214 J . Org. Chem., Vol. 62, No. 1, 1997
Notes
spectra. Starting materials and solvents were purchased from
commercial sources where available.
recrystallization from CH3OH/CH3CN: mp 205-207 °C dec; 1H
NMR δ 1.30-1.70 (m, 2 H), 1.95-2.03 (m, 4 H), 2.26 (s, 6 H),
2.81 (d, J ) 16.5 Hz, 2 H), 2.99 (d, J ) 16.5 Hz, 2 H), 3.94 (s, 3
H), 4.36 (dd, J ) 14.3, 5.0 Hz, 2 H), 4.56 (dd, J ) 14.3, 7.7 Hz,
2 H), 7.76 (t, J ) 6.0 Hz, 2 H), 8.13 (s, 2 H); MS m/ z 393 (M+).
Anal. Calcd for C18H27N5O5: C, 54.95; H, 6.92. Found: C, 55.16;
H, 7.02.
2,6-Bis[(2-ch lor oa cet a m id o)m et h yl]-4-n it r oa n isole (1)
(Sch em e 1). To a stirred solution of 4-nitroanisole (9.4 g, 60
mmol) in concd H2SO4 (60 mL) at rt was added N-(hydroxy-
methyl)-2-chloroacetamide (4) (30.3 g, 240 mmol). After being
stirred for 36 h, the mixture was poured into 200 g of ice. The
resulting aqueous suspension was filtered. The solid was
washed with a large amount of water, dried, and recrystallized
from ethanol to give 19 g (87%) of 1: mp 178-179 °C; 1H NMR
δ (DMSO-d6) 3.88 (s, 3 H), 4.19 (s, 4 H), 4.44 (d, J ) 5.9 Hz, 4
H), 8.09 (s , 2 H), 8.92 (t, J ) 5.9 Hz, 2 H); MS m/ z 364 (M+).
Anal. Calcd for C13H15Cl2N3O5: C, 42.87; H, 4.15. Found: C,
43.00; H, 4.36.
9-Oxa -6,12-d im et h yl-21-m et h oxy-19-n it r o-3,6,12,15-t et -
r a a za bicyclo[15.3.1]eicosa -1(21),17,19-tr ien e-4,14-d ion e (7)
(Sch em e 2). Compound 7 was obtained as above for 5 from
0.404 g (3 mmol) of N,N′-dimethyl-1,5-diamino-3-oxapentane,
1.1g (3 mmol) of 1, and 10 g (0.09 mol) of Na2CO3. Macrocycle
7 (0.826 g, 65%) was isolated after column chromatography and
1
recrystillization from toluene: mp 131-133 °C dec; H NMR δ
2.24 (s, 6 H), 2.34 (t, J ) 5.6 Hz, 4 H), 2.96 (s, 4 H), 3.31 (t, J )
5.6 Hz, 4 H), 3.86 (s, 3 H), 4.46 (d, J ) 5.9 Hz, 4 H), 7.69 (t, J )
5.9 Hz, 2 H), 8.12 (s, 2 H); MS m/ z 423 (M+). Anal. Calcd for
2,6-Bis[(tr iflu or oa ceta m id o)m eth yl]-4-n itr oa n isole (2, R
) H) (Sch em e 1). A mixture of 15.3 g (0.1 mol) of 4-nitroani-
sole, 42.9 g (0.3 mol) of N-(hydroxymethyl)trifluoroacetamide,
and 150 mL of H2SO4 (95%) was stirred at 60 °C for 12 h and
poured into 500 g of ice. One L of ether was added, and the
mixture was shaken and transferred to a separatory funnel. The
organic phase was separated, dried (Na2SO4), and evaporated.
The residue was recrystallized from toluene/C2H5OH (10:1) to
give 28.2 g (70%) of 2 (R ) H): mp 158-160 °C; 1H NMR δ
(DMSO-d6) 3.90 (s, 3 H), 4.55 (d, J ) 5.4 Hz, 4 H), 8.16 (s, 2 H),
10.10 (t, J ) 5.4 Hz, 2 H); MS m/ z 404 [M + 1]+. Anal. Calcd
for C13H11F6N3O5: C, 38.72; H, 2.75. Found: C, 38.80; H, 2.73.
2,6-Bis(a m in om eth yl)-4-n itr oa n isole (3, R ) H) (Sch em e
1). A mixture of 1 g (2.5 mmol) of diamide 2 (R ) H), 6 mL of
a 10% solution of (CH3)4NOH, and 4 mL of CH3OH was stirred
under reflux for 0.5 h. CH3OH was removed under reduced
pressure, and product was extracted three times with 10-mL
portions of CHCl3. After drying (Na2SO4), the CHCl3 was
evaporated under reduced pressure to give 0.5 g (95%) of 3 (R )
H): mp 57-59 °C; 1H NMR δ 1.50 (s, 4 H), 3.85 (s, 3 H), 3.94 (s,
4 H), 8.17 (s, 2 H); MS m/ z 212 [M + 1]+. Anal. Calcd for
C9H13N3O3: C, 51.18; H, 6.20. Found: C, 51.24; H, 6.25.
2,6-Bis[(N-m eth yltr iflu or oacetam ido)m eth yl]-4-n itr oan i-
sole (2, R ) CH3) (Sch em e 3). A mixture of 1 g (2.5 mmol) of
diamide 2 (R ) H), 1.03 g (5.5 mmol) of methyl tosylate, 7 g
(0.05 mol) of K2CO3, and 50 mL of CH3CN was stirred under
reflux for 5 h. The mixture was cooled and filtered, and the CH3-
CN was removed. The residue was treated with 100 mL of H2O
and 100 mL of CHCl3. The organic phase was dried (Na2SO4),
and the solvent was evaporated. The residue was recrystallized
from CCl4/C2H5OH (4:1) to give 0.88 g (82%) of 2 (R ) CH3):
C
19H29N5O6: C, 53.89; H, 6.90. Found: C, 54.00; H, 6.94.
9,12-Dioxa -6,15-d im eth yl-24-m eth oxy-22-n itr o-3,6,15,18-
t et r a a za b icyclo[18.3.1]t r icosa -1(24),20,22-t r ien e-4,17-d i-
on e (8) (Sch em e 2). Compound 8 was obtained as above for 5
from 0.54 g (3 mmol) of N,N′-dimethyl-1,8-diamino-3,6-dioxa-
octane, 1.1 g (3 mmol) of 1, and 10 g (0.09 mol) of Na2CO3.
Macrocycle 8 (1.04 g, 74%) was isolated after column chroma-
tography and recrystallization from CH3CN/C6H14: mp 140-
1
142 °C dec; H NMR δ 2.30 (s, 6 H), 2.42 (t, J ) 5.4 Hz, 4 H),
3.06 (s, 4 H), 3.15 (s, 4 H), 3.27 (t, J ) 5.4 Hz, 4 H), 3.81 (s, 3
H), 4.50 (d, J ) 5.9 Hz, 4 H), 7.94 (t, J ) 5.9 Hz, 2 H), 8.05 (s,
2 H); MS m/ z 467 (M+). Anal. Calcd for C21H33N5O7: C, 53.95;
H, 7.11. Found: C, 53.76; H, 7.10.
18,21,26,29-Tet r a oxa -32-m et h oxy-8-n it r o-1,4,12,15-t et -
r a a za tr icyclo[13.8.8.16,10]d otr ia cosa -6,8,10(32)-tr ien e-3,13-
d ion e (9) (Sch em e 2). Compound 9 was synthesized as above
for 5 from 0.787 g (3 mmol) of diaza-18-crown-6, 1.1 g (3 mmol)
of 1, and 10 g (0.09 mol) of Na2CO3. Macrobicycle 9 (1.03 g,
62%) was isolated after column chromatography and recrystal-
1
lization from toluene/hexane: mp 178-180 °C dec; H NMR δ
2.57 (m, 4 H), 2.72 (m, 4 H), 3.18 (s, 4 H), 3.27-3.43 (m, 16 H),
3.85 (s, 3 H), 4.54 (d, J ) 5.1 Hz, 4 H), 8.15 (m, 4 H); MS m/ z
553 (M+). Anal. Calcd for C25H39N5O9: C, 54.24; H, 7.10.
Found: C, 54.46; H, 7.13.
6-Oxa -3,9-b is(t r iflu or oa cet yl)-15-m et h oxy-13-n it r o-3,9-
diazabicyclo[9.3.1]tetr adeca-1(15),11,13-tr ien e (10) (Sch em e
3). A mixture of 2.02 g (5 mmol) of diamide 2 (R ) H), 2.07 g (5
mmol) of diethylene glycol ditosylate, 15 g (0.11 mol) of K2CO3,
and 250 mL of CH3CN was stirred under reflux for 120 h. The
mixture was filtered, and the solvent was evaporated under
reduced pressure. To the residue was added a mixture of 100
mL of CHCl3 and 100 mL of THF. The mixture was filtered,
and solvents were evaporated. The product was isolated after
column chromatography on silica gel using CHCl3/THF (12:1)
1
mp 125-127 °C; H NMR δ 3.16 (s, 6 H), 3.88 (s, 3 H), 4.76 (s,
4 H), 8.01 (s, 2 H); MS m/ z 432 [M + 1]+. Anal. Calcd for
C
15H15F6N3O5: C, 41.77; H, 3.51. Found: C, 41.85; H, 3.54.
2,6-Bis[(N-m eth yla m in o)m eth yl]-4-n itr oa n isole (3, R )
CH3) (Sch em e 3). Compound 3 (R ) CH3) was synthesized as
above for 3 (R ) H) from 0.5 g (1.16 mmol) of diamide 2 (R )
CH3), 3 mL of a 10% solution of (CH3)4NOH, and 3 mL of CH3-
OH and refluxed for 1.5 h. The product (0.27 g, 99%) was
isolated as an oil: 1H NMR δ 1.40 (s, 2 H), 2.45 (s, 6 H), 3.80 (s,
4 H), 3.85 (s, 3 H), 8.18 (s, 2 H); MS m/ z 240 [M + 1]+. Anal.
Calcd for C11H17N3O3: C, 55.22; H, 7.16. Found: C, 55.18; H,
7.12.
1
as eluant to give 0.44 g (19%) of 10: mp 123-125 °C; H NMR
δ 2.40-5.55 (m, 12 H), 3.80 (s, 3 H), 8.21 (m, 2 H); MS m/ z 474
[M + 1]+. Anal. Calcd for C17H17F6N3O6: C, 43.14; H, 3.62.
Found: C, 43.18; H, 3.70.
6,9-Dioxa -3,12-bis(tr iflu or oa cetyl)-18-m eth oxy-16-n itr o-
3,12-d ia za bicyclo[12.3.1]h ep ta d eca -1(18),14,16-tr ien e (11)
(Sch em e 3). Compound 11 was synthesized as above for 10
from 2.02 g (5 mmol) of diamide 2 (R ) H), 2.29 g (5 mmol) of
triethylene glycol ditosylate, and 15 g (0.11 mol) of K2CO3.
Macrocycle 11 (0.59 g, 23%) was isolated after column chroma-
tography as a solid: mp 125-128 °C; 1H NMR δ 2.40-5.35 (m,
16 H), 3.82 (s, 3 H), 7.95 (m, 2 H); MS m/ z 518 [M + 1]+. Anal.
Calcd for C19H21F6N3O7: C, 44.11; H, 4.10. Found: C, 44.10;
H, 4.17.
6,9,12-Tr ioxa -3,15-bis(tr iflu or oa cetyl)-21-m eth oxy-19-n i-
tr o-3,15-d ia za bicyclo[15.3.1]eicosa -1(21),17,19-tr ien e (12)
(Sch em e 3). Compound 12 was obtained as above for 10 from
2.02 g (5 mmol) of diamide 2 (R ) H), 2.51 g (5 mmol) of
tetraethylene glycol ditosylate, and 15 g (0.11 mol) of K2CO3.
Macrocycle 12 (0.85 g, 30%) was isolated after column chroma-
tography as a solid: mp 154-156 °C; 1H NMR δ 3.52 (m, 16 H),
3.83 (s, 3 H), 5.05 (m, 4 H), 7.91 (m, 2 H); MS m/ z 562 [M +
1]+. Anal. Calcd for C21H25F6N3O8: C, 44.93; H, 4.49. Found:
C, 45.01; H, 4.43.
6,9-Dim e t h yl-18-m e t h oxy-16-n it r o-3,6,9,12-t e t r a a za -
bicyclo[12.3.1]h ep ta d eca -1(18),14,16-tr ien e-4,11-d ion e (5)
(Sch em e 2). A mixture of 0.267 g (3 mmol) of N,N′-dimethyl-
ethylenediamine, 1.1 g (3 mmol) of diamide 1, 10 g (0.09 mol) of
anhydrous Na2CO3, and 1 L of CH3CN was refluxed for 24 h
under N2. The Na2CO3 was filtered, and the CH3CN was
evaporated. The solid residue was chromatographed on silica
gel using NH4OH/THF (1:20) as eluant to give 0.86 g (75%) of
5, which was recrystallized from CH3OH to give white prisms:
mp 232-233 °C dec; 1H NMR δ 2.02 (m, 2 H), 2.24 (s, 6 H), 2.30
(m, 2 H), 2.85 (d, J ) 16.2 Hz, 2 H), 2.93 (d, J ) 16.2 Hz, 2 H),
3.91 (s, 3 H), 4.22 (dd, J ) 14.3, 5.12 Hz, 2 H), 4.72 (dd, J )
14.3, 6.96 Hz, 2 H), 7.47 (t, J ) 5.58 Hz, 2 H), 8.09 (s, 2 H); MS
m/ z 379 (M+). Anal. Calcd for C17H25N5O5: C, 53.82; H, 6.64.
Found: C, 53.62; H, 6.78.
6,10-Dim et h yl-19-m et h oxy-17-n it r o-3,6,10,13-t et r a a za -
b icyclo[13.3.1]oct a d eca -1(19),15,17-t r ien e-4,12-d ion e (6)
(Sch em e 2). Compound 6 was obtained as above for 5 from
0.316 g (3 mmol) of N,N′-dimethyl-1,3-propanediamine, 1.1 g (3
mmol) of diamide 1, and 10 g (0.09 mol) of Na2CO3. Macrocycle
6 (0.93 g, 79%) was isolated after column chromatography and
6,9-Dioxa -3,12-d im e t h yl-18-m e t h oxy-16-n it r o-3,12-d i-
azabicyclo[12.3.1]h eptadeca-1(18),14,16-tr ien e (13) (Sch em e
3). A mixture of 0.19 g (0.8 mmol) of diamine 3 (R ) CH3), 0.36