2736 J . Org. Chem., Vol. 63, No. 8, 1998
Notes
(1 mmol). Trifluoroacetic acid (2 mmol) was then slowly added
over 15 min, and the reaction mixture was stirred for 1-2 h.
Saturated aqueous sodium hydrogen carbonate (5 mL) was
added, and the organic phase was separated. The aqueous phase
was extracted with dichloromethane (2 × 50 mL); the organic
extracts were combined, washed with saturated aqueous sodium
chloride (25 mL), and dried over magnesium sulfate. Removal
of the solvent under reduced pressure left a residue which was
purified by column chromatography on silica gel using the
developer indicated. The following compounds were prepared
in this manner.
25 (the major, crystalline diastereomer) and formaldehyde, was
obtained as a tan solid in 70% yield after chromatography
(dichloromethane-ethanol, 98:2): mp 90 °C (dichloromethane-
ethanol); 1H NMR (300 MHz, CDCl3) δ 1.09 (t, 3H, J ) 7.1 Hz),
1.55 (s, 3H), 3.97 (q, 2H, J ) 7.1 Hz), 4.02 (d, 1H, J ) 16.4 Hz),
4.76 (s, 1H), 4.86 (d, 1H, J ) 16.4 Hz), 6.20 (d, 1H, J ) 3.3 Hz),
7.08 (d, 1H, J ) 3.3 Hz), 7.50 (t, 2H, J ) 7.7 Hz), 7.61 (t, 1H, J
) 7.7 Hz), 7.78 (d, 2H, J ) 7.7 Hz); 13C NMR (75 MHz, CDCl3)
δ 13.6, 41.3, 61.1, 61.6, 65.0, 108.8, 121.3, 123.6, 126.7, 126.9,
130.2, 133.5, 138.8, 166.5; IR (KBr) 3400, 1733 cm-1; CIMS m/z
365 (MH)+. Anal. Calcd for C17H20N2O5S: C, 56.03; H, 5.53; N,
7.69; S, 8.80. Found: C, 56.32; H, 5.53; N, 7.22; S, 8.67.
Gen er a l P r oced u r e for th e Ar om a tiza tion of th e Tet-
r a h yd r oa za in d ole Der iva tives 9, 18, 21, a n d 26. A solution
of the tetrahydroazaindole (0.1-1 mmol) in xylene (25 mL)
containing 10% palladium on carbon (25-300 mg) was refluxed
for 12 h. The reaction mixture was cooled and filtered through
a pad of Celite, and the filter pad was washed copiously with
ethanol. The filtrate and washings were combined and evapo-
rated to dryness under reduced pressure, leaving the crude
product which was purified as indicated below.
Met h yl (R,S)-1-(Ben zen esu lfon yl)-4,5,6,7-t et r a h yd r o-
p yr r olo[2,3-c]p yr id in e-5-ca r boxyla te (9). Compound 9, pre-
pared from 8 and formaldehyde as described above, was obtained
as a white solid in 52% yield after chromatography (dichlo-
romethane-ethanol, 98:2): mp 65 °C (dichloromethane); 1H
NMR (250 MHz, CDCl3) δ 2.40 (br s, 1H, exchangeable with
D2O), 2.63 (dd, 1H, J ) 9.4 and 15.6 Hz), 2.81 (dd, 1H, J ) 4.8
and 15.6 Hz), 3.61 (dd, 1H, J ) 4.8 and 9.4 Hz), 3.73 (s, 3H),
4.01 (d, 1H, J ) 16.4 Hz), 4.24 (d, 1H, J ) 16.4 Hz), 6.13 (d, 1H,
J ) 3.3 Hz), 7.15 (d, 1H, J ) 3.3 Hz), 7.50 (t, 2H, J ) 7.7 Hz),
7.61 (t, 1H, J ) 7.7 Hz), 7.78 (d, 2H, J ) 7.7 Hz); 13C NMR (75
MHz, CDCl3) δ 26.4, 42.1, 52.6, 54.9, 112.6, 120.6, 121.6, 126.8,
Met h yl 1-(Ben zen esu lfon yl)p yr r olo[2,3-c]p yr id in e-5-
ca r boxyla te (10a ). This was prepared from 9 (56 mg, 0.18
mmol) and palladium on carbon (20 mg) as described above. The
crude product was purified by crystallization in dichloromethane,
129.2, 129.7, 134.1, 138.9, 172.3; IR (KBr) 3330, 1738 cm-1
;
HRCIMS calcd for C15H17N2O4S m/z 321.0909, found 321.0886.
Anal. Calcd for C15H16N2O4S·0.8H2O: C, 53.82; H, 5.30; N, 8.37;
S, 9.58. Found: C, 53.48; H, 4.76; N, 8.19; S, 9.57.
1
affording 10a as a white powder in 74% yield: mp 150 °C; H
NMR (200 MHz, CDCl3) δ 4.03 (s, 3H), 6.82 (d, 1H, J ) 3.6 Hz),
Eth yl (4S,5S)- a n d (4R,5R)-1-(Ben zen esu lfon yl)-4-h y-
d r oxy-4,5,6,7-tetr a h yd r op yr r olo[2,3-c]p yr id in e-5-ca r box-
yla te (18). Compound 18, prepared from 14 and formaldehyde
as described above, was obtained as a white powder in 79% yield
after chromatography (dichloromethane-ethanol, 95:5): mp 116
7.45 (t, 2H, J ) 7.7 Hz), 7.60 (t, 1H, J ) 7.7 Hz), 7.80 (d, 1H, J
) 3.6 Hz), 7.98 (d, 2H, J ) 7.7 Hz), 8.41 (s, 1H), 9.46 (s, 1H); 13
C
NMR (50 MHz, CDCl3) δ 53.2, 108.7, 118.9, 127.1, 129.8, 130.7,
132.9, 134.8, 135.5, 136.8, 137.5, 141.5, 165.4; IR (KBr) 1732
cm-1; EIMS m/z 316 (M)+. Anal. Calcd for C15H12N2O4S: C,
56.95; H, 3.82; N, 8.86; S, 10.13. Found: C, 56.92; H, 4.09; N,
8.81; S, 10.15.
1
°C (ethanol); H NMR (250 MHz, CDCl3) δ 1.24 (t, 3H, J ) 7.1
Hz), 2.40 (br s, 2H, exchangeable with D2O), 3.47 (d, 1H, J )
6.2 Hz), 4.02 (d, 1H, J ) 16.4 Hz), 4.22 (q, 2H, J ) 7.1 Hz), 4.23
(d, 1H, J ) 16.4 Hz), 4.80 (d, 1H, J ) 6.2 Hz), 6.37 (d, 1H, J )
3.3 Hz), 7.18 (d, 1H, J ) 3.3 Hz), 7.50 (t, 2H, J ) 7.7 Hz), 7.61
(t, 1H, J ) 7.7 Hz), 7.78 (d, 2H, J ) 7.7 Hz); 13C NMR (75 MHz,
CDCl3) δ 14.1, 41.8, 61.6, 62.1, 65.5, 111.2, 121.8, 124.1, 126.8,
Eth yl 1-(Ben zen esu lfon yl)p yr r olo[2,3-c]p yr id in e-5-ca r -
boxyla te (10b). This was prepared from 18 (39 mg, 0.11 mmol)
and palladium on carbon (35 mg) as described above. The crude
product was purified by crystallization in ethyl acetate-heptane,
affording 10b as pale-yellow needles in 95% yield: mp 152-
128.4, 129.6, 134.1, 139.0, 171.6; IR (KBr) 3330, 1720 cm-1
;
1
153 °C; H NMR (250 MHz, CDCl3) δ 1.44 (t, 3H, J ) 7.1 Hz),
CIMS m/z 351 (MH)+. Anal. Calcd for C16H18N2O5S·0.1H2O: C,
54.57; H, 5.21; N, 7.55; S, 9.10. Found: C, 54.57; H, 5.41; N,
7.77; S, 8.91.
4.46 (q, 2H, J ) 7.1 Hz), 6.80 (d, 1H, J ) 3.6 Hz), 7.45 (t, 2H, J
) 7.7 Hz), 7.56 (t, 1H, J ) 7.7 Hz), 7.78 (d, 1H, J ) 3.6 Hz),
7.98 (d, 2H, J ) 7.7 Hz), 8.40 (s, 1H), 9.40 (s, 1H); 13C NMR (75
MHz, CDCl3) δ 14.4, 61.9, 108.7, 118.8, 127.0, 129.8, 130.7, 132.9,
Eth yl (4S,5R)- a n d (4R,5S)-1-(Ben zen esu lfon yl)-4-h y-
d r oxy-4,5,6,7-tetr a h yd r op yr r olo[2,3-c]p yr id in e-5-ca r box-
yla te (19). Compound 19, prepared from 15 and formaldehyde
as described above, was obtained as a white solid in 78% yield
after chromatography (dichloromethane-ethanol, 98:2): mp 86
134.8, 135.5, 136.8, 137.5, 141.5, 165.4; IR (KBr) 1714 cm-1
;
EIMS m/z 330 (M)+. Anal. Calcd for C16H14N2O4S: C, 58.17;
H, 4.27; N, 8.48; S, 9.70. Found: C, 58.04; H, 4.36; N, 8.47; S,
9.77.
1
°C (ethanol); H NMR (250 MHz, CDCl3) δ 1.24 (t, 3H, J ) 7.1
Eth yl 1-(Ben zen esu lfon yl)-7-m eth ylp yr r olo[2,3-c]p yr i-
d in e-5-ca r boxyla te (22). This was prepared from 21 (40 mg,
0.11 mmol) and palladium on carbon (35 mg) as described above.
The crude product was purified by crystallization in dichlo-
romethane-hexane, affording compound 22 as a white solid in
96% yield: mp 152 °C; 1H NMR (200 MHz, CDCl3) δ 1.43 (t,
3H, J ) 7.1 Hz), 2.88 (s, 3H), 4.46 (q, 2H, J ) 7.1 Hz), 6.84 (d,
1H, J ) 3.7 Hz), 7.46 (t, 2H, J ) 7.7 Hz), 7.59 (t, 1H, J ) 7.7
Hz), 7.67 (t, 2H, J ) 7.7 Hz), 8.06 (d, 1H, J ) 3.7 Hz), 8.24 (s,
1H); 13C NMR (75 MHz, CDCl3) δ 14.5, 25.3, 62.0, 108.0, 117.1,
126.6, 129.8, 133.1, 133.9, 134.5, 139.0, 139.2, 140.9, 145.6, 165.3;
IR (KBr) 1735 cm-1; CIMS m/z 345 (MH)+. Anal. Calcd for
Hz), 2.40 (br s, 2H, exchangeable with D2O), 3.44 (d, 1H, J )
2.3 Hz), 3.83 (d, 1H, J ) 16.6 Hz), 4.19 (d, 1H, J ) 16.6 Hz),
4.20 (q, 2H, J ) 7.1 Hz), 4.70 (d, 1H, J ) 2.3 Hz), 6.27 (d, 1H,
J ) 3.3 Hz), 7.14 (d, 1H, J ) 3.3 Hz), 7.50 (t, 2H, J ) 7.7 Hz),
7.61 (t, 1H, J ) 7.7 Hz), 7.78 (d, 2H, J ) 7.7 Hz); 13C NMR (75
MHz, CDCl3) δ 14.1, 42.8, 61.3, 61.4, 63.4, 111.8, 121.4, 124.0,
126.7, 129.5, 129.6, 134.1, 138.6, 170.8; IR (KBr) 3329, 2983,
1742 cm-1
;
CIMS m/z 351 (MH)+. Anal. Calcd for
C
16H18N2O5S·1.2C2H5OH: C, 54.28; H, 6.26; N, 6.91; S, 7.90.
Found: C, 54.13; H, 6.15; N, 6.97; S, 8.19.
Eth yl (4R,5R,7S-) a n d (4S,5S,7R)-1-(Ben zen esu lfon yl)-
4-h yd r oxy-7-m et h yl-4,5,6,7-t et r a h yd r op yr r olo[2,3-c]p yr i-
d in e-5-ca r boxyla te (21). Compound 21, prepared from 14 and
acetaldehyde as described above, was obtained as a white solid
in 82% yield after chromatography (dichloromethane-ethanol,
98:2): mp 80 °C (ethanol); 1H NMR (300 MHz, CDCl3) δ 1.29 (t,
3H, J ) 7.2 Hz), 1.54 (d, 3H, J ) 6.4 Hz), 3.67 (d, 1H, J ) 7.8
Hz), 4.22 (q, 2H, J ) 7.2 Hz), 4.44 (q, 1H, J ) 6.4 Hz), 4.74 (d,
1H, J ) 7.8 Hz), 6.38 (d, 1H, J ) 3.4 Hz), 7.16 (d, 1H, J ) 3.4
Hz), 7.48 (t, 2H, J ) 7.7 Hz), 7.59 (t, 1H, J ) 7.7 Hz), 7.72 (d,
2H, J ) 7.7 Hz); 13C NMR (75 MHz, CDCl3) δ 13.5, 21.4, 46.5,
57.4, 60.9, 66.5, 111.7, 123.3, 124.6, 126.5, 129.5, 134.0, 134.6,
139.2, 172.4; IR (KBr) 3325, 1735 cm-1; CIMS m/z 365 (MH)+.
Anal. Calcd for C17H20N2O5S·0.25H2O: C, 55.35; H, 5.60; N, 7.59;
S, 8.69. Found: C, 55.25; H, 5.63; N, 7.39; S, 8.79.
C
17H16N2O4S: C, 59.29; H, 4.68; N, 8.13; S, 9.31. Found: C,
59.51; H, 4.91; N, 8.31; S, 9.17.
Eth yl 1-(Ben zen esu lfon yl)-4-m eth ylp yr r olo[3,4-c]p yr i-
d in e-5-ca r boxyla te (27). This was prepared from 26 (352 mg,
0.97 mmol) and palladium on carbon (310 mg) as described
above. The crude product was purified by column chromatog-
raphy on silica gel (dichloromethane) affording compound 27 as
pale-yellow needles in 88% yield: mp 149 °C (hexane); 1H NMR
(250 MHz, CDCl3) δ 1.30 (t, 3H, J ) 7.2 Hz), 2.58 (s, 3H), 4.31
(q, 2H, J ) 7.2 Hz), 6.69 (d, 1H, J ) 3.6 Hz), 7.30 (t, 2H, J ) 7.7
Hz), 7.45 (t, 1H, J ) 7.7 Hz), 7.60 (d, 1H, J ) 3.6 Hz), 7.78 (d,
2H, J ) 7.7 Hz), 9.10 (s, 1H); 13C NMR (62.5 MHz, CDCl3) δ
14.5, 15.8, 61.7, 107.5, 127.0, 129.4, 129.7, 131.8, 132.9, 134.7,
137.6, 137.9, 140.2, 166.5; IR (KBr) 1725 cm-1; EIMS m/z 345
(MH)+. Anal. Calcd for C17H16N2O4S·0.1H2O: C, 58.83; H, 4.73;
N, 8.07; S, 9.24. Found: C, 58.99; H, 4.68; N, 8.10; S, 9.25.
Eth yl (4RS,5RS)-1-(Ben zen esu lfon yl)-4-h yd r oxy-4-m eth -
y l-4,5,6,7-t e t r a h y d r o p y r r o lo [2,3-c]p y r id in e -5-c a r b o x -
yla te (26). Compound 26, prepared as described above from