Tethered Biginelli Condensations
J . Org. Chem., Vol. 64, No. 5, 1999 1527
Calcd for C20H33N3O4S: C, 58.37; H, 8.08; N, 10.21.
Found: C, 58.31; H, 8.05; N, 10.21.
(m, 3H); 13C NMR (125 MHz, CDCl3) 165.6, 165.3, 158.5,
146.7, 143.0, 138.4, 136.9, 135.8, 133.0, 131.6, 131.0,
128.7, 128.6, 128.3, 128.2, 128.0, 124.8, 111.6, 100.6, 66.2,
62.0, 56.2, 56.1, 55.4, 34.5, 33.2, 27.7, 24.0, 18.9, 18.3,
(S)-N-[(Am in om eth ylen e)-4-m eth oxy-2,3,6-tr im e-
t h ylb en zen esu lfon a m id e]-3-a m in o-1-b en zyloxy-7-
m eth yl-6-octen e (25b). Following the procedure de-
scribed for preparing 25a , 13 (0.807 g, 3.262 mmol) was
converted in 80% overall yield to 25b: a colorless oil; 1H
NMR (500 MHz, DMSO, 80 °C) δ 7.25-7.32 (m, 5H) 6.65
(s, 1H) 6.45 (s, 1H) 6.42 (s, 1H) 5.01 (m, 1H) 4.35 (s, 2H)
3.77 (s, 3H) 3.73 (m, 1H) 3.38-3.41 (m, 2H) 3.09 (s, 3H)
2.63 (s, 3H) 2.56 (s, 3H) 1.88 (m, 2H) 1.69 (m, 1H) 1.60
(m, 4H) 1.49 (s, 3H) 1.36-1.42 (m, 2H); 13C NMR (125
MHz, DMSO, 80 °C) 157.3, 155.6, 138.2, 137.2, 135.3,
134.8, 130.5, 127.7, 126.9, 126.8, 123.4, 123.2, 111.6, 71.6,
66.5, 55.1, 47.5, 34.3, 34.2, 24.8, 23.5, 22.8, 17.4, 16.9,
11.8 ppm; IR (film) 3298, 1716, 1614 cm-1; [R]23 -17.7,
D
[R]23577 -16.1, [R]23546 -18.3, [R]23435 -19.4, [R]23405 -13.3
(c 0.75, CHCl3). Anal. Calcd for C35H38BrN3O7S: C, 58.01;
H, 5.29; N, 5.80. Found: C, 58.06; H, 5.41; N, 5.55.
Con ver sion of 25b to 27b a n d 28b u n d er Kn oev-
en a gel Bigin elli Con d ition s. Following the represena-
tive olefin dihydroxylation and 1,2-diol cleavage proce-
dure, 25b (100 mg, 0.20 mmol) was converted to 26b, and
this crude material was condensed with 16 following the
representative procedure for Biginelli condensation under
Knoevenagel conditions with the exception that the
concentration of 26b in 2,2,2-trifluoroethanol was 0.5 M.
Purification of the crude product on silica gel (4:1
hexanes-EtOAc to 2:1 hexanes-EtOAc) provided 106 mg
(84%) of a 7:1 mixture of 27b and 28b. Characterization
data for the major product (4aR,7S)-7-(2-Benzyloxyethyl)-
1-(4-methoxy-2,3,6-trimethylbenzenesulfonylimino)-3-
methyl-1,2,4a,5,6,7-hexahydropyrrolo[1,2-c]pyrimidine-4-
carboxylic acid benzyl ester (27b) as determined from this
mixture: 1H NMR (500 MHz, CDCl3) δ 9.42 (s, 1H) 7.23-
7.42 (m, 10H) 6.52 (s, 1H) 5.15-5.25 (m, 2H) 4.28-4.36
(m, 2H) 4.23 (d, J ) 11.1, 4.0 Hz, 1H) 4.03-4.07 (m, 1H)
3.82 (m, 3H) 3.40-3.42 (m, 2H) 2.70 (s, 3H) 2.62 (s, 3H)
2.48-2.50 (m, 1H) 2.31 (s, 3H) 2.13 (s, 3H) 2.00-2.05 (m,
1H) 1.93-1.95 (m, 2H) 1.79-1.83 (m, 1H) 1.47-1.53 (m,
1H); 13C NMR (125 MHz, CDCl3) 165.1, 158.5, 148.1,
145.6, 138.5, 138.2, 136.4, 135.7, 133.2, 128.6, 128.4,
128.2, 128.2, 127.5, 127.4, 124.7, 111.7, 103.9, 72.5, 67.7,
66.3, 57.0, 55.9, 55.3, 33.4, 30.0, 28.8, 24.0, 18.5, 18.3,
11.9 ppm; IR (film) 3289, 1704, 1614 cm-1. Anal. Calcd
for C35H41N3O6S: C, 66.54; H, 6.54; N, 6.65. Found: C,
66.66; H, 6.57; N, 6.66.
11.2 ppm; IR (film) 3445, 3336, 1622, 1538 cm-1; [R]23
D
+14.6, [R]23577 +15.3, [R]23546 +18.2, [R]23435 +37.4, [R]23
405
+48.9 (c 1.80, CHCl3). Anal. Calcd for C27H39N3O4S: C,
64.64; H, 7.84; N, 8.38. Found: C, 64.77; H, 7.88; N, 8.32.
Con ver sion of 25a to 27c a n d 28c u n d er Kn oev-
en a gel Bigin elli Con d ition s. Following the represena-
tive olefin dihydroxylation and 1,2-diol cleavage proce-
dure, 25a (100 mg, 0.24 mmol) was converted to 26a .
Aminal 26a was then condensed with 16 following the
representative procedure for Biginelli condensation under
Knoevenagel conditions with the exception that the
concentration of 26a in 2,2,2-trifluoroethanol was 0.5 M.
Purification of the crude product on silica gel (1:1
hexanes-EtOAc) provided 80 mg (61%) of a 6:1 mixture
of 27a and 28a .
A 120 mg (0.22 mmol) sample of a comparable product
was esterified with 4-bromobenzoyl chloride (160 mg, 0.72
mmol) following the procedure described for the prepara-
tion of 24 to provide a crude residue that was purified
on silica gel (3:1 hexanes-EtOAc) to provide 160 mg
(100%) of a 6:1 mixture 27c and 28c. These isomers were
separated by HPLC (6:1 hexanes-EtOAc; 20 mL/min,
300 × 22 mm 10 µm silica Alltech column) to give pure
samples of 27c (tR ) 62 min) and 28c tR ) 53 min).
(4aR,7S)-7-[2-(4-Br om oben zoyloxy)eth yl]-1-(4-m eth -
oxy-2,3,6-tr im eth ylben zen esu lfon ylim in o)-3-m eth -
yl-1,2,4a ,5,6,7-h exa h yd r op yr r olo[1,2-c]p yr im id in e-
Con ver sion of 25b to (4a S,7S)-7-(2-Ben zyloxy-
et h yl)-1-(4-m et h oxy-2,3,6-t r im et h ylb en zen esu lfo-
n ylim in o)-3-m eth yl-1,2,4a ,5,6,7-h exa h yd r op yr r olo-
[1,2-c]p yr im id in e-4-ca r boxylic Acid Ben zyl Ester
(28b) by Bigin elli Con d en sa tion in th e P r esen ce of
P P E. Following the representative procedure for olefin
dihydroxylation and 1,2-diol cleavage, 25b (100 mg, 0.20
mmol) was converted to 26b. Crude aminal 26b was then
condensed with 16 following the representative procedure
for Biginelli condensation in the presence of PPE to give,
after purification on silica gel (2:1 hexanes-EtOAc to 1:1
hexanes-EtOAc), 77 mg (61%) of 28b, which was con-
taminated with a trace of 27b (3%). 28b: 1H NMR (500
MHz, CDCl3) δ 9.23 (s, 1H) 7.22-7.42 (m, 10H) 6.54 (s,
1H) 5.16-5.26 (m, 2H) 4.36-4.40 (m, 2H) 4.26-4.35 (m,
2H) 3.84 (m, 3H) 3.45-3.48 (m, 2H) 2.72 (s, 3H) 2.65 (s,
3H) 2.45-2.50 (m, 1H) 2.32 (s, 3H) 2.15-2.20 (m, 1H)
2.14 (s, 3H) 2.00-2.05 (m, 1H) 1.62-1.72 (m, 1H) 1.51-
1.60 (m, 2H); 13C NMR (125 MHz, CDCl3) δ 165.4, 158.5,
146.4, 142.9, 138.6, 136.4, 135.8, 133.4, 128.6, 128.3,
128.2 128.2, 127.5, 127.4, 127.4, 124.7, 111.6, 100.5, 72.5,
67.2, 66.1, 56.4, 56.0, 55.3, 34.5, 34.1, 27.7, 24.0, 18.8,
1
4-ca r boxylic a cid ben zyl ester (27c): H NMR (500
MHz, CDCl3) δ 9.33 (s, 1H) 7.76 (d, J ) 8.4 Hz, 2H) 7.51
(d, J ) 8.4 Hz, 2H) 7.32-7.39 (m, 5H) 6.48 (s, 1H) 5.12-
5.21 (m, 2H) 4.20-4.29 (m, 2H) 4.13-4.18 (m, 1H) 4.05-
4.09 (m, 1H) 3.78 (s, 3H) 2.66 (s, 3H) 2.59 (s, 3H) 2.46-
2.55 (m, 1H) 2.34 (s, 3H) 2.13-2.19 (m, 1H) 2.06 (s, 3H)
1.93-2.00 (m, 1H) 1.75-1.87 (m, 2H) 1.64-1.71 (m, 1H);
13C NMR (125 MHz, CDCl3) 165.5, 164.9, 158.5, 148.1,
145.6, 138.4, 136.5, 135.6, 132.9, 131.6, 131.0, 128.7,
128.6, 128.4, 128.3, 128.0, 124.7, 111.6, 103.8, 66.3, 62.4,
57.0, 55.3, 54.9, 32.5, 30.0, 28.5, 24.1, 18.5, 18.3, 11.8
ppm; IR (film) 3292, 1716, 1614 cm-1; [R]23D +55.5, [R]23
577
+57.7, [R]23 +66.5, [R]23 +121, [R]23 +150 (c 2.1,
546
435
405
CHCl3). Anal. Calcd for C35H38BrN3O7S: C, 58.01; H,
5.29; N, 5.80. Found: C, 57.98; H, 5.42; N, 5.52.
(4aS,7S)-7-[2-(4-Br om oben zoyloxy)eth yl]-1-(4-m eth -
oxy-2,3,6-tr im eth ylben zen esu lfon ylim in o)-3-m eth -
yl-1,2,4a ,5,6,7-h exa h yd r op yr r olo[1,2-c]p yr im id in e-
18.3, 11.9 ppm; IR (film) 3290, 1712, 1614 cm-1; [R]23
D
-65.8, [R]23577 -67.5, [R]23546 -76.7, [R]23435 -117, [R]23
405
1
-128 (c 1.1, CHCl3). Anal. Calcd for C35H41N3O6S: C,
66.54; H, 6.54; N, 6.65. Found: C, 66.49; H, 6.51; N, 6.56.
Con ver sion of 28c to 24. A solution of 28c (15 mg,
20 mmol) and TFA (2 mL) was maintained for 1 h at room
temperature. The reaction was concentrated, and the
resulting crude was oil used without purification. 4-Bro-
4-ca r boxylic a cid ben zyl ester (28c): H NMR (500
MHz, CDCl3) δ 9.20 (s, 1H) 7.76 (d, J ) 8.4 Hz, 2H) 7.51
(d, J ) 8.4 Hz, 2H) 7.33-7.54 (m, 5H) 6.44 (s, 1H) 5.12-
5.23 (m, 2H) 4.36-4.44 (m, 2H) 4.27-4.29 (m, 2H) 3.80
(s, 3H) 2.65 (s, 3H) 2.56 (s, 3H) 2.46-2.51 (m, 1H) 2.29
(s, 3H) 2.02-2.10 (m, 4H) 1.75-1.82 (m, 1H) 1.48-1.62