A. I. Oliva et al. / Tetrahedron 60 (2004) 3755–3762
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added to a cold (210 8C) solution of compound 3 (30.0 g,
84.1 mmol) in acetic anhydride (100 ml). Fuming nitric acid
(3 ml) in acetic anhydride (60 ml) was then added dropwise,
keeping the reaction mixture below 25 8C. Once nitration is
finished, the reaction mixture was poured over ice water
(1000 ml). After stirring for 2 h, the crude product was
filtered. Crystallization in methanol yielded the pure
compound (32.0 g, 95%). Mp: 147–149 8C. 1H NMR
(400 MHz, CDCl3) d (ppm): 8.08 (1H, d, J¼8 Hz), 7.72
(1H, d, J¼2 Hz), 7.56 (1H, t, J¼8 Hz), 7.39 (1H, t, J¼8 Hz),
7.26 (1H, d, J¼8 Hz), 7.26 (1H, d, J¼2 Hz), 4.28 (2H, q,
J¼7 Hz), 3.33 (1H, m), 3.1–3.0 (3H, m), 2.76 (1H, dd, J¼4,
17 Hz), 1.22 (3H, t, J¼7 Hz). IR n (cm21): 2953, 2866,
1750, 1684, 1601, 1528, 1296, 1252, 1204, 1132, 1045, 756,
723. MS (EI): 118, 100%; 105, 55%; 77, 25%; 216, 40%;
170, 38%; 401 (Mþ), 25%; 355, 15%; 403, 10%. HRMS
(EI): calcd for C20H16ClNO6: 401.0666, found: 401.0623.
Calcd analysis for C20H16ClNO6: C, 59.78; H, 4.01; N, 3.49.
Found: C, 59.69; H, 3.93; N, 3.64.
for 20 min until no more gases evolved. Thionyl chloride
was eliminated under reduced pressure and the crude acid
chloride was reacted with an aqueous solution (40 ml) of
(L)-leucine sodium salt (11.6 g, 75.7 mmol). After stirring
for 30 min, the reaction was filtered and the aqueous
solution was acidified with 2 M HCl. Filtration provided
5.6 g of the product (74%). Mp: 72–74 8C. 1H NMR
(200 MHz, CDCl3) d (ppm): 8.42 (1H, s), 8.02 (1H, d,
J¼8 Hz), 7.80 (1H, d, J¼8 Hz), 7.68 (1H, d, J¼8 Hz), 7.42
(1H, t, J¼8 Hz), 6.62 (1H, s), 5.0–4.9 (1H, s), 3.46 (2H, q,
J¼6 Hz), 1.9–1.3 (7H, m), 1.0–0.84 (9H, m). IR n (cm21):
3329, 2926, 1721, 1638, 1541, 1466, 1302, 1152, 926, 729,
665. MS (FAB): 204, 100%; 335 (Mþþ1), 70%; 86, 30%;
289, 20%. HRMS (FAB): calcd for C18H27N2O4: 335.1971,
found: 335.1942. Calcd analysis for C18H26N2O4: C, 64.65;
H, 7.84; N, 8.38. Found: C, 64.49; H, 7.57; N, 8.45.
3.2.8. 2-(3-Butylsulfamoyl-benzoylamino)-4-methyl-
pentanoic acid (8). m-Butylaminosulfonyl-benzoic acid
(19.6 g, 76.2 mmol) was refluxed in thionyl chloride until
gas evolution ceased. Thionyl chloride was evaporated and
the acid chloride was added over an aqueous solution
(40 ml) of (L)-leucine sodium salt (11.6 g, 75.7 mmol). The
reaction product was precipitated from the clear solution by
adding 2 M HCl. Filtration afforded the expected guest
(16.1 g, 57%). Mp: 90–92 8C. 1H NMR (200 MHz, CDCl3)
d (ppm): 8.34 (1H, s), 8.06 (1H, d, J¼8 Hz), 7.97 (1H, d,
J¼8 Hz), 7.57 (1H, t, J¼8 Hz), 7.46 (1H, d, J¼8 Hz), 5.30
(1H, s), 4.67 (1H, s), 2.92 (2H, q, J¼6 Hz), 1.8–1.1 (7H, m),
0.93 (6H, d, J¼5 Hz), 0.62 (3H, t, J¼7 Hz). IR n (cm21):
3266, 2945, 1724, 1647, 1541, 1462, 1328, 1159, 1088, 759.
MS (FAB): 240, 100%; 371 (Mþþ1), 55%; 86, 52%; 137,
50%. HRMS (FAB): calcd for C17H27N2O5S: 371.1641,
found: 371.1622. Calcd analysis for C17H26N2O5S: C,
55.12; H, 7.07; N, 7.56; S, 8.66. Found: C, 54.96; H, 7.23;
N, 7.58; S, 8.46.
3.2.5. cis 4-Amino-2-chloro-6-oxo-6,11,11a,12-tetra-
hydro-benzo[b]xanthene-5a-carboxylic acid ethyl ester
(5). Compound 4 (17.0 g, 0.04 mol) was slowly added to a
warm solution of SnCl2–2H2O (29.0 g, 0.13 mol) in
methanol (35 ml). Aqueous saturated Na2CO3 was added
and the suspension was stirred for 30 min. Extraction with
hot ethyl acetate yielded 14.1 g of an oily product (90%). 1H
NMR (400 MHz, CDCl3) d (ppm): 8.08 (1H, d, J¼8 Hz),
7.54 (1H, t, J¼8 Hz), 7.36 (1H, t, J¼8 Hz), 7.23 (1H, d,
J¼8 Hz), 6.53 (1H, d, J¼2 Hz), 6.41 (1H, d, J¼2 Hz), 4.26
(2H, q, J¼7 Hz), 3.28 (1H, m), 3.10–2.80 (3H, m), 2.59
(1H, dd, J¼2, 17 Hz), 1.23 (3H, t, J¼7 Hz). IR n (cm21):
2924, 2855, 1751, 1688, 1601, 1487, 1456, 1292, 1196,
1026, 756. MS (EI): 77, 100%; 89, 65%; 106, 36%; 371
(Mþ), 8%. HRMS (EI): calcd for C20H18ClNO4: 371.0956,
found: 371.0958. Calcd analysis for C20H18ClNO4: C,
64.61; H, 4.88; N, 3.77. Found: C, 64.38; H, 4.61; N, 3.57.
3.2.9. cis 2-Chloro-4-[3-(4-chloro-phenyl)-ureido]-6-
hydroxy-6,11,11a,12-tetrahydro-benzo[b] xanthene-5a-
carboxylic acid (2-ethyl-hexyl)-amide (9). BuLi (1.2 ml,
1.92 mmol, 1.6 M in hexane) was added to a solution of
2-ethylhexylamine (0.24 g, 1.93 mmol) in THF (5 ml) with
stirring at 230 8C under an argon atmosphere. After drying
by azeotropic distillation, a solution of receptor 1 (0.10 g,
0.19 mmol) in toluene (3 ml) was added to the reaction
mixture. The reaction mixture was stirred for 1 h at 230 8C
and was then extracted with ethyl acetate and washed with
HCl, Na2CO3 and water several times. Purification of the
product was accomplished by crystallization from a
CH2Cl2/hexane mixture to give 0.09.g (75%) of a white
solid. Mp: 90–92 8C. 1H NMR (400 MHz, CDCl3) d (ppm):
7.75 (1H, s), 7.6–6.8 (1H, s), 7.54 (1H, d, J¼8 Hz), 7.26–
6.96 (7H, m), 6.81 (1H, d, J¼2 Hz), 5.27 (1H, s), 3.4–2.4
(5H, m), 1.4–0.7 (14H, m), 0.67 (3H, t, J¼7 Hz). 13C NMR
(400 MHz, DMSO) d (ppm): 170.5 (1C), 152.2 (1C), 140.9
(1C), 138.2 (1C), 137.3 (1C), 134.1 (1C), 135.1 (1C), 128.6
(2C), 127.8 (1C), 127.1 (1C), 126.2 (1C), 125.7 (1C), 125.3
(2C), 124.6 (1C), 122.2 (1C), 120.0 (2C), 1167.0 (1C), 83.0
(1C), 71.1 (1C), 56.0 (1C), 38.8 (1C), 30.6 (1C), 30.2 (1C),
29.7 (1C), 29.4 (1C), 28.3 (1C), 23.5 (1C), 22.5 (1C), 13.9
(1C), 10.8 (1C). IR n (cm21): 3314, 2924, 1643, 1599, 1537,
1464, 1306, 1209, 1127, 1094, 828, 752. MS (FAB): 300,
50%; 437, 28%; 610 (Mþþ1), 15%. HRMS (FAB): calcd
3.2.6. cis 2-Chloro-4-[3-(4-chloro-phenyl)-ureido]-6-oxo-
6,11,11a,12-tetrahydrobenzo[b]xanthene-5a-carboxylic
acid ethyl ester (6). One third of a toluene (80 ml) solution
of the amine 5 (15.5 g, 41.7 mmol) was distilled to eliminate
traces of water. p-Chlorophenylisocyanate (6.4 g,
41.7 mmol) was added at room temperature. When the
reaction was completed, toluene was evaporated under
vacuum and the crude product was crystallized in methanol
to yield the expected urea (17.5 g, 80%). Mp: decompo-
1
sition over 127 8C. H NMR (400 MHz, CDCl3) d (ppm):
8.12 (1H, d, J¼2 Hz), 8.10 (1H, d, J¼8 Hz), 7.60 (1H, t,
J¼8 Hz), 7.54 (1H, s), 7.40 (1H, t, J¼8 Hz), 7.33 (2H, d,
J¼8 Hz), 7.29 (1H, d, J¼8 Hz), 7.24 (2H, d, J¼8 Hz), 6.74
(1H, d, J¼2 Hz), 4.29 (2H, q, J¼7 Hz), 3.35–3.31 (1H, m),
3.10–2.94 (3H, m), 2.69 (1H, dd, J¼3, 18 Hz), 1.25 (3H, t,
J¼7 Hz). IR n (cm21): 3374, 2959, 1746, 1715, 1676, 1601,
1539, 1294, 1188, 1088, 1045, 949, 835, 723. MS (FAB):
217, 75%; 105, 45%; 77, 37%; 525 (Mþþ1), 25%; 371,
15%. HRMS (FAB): calcd for C27H23Cl2N2O5: 525.0984,
found: 525.1021. Calcd analysis for C27H22Cl2N2O5: C,
61.72; H, 4.22; N, 5.33. Found: C, 61.48; H, 4.29; N, 5.42.
3.2.7. 2-(3-Butylcarbamoyl-benzoylamino)-4-methyl-
pentanoic acid (7). Isophthalic acid monobutyl amide
(5.0 g, 22.6 mmol) was refluxed in thionyl chloride (25 ml)