May-Jun 2007
Synthesis of Mixed-donor Azaoxathia Macrocyclic Tetraamides
657
with water (50 ml) and crystallized from the proper solvent to
give compounds 9, 19a,b, 11a-e and 23a-c.
which was crystallized from toluene as colorless crystals (53%),
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mp. 162-164°C; ir: NH 3329, CO 1697, 1639 cm-1; H nmr
(CDCl3) ꢀ 1.15-1.21 (m, 4H, SCH2CH2), 2.28-2.34 (m, 4H,
SCH2), 3.81 (brs, 4H, CH2NH), 4.97 (s, 4H, COCH2), 6.77-8.37
(m, 16H, ArH's), 8.65 (brs, 2H, CH2NHCO), 9.36 (s, 2H,
NHCOCH2) ppm; ms: m/z 684 (M+, 5%). Anal. Calcd. for
C36H36N4O6S2 (684.835): C, 63.14; H, 5.30; N, 8.18. Found: C,
63.25; H, 5.40; N, 7.95.
1,3-Bis[2-(2-nitrophenoxy)acetamidothiophenoxy]propane
(9). With the use of the general procedure the potassium salt of
8a and 5a gave crude 9 which was crystallized from ethanol as
pale yellow crystals (50%), mp. 138-40°C; ir: NH 3305, CO
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1681, NO2 1523, 1350 cm-1; H nmr (CDCl3) ꢀ 1.75 (quintet,
J=7.2 Hz, 2H, SCH2CH2), 2.79 (t, J=7.2 Hz, 4H, SCH2), 4.75 (s,
4H, COCH2), 6.98-8.33 (m, 16H, ArH's), 9.52 (brs, 2H, NH)
ppm. Anal. Calcd. for C31H28N4O8S2 (648.716): C, 57.40; H,
4.35; N, 8.64. Found: C, 57.55; H, 4.30; N, 8.50.
6,14,15,16,17,25,33,34-Octahydro-35H-tetrabenzo[e,m,s,b1]-
[1,18]dioxa[7,12]dithia[4,15,22,26]-tetraazacyclononacosin-
7,24,31,37-(8H,23H,32H,36H)tetraone (11d). With the use of the
general procedure the potassium salt of 10b and 5b gave crude 11d
which was purified by column chromatography using ethyl
acetate/petroleum ether (40-60°C) as an eluent, to give colorless
crystals of 11d, (45%), mp. 174-76°C; ir: NH 3336, CO 1693,
2-Hydroxy-1,3-bis[2-(2-nitrophenoxy)acetamidothio-
phenoxy]propane (19a). With the use of the general procedure
the potassium salt of 8a and 15 gave crude 19a which was
crystallized from ethanol as pale yellow crystals (55%), mp.
160-2°C; ir: OH 3444, NH 3298, CO 1678, NO2 1527, 1350
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1639 cm-1; H nmr (CDCl3) ꢀ 1.20-1.26 (m, 4H, SCH2CH2), 1.89
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cm-1; H nmr (CDCl3) ꢀ 2.87 (dd, J=7.5, 13.5 Hz, 2H, upfield of
(brs, 2H, CH2CH2N), 2.42 (brs, 4H, SCH2), 3.63-3.69 (m, 4H,
CH2NH), 4.99 (s, 4H, COCH2), 6.89-8.43 (m, 16H, ArH's), 8.49
(brs, 2H, CH2NHCO), 9.49 (s, 2H, NHCOCH2) ppm; ms: m/z 698
(M+, 6%). Anal. Calcd. for C37H38N4O6S2 (698.862): C, 63.59; H,
5.48; N, 8.02. Found: C, 63.66; H, 5.30; N, 7.92.
SCH2), 3.0 (dd, J=4.5, 13.5 Hz, 2H, downfield of SCH2), 3.21
(d, J=4.2 Hz, 1H, OH), 3.69-3.74 (m, 1H, CHOH), 4.75 (s, 4H,
COCH2), 7.0-8.29 (m, 16H, ArH's), 9.51 (s, 2H, NH) ppm. Anal.
Calcd. for C31H28N4O9S2 (664.715): C, 56.02; H, 4.25; N, 8.43.
Found: C, 55.90; H, 4.17; N, 8.38.
6,14,15,16,17,25,33,34,35,36-Decahydrotetrabenzo[e,m,s,c1]-
[1,18]dioxa[7,12]dithia[4,15,22,27]-tetraazacyclodecacosin-
7,24,31,38-(8H,23H,32H,37H)tetraone (11e). With the use of
the general procedure the potassium salt of 10c and 5b gave
crude 11e which was crystallized from ethanol as colorless
crystals (38%), mp. 216-218°C; ir: NH 3267, CO 1681, 1639
cm-1; 1H nmr (CDCl3) ꢀ 1.25 (brs, 4H, SCH2CH2), 1.80 (brs, 4H,
CH2CH2N), 2.44 (brs, 4H, SCH2), 3.57 (d, J=5.7 Hz, 4H,
CH2NH), 4.89 (s, 4H, COCH2), 6.91-8.4 (m, 16H, ArH's), 7.67
(brs, 2H, CH2NHCO), 9.37 (s, 2H, NHCOCH2) ppm; ms: m/z
712 (M+, 5%). Anal. Calcd. for C38H40N4O6S2 (712.889): C,
64.02; H, 5.66; N, 7.86. Found: C, 64.15; H, 5.74; N, 7.92.
15-Hydroxy-6,14,15,24,32,33-hexahydro-16H-tetrabenzo-
[e,l,r,z][1,17]dioxa[7,11]dithia-[4,14,21,24]tetraazacyclohepta-
cosin-7,23,30,35-(8H,22H,31H,34H)tetraone (23a). With the
use of the general procedure the potassium salt of 10a and 15
gave crude 23a which was purified by column chromatography
using ethyl acetate and petroleum ether (40-60) as an eluent as
colorless crystals (45%), mp. 127-75°C; ir: OH, NH 3321, 3066,
CO 1689, 1639 cm-1; 1H nmr (CDCl3) ꢀ 2.55-2.72 (m, 5H, SCH2
& OH), 3.42-3.49 (m, 1H, CH-OH), 3.81 (brs, 4H, CH2N), 4.70
(d, J=15 Hz, 2H, upfield of COCH2), 4.81 (d, J=15.5 Hz, 2H,
downfield of COCH2), 6.70-8.23 (m, 18H, ArH's & NHCH2),
9.51 (s, 2H, NHCOCH2) ppm; ms: m/z 686 (M+, 5%). Anal.
Calcd. for C35H34N4O7S2 (686.808): C, 61.21; H, 4.99; N, 8.16.
Found: C, 61.30; H, 5.03; N, 8.29.
2-Hydroxy-1,3-bis[2-(4-formylphenoxy)acetamidothio-
phenoxy]propane (19b). With the use of the general procedure
the potassium salt of 8b and 15 gave crude 19b which was
purified by column chromatography using ethyl acetate/
petroleum ether (40-60°C) as an eluent to give semisolid product
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(53%); ir: OH 3425, NH 3313, CO 1689, 1600 cm-1; H nmr
(CDCl3) ꢀ 2.61-2.84 (m, 5H, SCH2 & OH), 3.49 (brs, 1H,
CHOH), 4.67 (s, 4H, COCH2), 6.96-8.41 (m, 16H, ArH's), 9.61
(brs, 2H, NH), 9.90 (s, 2H, CHO) ppm. Anal. Calcd. for
C33H30N2O7S2 (630.741): C, 62.84; H, 4.79; N, 4.44. Found: C,
62.75; H, 4.60; N, 4.55.
6,14,15,24,32,33-Hexahydro-16H-tetrabenzo[e,l,r,z][1,17]-
dioxa[7,11]dithia[4,14,21,24]tetraaza-cycloheptacosin-7,23,30,
35-(8H,22H,31H,34H)tetraone (11a). With the use of the
general procedure the potassium salt of 10a and 5a gave crude
11a which was purified by column chromatography using ethyl
acetate/petroleum ether (40-60°C) as an eluent, to give colorless
crystals of 11a, (50%), mp. 130-32°C; ir: NH 3321, CO 1689,
1643 cm-1; 1H nmr (CDCl3) ꢀ 1.23 (quintet, J=6.7 Hz, 2H,
SCH2CH2), 2.25 (t, J=6.7 Hz, 4H, SCH2), 3.84 (brs, 4H, CH2N),
4.99 (s, 4H, COCH2), 6.78-8.36 (m, 16H, ArH's), 8.67 (brs, 2H,
CH2NHCO), 9.33 (s, 2H, NHCOCH2) ppm; ms: m/z 670 (M+,
5%). Anal. Calcd. for C35H34N4O6S2 (670.808): C, 62.67; H,
5.11; N, 8.35. Found: C, 62.55; H, 5.01; N, 8.23.
6,14,15,24,32,33,34,35-Octahydro-16H-tetrabenzo[e,l,r,b1]-
[1,17]dioxa[7,11]dithia- [4,14,21,26]tetra-azacyclononacosin-
7,23,30,37-(8H,22H,31H,36H)tetraone (11b). With the use of
the general procedure the potassium salt of 10c and 5a gave crude
11b which was crystallized from ethanol as colorless crystals
(40%), mp. 218-20°C; ir: NH 3267, CO 1681, 1639 cm-1; 1H nmr
(CDCl3) ꢀ 1.46 (quintet, J=6.6 Hz, 2H, SCH2CH2), 1.81 (s, 4H,
CH2CH2N), 2.49 (t, J=6.6 Hz, 4H, SCH2), 3.57 (d, J=5.7 Hz, 4H,
CH2N), 4.88 (s, 4H, COCH2), 6.89-8.34 (m, 16H, ArH's), 7.66
(brs, 2H, CH2NHCO), 9.30 (s, 2H, NHCOCH2) ppm; ms: m/z 698
(M+, 4%). Anal. Calcd. for C37H38N4O6S2 (698.862): C, 63.59; H,
5.48; N, 8.02. Found: C, 63.65; H, 5.39; N, 7.90.
15-Hydroxy-6,14,15,24,32,33-hexahydro-16H,34H-tetra-
benzo[e,l,r,a1][1,17]dioxa[7,11]dithia-[4,14,21,25]tetraaza-
cyclooctacosin-7,23,30,36-(8H,22H,31H,35H)tetraone (23b).
With the use of the general procedure the potassium salt of 10b
and 15 gave crude 23b which was purified by column
chromatography using ethyl acetate and petroleum ether (40-60)
as an eluent as colorless crystals (40%), mp. 172-5°C; ir: OH,
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NH, 3321, 3066, CO 1689, 1639 cm-1; H nmr (CDCl3) ꢀ 1.95
(brs, 2H, NCH2CH2), 2.54 (dd, J=8.1, 13 Hz, 2H, upfield of
SCH2), 2.64 (dd, J=4.0, 13.1 Hz, 2H, downfield of SCH2), 3.43-
3.46 (m, 1H, CH-OH), 3.61-3.75 (m, 4H, NCH2), 4.54 (d, J=4.8
Hz, 1H, OH), 4.87 (d, J=15.9 Hz, 2H, upfield of COCH2), 4.97
(d, J=15.9 Hz, 2H, downfield of COCH2), 6.96-8.38 (m, 16H,
ArH's), 7.98 (t, J=5.7 Hz, 2H, CH2NHCO), 9.59 (s, 2H,
NHCOCH2) ppm; 13C NMR (APT & DEPT pulse sequences,
6,14,15,16,17,25,33,34-Octahydrotetrabenzo[e,m,s,a1][1,18]-
dioxa[7,12]dithia[4,15,22,25]tetraazacyclooctacosin-7,24,31,36-
(8H,23H,32H,35H)-tetraone (11c). With the use of the general
procedure the potassium salt of 10a and 5b gave crude 11c