3.44 (1 H, s, broad), 1.48 (9 H, s), 1.46 (9 H,
s); MS m/z 474 (36, M+), 374 (42), 317 (44), 269 (100). Anal.
Calcd for C25H34N2O7 (474.55): C, 63.28; H, 7.22. Found: C,
63.12; H, 7.29. Biscarbamate 9: white platelets; mp 143-145
°C dec; yield 50%; 1H-NMR δ 7.52 (2 H, s, broad), 7.05 (2 H, s,
broad), 6.81 (2 H, dd, J ) 8.8, 3.0), 6.69 (2 H, s, broad), 5.85 (1
H, d, J ) 2.9), 4.10 (1 H, d, broad), 3.70 (6 H, s), 1.45 (18 H,
s); MS 474 (19, M+), 279 (31), 240 (100). Anal. Calcd for
C25H34N2O7 (474.55): C, 63.28; H, 7.22. Found: C, 63.16; H,
7.24.
(3) Rea ction s In volvin g N-Ca r ba m oyl-P r otected p-
An isid in e. N′-(4-Meth oxyp h en yl)-N,N-d im eth ylu r ea . A
solution of p-anisidine (25 g, 0.20 mol), N,N-dimethylcarbamoyl
chloride (18 mL, 21 g, 0.20 mol), and pyridine (16 mL, 16 g,
0.20 mol) in dichloromethane (0.15 L) was heated to reflux
for 20 h, before being washed with 1 M hydrochloric acid (2 ×
0.10 L) and water (2 × 0.10 L), dried, and evaporated. The
colorless residue was crystallized from a 1:1 (v/v) mixture of
dichloromethane and hexane: mp 128.5-130.5 °C (from
dichloromethane/hexane 1:3); white needles; yield 80%; 1H-
NMR δ 7.25 (2 H, d, J ) 9.0), 6.81 (2 H, d, J ) 9.0), 6.38 (1 H,
s, broad), 3.76 (3 H, s), 2.97 (6 H, s); MS m/z 194 (23, M+), 149
(32), 72 (100). Anal. Calcd for C10H14N2O2 (194.23): C, 61.84;
H 7.27. Found: C, 61.84; H, 7.15.
N,N-Dieth yl-N′-(4-m eth oxyp h en yl)u r ea was obtained
analogously by employing N,N-diethylcarbamoyl chloride (25
mL, 27 g, 0.20 mol): mp 60.5-62.0 °C (from dichloromethane/
hexane 1:3); white needles; yield 55%; 1H-NMR δ 7.28 (2 H, d,
J ) 8.9), 6.83 (2 H, d, J ) 9.0), 6.18 (1 H, s, broad), 3.78 (3 H,
s), 3.36 (4 H, q, J ) 7.1), 1.21 (6 H, t, J ) 7.1); MS m/z 223
(23, M+ + 1); 149 (2); 100 (100). Anal. Calcd for C12H18N2O2
(222.29): C 64.84; H, 8.16. Found: C, 64.81; H, 8.08.
Meth yl 2-[[(Dim eth yla m in o)ca r bon yl]a m in o]-5-m eth -
oxyben zoa te [2-(N′,N′-Dim eth ylu r eid o)-5-m eth oxyben -
zoic Acid Meth yl Ester (10)], N-[[(2-Ca r boxy-4-m eth oxy-
ph en yl)am in o]car bon yl]-N-(m eth ylam in o)acetic Acid (11),
a n d 3-(4-Meth oxyp h en yl)-1-m eth ylim id a zolid in e-2,4-d i-
on e (12). At -75 °C, tert-butyllithium (50 mmol) in pentane
(33 mL) was added to a solution of N′-(4-methoxyphenyl)-N,N-
(16) J uaristi, E. Introduction to Stereochemistry and Conformational
Analysis; Wiley, New York, 1991; pp 253-254. Gu¨nther, H. NMR-
Spektroskopie; Thieme: Stuttgart, 1983; pp 226-231. Gu¨nther, H.;
NMR Spectroscopy; Wiley: Chichester, 1973; pp 240-244.
(17) Reed, J . N.; Rotchford, J .; Strickland, D. Tetrahedron Lett. 1988,
29, 5725-5728. Cho, I.-s.; Gong, L.; Muchowski, J . M. J . Org. Chem.
1991, 56, 7288-7291.
(18) Cˇ egan, A.; Vecˇera, M. Collect Czech. Chem. Commun. 1984, 49,
1521-1528.