Notes
J . Org. Chem., Vol. 63, No. 22, 1998 8047
cooling bath under N2, and n-butyllithium (8.70 mL, 1.5 M in
pentane, 13 mmol) was added over 5 min; the mixture was
allowed to stir for 2 h, after which time a solution of 3.30 g of I2
(13.0 mmol) in 20.0 mL of anhydrous THF was added dropwise
until the iodine color persisted (approximately 12.0 mL of the
iodine solution, 7.8 mmol of iodine, was added over 1 min). The
cooling bath was then removed, and the reaction was allowed
to warm on its own to room temperature (over ca. 1 h). THF
was removed on the rotary evaporator, and the residual solid
was redissolved in 100 mL of CH2Cl2 and washed with two 50
mL portions of a saturated aqueous solution of Na2S2O3; the
organic layer was then dried over anhydrous MgSO4. Subse-
quent removal of solvent in vacuo and purification by flash
column chromatography (silica gel, 50 mm × 250 mm, 1:1 CH2-
Cl2/Et2O) afforded 1.75 g (78%) of 10 (Rf ) 0.63 for the desired
product and Rf ) 0.56 for the starting material, silica TLC, 1:1
CH2Cl2/Et2O) as a white solid: mp 94-95 °C; IR (CH2Cl2) ν 3276,
3068, 2961, 1646, 1545 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.12
(d, J ) 8.4 Hz, 1H), 6.84 (d, J ) 8.4 Hz, 1H), 5.82 (br s, 1H),
5.15 (s, 2H), 3.84 (s, 3H), 3.67 (s, 3H), 3.39 (apparent q, J ) 7.2
Hz, 2H), 1.64 (apparent sextet, J ) 7.2 Hz, 2H), 0.99 (t, J ) 7.2
Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 169.1, 152.6, 145.6, 136.1,
123.9, 112.0, 98.6, 92.1, 58.3, 55.9, 41.6, 22.5, 11.4. Anal. Calcd
for C13H18INO4: C, 41.18; H, 4.78; N, 3.69. Found: C, 40.93;
H, 5.01; N, 3.58.
2,2′-Bis[4-m et h oxy-3-(m et h oxym et h oxy)-N-p r op ylb en -
zen eca r boxa m id e] (11). Cop p er Br on ze Activa tion . Com-
mercial copper bronze (Aldrich Catalog No. 29,258-3) was
activated following Kleiderer and Adams’s procedure.13 For a
typical case, 2.50 g of copper bronze was treated with 25 mL of
a 2% (w/v) solution of iodine in acetone at room temperature for
10 min. The gray-colored copper was then collected by vacuum
filtration (open to the air) and subsequently stirred in 12.5 mL
of a 1:1 acetone/HCl (12.0 N) mixture at room temperature for
10 min. It was filtered again and washed thoroughly with
acetone. At this time, the copper bronze had a shiny brown color.
It was dried in a vacuum desiccator (vacuum: ∼2 Torr) with
P2O5 for 30 min and used immediately afterward.
complished in nine steps (9.6% overall yield) from com-
mercially available 7 and provides an efficient route to 1
and, potentially, its analogues.
Exp er im en ta l Section 24
3-Hydr oxy-4-m eth oxy-N-pr opylben zen ecar boxam ide (8).
Acid 7 (5.00 g, 29.7 mmol) was dissolved under N2 in 200 mL of
a 4:1 (v/v) mixture of anhydrous THF and HPLC-grade aceto-
nitrile in a 500 mL round-bottomed flask. The solution was
cooled to 0 °C (ice bath), followed by additions of dicyclohexyl-
carbodiimide (DCC; CAUTION: potential allergen) (6.20 g, 30.0
mmol) and N-hydroxysuccimide (3.50 g, 30.4 mmol) in single
portions. The reaction mixture was allowed to warm to room
temperature and stirred for 12 h. Formation of a white solid
was observed as the temperature rose. Propylamine (3.30 mL,
40.1 mmol) was then added to the reaction mixture in one
portion, and the reaction was heated at reflux for 2 h. After
the reaction mixture was cooled to room temperature, the white
solid (dicyclohexylurea) was removed from the crude mixture
by vacuum filtration and the filtrate was subsequently washed
with 2 × 50 mL of distilled water and then with 2 × 50 mL of
saturated brine. The organic layer was then further dried over
anhydrous MgSO4 and filtered through a fritted funnel. Solvent
removal in vacuo afforded a colorless solid [TLC (silica): Rf )
0.6, EtOAc], which was purified by silica gel flash column
chromatography (75 mm × 300 mm, EtOAc) to afford 5.77 g (27.7
mmol, 93%) of the desired amide 8 as a colorless solid: mp 110-
112 °C; IR (CH2Cl2) ν 3313, 2974, 2936, 2879, 1630, 1580 cm-1
;
1H NMR (400 MHz, CDCl3) δ 7.34 (dd, J ) 8.4, 2.0 Hz, 1H),
7.33 (d, J ) 2.0 Hz, 1H), 6.87 (d, J ) 8.4 Hz, 1H), 6.03 (br s,
1H), 5.81 (s, 1H), 3.93 (s, 3H), 3.39 (apparent q, J ) 6.8 Hz,
2H), 1.62 (apparent sextet, J ) 7.2 Hz, 2H), 0.97 (t, J ) 7.2 Hz,
3H); 13C NMR (100 MHz, CDCl3) δ 167.2, 149.4, 145.6, 127.7,
119.3, 113.4, 110.2, 55.9, 41.7, 22.8, 11.3. Anal. Calcd for C11H15
-
NO3: C, 63.14; H, 7.23; N, 6.69. Found: C, 63.23; H, 7.25; N,
6.75.
4-Met h oxy-3-(m et h oxym et h oxy)-N-p r op ylb en zen eca r -
boxa m id e (9). Phenol 8 (3.00 g, 14.3 mmol) was dissolved in
150 mL of distilled CH2Cl2. NaOH (0.850 g, 21.2 mmol) in 2.5
mL of distilled water was added in one portion at room
temperature followed by 4.2 mL of Adogen 464. The reaction
mixture was allowed to stir for 30 min at room temperature and
was then cooled to 0 °C (ice bath). Chloromethyl methyl ether
(MOMCl; CAUTION: cancer suspect agent) was then added
dropwise over 1 h until reaction was complete [2.00 mL, 26.3
mmol, judged by TLC (silica): Rf ) 0.56 for the desired product,
and Rf ) 0.37 for the starting material, 1:1 CH2Cl2/Et2O]. The
organic and aqueous phases were separated, and the aqueous
layer was extracted with CH2Cl2 (2 × 20 mL). The combined
organic phase and organic extracts were dried over anhydrous
MgSO4 and evaporated in vacuo to leave behind a colorless solid.
Purification by flash column chromatography (silica gel, 50 mm
× 250 mm, 1:1 CH2Cl2/Et2O) afforded the pure product 9 as a
white crystalline solid (3.40 g, 94% yield): mp 85-86 °C; IR
Then, into a magnetically stirred, refluxing mixture of 1.20 g
of freshly activated copper bronze and 20.0 mL of anhydrous
DMF under nitrogen was added 1.05 g of 10 (2.77 mmol) in 20.0
mL of dry DMF via an addition funnel in a dropwise fashion
over 1 h. The reaction mixture was then refluxed for another 2
h. An aliquot of reaction mixture was worked up by removing
the solvent (DMF) with a vacuum pump (vacuum: ∼2 Torr) and
redissolving the residue with CH2Cl2. TLC (silica, 9:1 dichlo-
romethane/methanol, Rf ) 0.55 and 0.80 for the desired product
and the starting material, respectively) indicated that no starting
material was left. The reaction mixture was then cooled to room
temperature. The reaction mixture was filtered through Celite,
and the Celite and solid were washed with DMF (2 × 10 mL).
The combined filtrate and washes were evaporated to dryness
under vacuum (∼2 Torr) to give a gray solid residue which was
subsequently purified by flash column chromatography on silica
gel (50 mm × 150 mm, 9:1 dichloromethane/methanol) to afford
463 mg (0.918 mmol, 66% yield) of the desired dimer 11 as a
white solid: mp 148-149 °C; IR (CH2Cl2) ν 3270, 3074, 1646,
(CH2Cl2) ν 3326, 3087, 2961, 2936, 1633, 1507 cm-1 1H NMR
;
(400 MHz, CDCl3) δ 7.56 (d, J ) 2.0 Hz, 1H), 7.41 (dd, J ) 8.0,
2.0 Hz, 1H), 6.84 (d, J ) 8.0 Hz, 1H), 6.38 (br s, 1H), 5.20 (s,
2H), 3.86 (s, 3H), 3.46 (s, 3H), 3.33 (apparent q, J ) 7.2 Hz,
2H), 1.57 (apparent sextet, J ) 7.2 Hz, 2H), 0.91 (t, J ) 7.2 Hz,
3H); 13C NMR (100 MHz, CDCl3) δ 166.8, 152.2, 146.0, 127.5,
121.4, 115.1, 110.8, 95.4, 56.2, 55.8, 41.6, 22.8, 11.3. Anal. Calcd
for C13H19NO4: C, 61.64; H, 7.56; N, 5.53. Found: C, 61.85; H,
7.31; N, 5.29.
2-Iodo-4-m eth oxy-3-(m eth oxym eth oxy)-N-pr opylben zen -
eca r boxa m id e (10). The starting material 9 (1.50 g, 5.92
mmol) was dissolved in 150 mL of anhydrous THF in a 250 mL
round-bottomed flask. The solution was cooled with a -60 °C
1596 cm-1 1H NMR (400 MHz, CDCl3) δ 7.34 (d, J ) 8.4 Hz,
;
2H), 6.96 (t, J ) 5.2 Hz, 2H), 6.89 (d, J ) 8.4 Hz, 2H), 4.93 (d,
J ) 6.0 Hz, 2H), 4.77 (d, J ) 6.0 Hz, 2H), 3.80 (s, 6H), 2.99 (dt,
J ) 5.2, 6.8 Hz, 4H), 2.81 (s, 6H), 1.11 (tq, J ) 6.8, 7.2 Hz, 4H),
0.590 (t, J ) 7.2 Hz, 6H); 13C NMR (100 MHz, CDCl3) δ 168.6,
153.0, 143.2, 131.4, 129.0, 124.2, 111.5, 98.0, 56.1, 55.7, 41.2,
22.1, 11.1; HRMS calcd for C26H36N2O8 504.2471, found 504.2468.
Anal. Calcd for
C26H36N2O8: C, 61.89; H, 7.19; N, 5.55.
Found: C, 61.54; H, 7.26; N, 5.41.
1-I o d o -3,8-d im e t h o x y [1]b e n zo p y r a n o [5,4,3-cd e][1]-
ben zop yr a n -5,10-d ion e (13). Dimer 11 (400 mg, 0.793 mmol)
was dissolved under N2 in 20.0 mL of dry THF in a 100 mL
round-bottomed flask. The solution was cooled with a -60 °C
cooling bath under nitrogen, and n-butyllithium (1.75 mL, 1.5
M in pentane, 2.6 mmol) was added over 5 min. The mixture
was allowed to stir for 2 h at that temperature, after which a
solution of 667 mg (2.63 mmol) of iodine in dry THF was
transferred in 1 min via cannula into the reaction flask (5.0 mL
of THF was used to dissolve the iodine and 2 mL of THF to rinse
the flask and cannula, for a total volume of 7 mL of THF). The
(24) For most general experimental procedures, see: Kelly, T. R.;
Lang, F. J . Org. Chem. 1996, 61, 4623-4633. 1,2-Dichloroethane was
distilled from calcium hydride. Neutral alumina (activated, Brockmann
I, ∼150 mesh) was purchased from Aldrich (catalog no. 19,997-4). For
reactions monitored by alumina analytical TLC, neutral aluminum
oxide plates were used. Ozone was generated using an OSMONICS
OREC V5-O ozone generator (Phoenix Operations, Phoenix, AZ) and
bubbled into the reaction mixture.