Katritzky et al.
Da ta for (5S)-1-(ben zotr ia zolylm eth yl)-3,5-d iben zyltet-
r a h yd r o-4H-im id a zol-4-on e (14c): obtained as a mixture
of Bt1 and Bt2 isomers in 5:1 ratio, and NMR data are reported
crystals; yield 31%; mp 97-98 °C; [R]25D -29.8 (c 1.58, CHCl3);
1H NMR δ 1.88 (br s, 1H), 2.20 (s, 3H), 3.17 (dd, J ) 14.1, 4.8
Hz, 1H), 3.40 (dd, J ) 14.1, 5.4 Hz, 1H), 4.00 (t, J ) 4.6 Hz,
1H), 5.81 (s, 1H), 6.81 (d, J ) 7.0 Hz, 2H), 6.98-7.33 (m, 12H);
13C NMR δ 20.9, 36.6, 60.9, 77.2, 122.8, 127.0, 127.1, 128.8,
128.9, 129.1, 129.3, 129.9, 134.0, 135.3, 136.4, 138.5, 174.0.
Anal. Calcd for C23H22N2O: C, 80.67; H, 6.48; N, 8.18. Found:
C, 80.40; H, 6.30; N, 8.28.
Da t a for (2R,5S)-5-b en zyl-3-cycloh exyl-2-p h en ylt et -
r a h yd r o-4H-im id a zol-4-on e (16b): colorless microcrystals;
yield 69%; mp 92-93 °C; [R]25D -32.2 (c 1.81, CHCl3); 1H NMR
δ 0.87-0.99 (m, 2H), 1.07-1.28 (m, 2H), 1.43-1.61 (m, 5H),
1.65-1.70 (m, 1H), 1.99 (br s, 1H), 2.90 (dd, J ) 13.5, 7.5 Hz,
1H), 3.13 (dd, J ) 13.6, 3.9 Hz, 1H), 3.53-3.64 (m, 1H), 4.07-
4.11 (m, 1H), 5.16 (s, 1H), 7.20-7.34 (m, 10H); 13C NMR δ
25.1, 25.6, 25.7, 29.9, 30.9, 38.7, 52.8, 59.7, 75.0, 126.4, 126.5,
128.3, 128.8, 129.0, 129.7, 137.8, 141.9, 173.6. Anal. Calcd for
1
for the major Bt1 isomer; pale brown oil; yield 94%; H NMR
δ 3.04 (dd, J ) 14.0, 6.8 Hz, 1H), 3.29 (dd, J ) 14.0, 3.7 Hz,
1H), 3.87-3.90 (m, 1H), 4.09, 4.57 (AB, J ) 10.7 Hz, 2H), 4.11-
4.13 (m, 1H), 4.32 (d, J ) 5.2 Hz, 1H), 5.35 (s, 2H), 6.91-6.93
(m, 2H), 7.11-7.45 (m, 11H), 8.05 (d, J ) 8.1 Hz, 1H); 13C NMR
δ 37.4, 44.9, 62.9, 63.3, 65.1, 109.1, 120.0, 124.2, 126.8, 127.5,
127.7, 127.9, 128.5, 128.7, 130.0, 133.4, 134.9, 137.3, 145.7,
170.6.
Gen er a l P r oced u r e for th e P r ep a r a tion of 2,3,10,10a -
Tetr a h yd r oim id a zo[1,5-b]isoqu in olin -1(5H)-on es 15a -c.
Treatment of crude 14a -c with 3 equiv of AlCl3 afforded
15a -c with use of the same procedure as for the preparation
of 1a -c. The isolated yields of 15a -c were based on R-amino-
amides 10a -c.
C
22H26N2O: C, 79.00; H, 7.84; N, 8.38. Found: C, 78.55; H,
Da ta for (10a S)-2-(4-m eth ylp h en yl)-2,3,10,10a -tetr a h y-
d r oim id a zo[1,5-b]isoqu in olin -1(5H)-on e (15a ): colorless
7.99; N, 8.29.
needles; yield 82%; mp 185-186 °C; [R]25 -62.7 (c 1.66,
Da ta for (2R,5S)-3,5-d iben zyl-2-p h en yltetr a h yd r o-4H-
im id a zol-4-on e (16c): colorless needles (from hexanes/
D
CHCl3); 1H NMR δ 2.32 (s, 3H), 3.04-3.21 (m, 2H), 3.38-3.43
(m, 1H), 3.83, 4.05 (AB, J ) 14.0 Hz, 2H), 4.48 (dd, J ) 4.8,
1.6 Hz, 1H), 4.76 (d, J ) 5.0 Hz, 1H), 7.10-7.21 (m, 6H), 7.44
(d, J ) 8.5 Hz, 2H); 13C NMR δ 20.8, 29.9, 52.3, 61.4, 69.6,
119.2, 126.2, 126.6, 126.9, 129.4, 129.5, 133.3, 133.7, 134.5,
135.0, 170.9. Anal. Calcd for C18H18N2O: C, 77.67; H, 6.52; N,
10.06. Found: C, 77.28; H, 6.54; N, 10.10.
EtOAc); yield 74%; mp 128-129 °C; [R]25 -19.7 (c 1.73,
D
1
CHCl3); H NMR δ 2.15 (br s, 1H), 3.04 (AB dd, J ) 13.8, 6.9
Hz, 1H), 3.16 (AB dd, J ) 13.8, 4.2 Hz, 1H), 3.46, 5.02 (AB, J
) 14.9 Hz, 2H), 4.17 (br s, 1H), 4.96 (s, 1H), 6.85-6.87 (m,
2H), 7.14-7.36 (m, 13H); 13C NMR δ 38.1, 43.9, 59.8, 74.8,
126.7, 126.8, 127.5, 128.0, 128.5, 128.6, 129.1, 129.2, 129.8,
135.5, 137.2, 139.3, 173.6. Anal. Calcd for C23H22N2O: C, 80.67;
H, 6.48; N, 8.18. Found: C, 80.31; H, 6.63; N, 8.13.
Da ta for (10a S)-2-cycloh exyl-2,3,10,10a -tetr a h yd r oim i-
d a zo[1,5-b]isoq u in olin -1(5H )-on e (15b ): colorless micro-
crystals; yield 83%; mp 72-73 °C; [R]25D -89.8 (c 1.75, CHCl3);
1H NMR δ 1.03-1.16 (m, 1H), 1.23-1.42 (m, 4H), 1.66-1.82
(m, 5H), 2.98 (AB dd, J ) 15.6, 9.6 Hz, 1H), 3.10 (AB dd, J )
15.6, 4.8 Hz, 1H), 3.28 (dd, J ) 9.2, 4.8 Hz, 1H), 3.78, 3.96
(AB, J ) 14.1 Hz, 2H), 3.90-3.95 (m, 1H), 4.04 (dd, J ) 4.8,
2.1 Hz, 1H), 4.36 (d, J ) 4.8 Hz, 1H), 7.08-7.10 (m, 1H), 7.17-
7.20 (m, 3H); 13C NMR δ 25.2, 25.2, 25.4, 29.8, 30.2, 30.6, 49.9,
52.3, 60.9, 65.1, 126.1, 126.5, 126.8, 129.3, 133.6, 133.9, 171.3;
HRMS m/z calcd for C17H22N2O 270.1732 (M), found 270.1738.
Anal. Calcd for C17H22N2O: C, 75.52; N, 10.36. Found: C,
75.18; N, 10.32.
Gen er a l P r oced u r e for th e P r ep a r a tion of Bt In ter -
m ed ia tes 17a -c a n d 17′a . A mixture of 16a -c or 16′a (1.0
mmol), benzotriazole (0.14 g, 1.2 mmol), and formaldehyde
(37% aqueous solution, 0.12 g, 1.5 mmol) was stirred in CH3-
OH (15 mL) at 25 °C overnight. After evaporation of CH3OH,
EtOAc was added to the mixture. The organic phase was
washed with 1 M NaOH aqueous solution, brine, and water
and dried over anhydrous K2CO3. Removal of solvent in vacuo
gave essentially pure 17a and 17′a , which were purified by
recrystallization for analytical purposes. Attempt to purify
17b,c (both obtained as sticky oil) by column chromatography
(silica gel) failed, thus they were used directly for the subse-
quent reaction as crude products.
Data for (10aS)-2-ben zyl-2,3,10,10a-tetr ah ydr oim idazo-
[1,5-b]isoqu in olin -1(5H)-on e (15c): colorless prism; yield
1
78%; mp 50-51 °C; [R]25 -64.8 (c 1.66, CHCl3); H NMR δ
Da ta for (2R,5S)-1-(1H-1,2,3-ben zotr ia zol-1-ylm eth yl)-
5-ben zyl-3-(4-m eth ylp h en yl)-2-p h en yltetr a h yd r o-4H-im i-
D
3.10 (d, J ) 6.6 Hz, 2H), 3.49 (t, J ) 6.9 Hz, 1H), 3.77, 3.84
(AB, J ) 14.5 Hz, 2H), 4.05 (dd, J ) 5.2, 1.8 Hz, 1H), 4.12 (d,
J ) 5.0 Hz, 1H), 4.29, 4.65 (AB, J ) 15.3 Hz, 2H), 7.02-7.15
(m, 3H), 7.16-7.27 (m, 6H); 13C NMR δ 30.0, 44.8, 52.4, 60.4,
68.4, 126.3, 126.6, 127.0, 127.5, 127.6, 128.7, 129.2, 133.8,
134.4, 135.6, 172.3. Anal. Calcd for C18H18N2O: C, 77.67; H,
6.52; N, 10.06. Found: C, 77.50; H, 6.83; N, 10.09.
d a zol-4-on e (17a ): white needles (from EtOH); yield 89%; mp
1
153-154 °C; [R]25 -20.4 (c 1.80, CHCl3); H NMR δ 2.19 (s,
D
3H), 3.30-3.43 (m, 2H), 4.46 (br s, 1H), 5.34, 5.65 (AB, J )
13.8 Hz, 2H), 5.45 (d, J ) 2.1 Hz, 1H, NCHN), 6.84-6.97 (m,
5H), 7.08-7.32 (m, 12H), 7.98-8.01 (m, 1H); 13C NMR δ 20.8,
36.3, 60.2, 63.2, 80.1, 109.7, 119.7, 123.6, 123.9, 126.8, 127.2,
128.0, 128.5, 128.8, 129.4, 129.6, 129.8, 132.3, 132.9, 135.9,
136.0, 136.7, 145.9, 170.6. Anal. Calcd for C30H27N5O: C, 76.09;
H, 5.75; N, 14.79. Found: C, 75.74; H, 6.01; N, 14.69.
Gen er a l P r oced u r e for t h e P r ep a r a t ion of 2,3,5-
Tr isu bstitu ted -tetr a h yd r o-4H-im id a zol-4-on es 16a -c. A
mixture of R-amino-amide 10a -c (2.0 mmol), benzaldehyde
(0.27 g, 2 mmol), and p-TsOH (0.4 mmol) was refluxed in CH3-
OH (15 mL) with anhydrous Na2SO4 (3.0 g) for 12 h. After
evaporation of CH3OH in vacuo, the reaction mixture was
diluted with EtOAc. The organic phase was washed with 2 M
NaOH, water, and brine and dried over anhydrous K2CO3.
After removal of solvent in vacuo, the residue was purified by
column chromatography with hexanes/EtOAc (6:4) as an eluent
to give trans-16a , cis-16′a , and trans-16b,c.
Da ta for (2S,5S)-1-(ben zotr ia zolylm eth yl)-5-ben zyl-3-
(4-m e t h ylp h e n yl)-2-p h e n ylt e t r a h yd r o-4H -im id a zol-4-
on e (17′a ): obtained as a mixture of Bt1 and Bt2 isomers in
17:1 ratio, and NMR data are reported for the major Bt1
isomer; white prism (from EtOH); yield 85%; mp 197-198 °C;
1
[R]25 -185 (c 1.56, CHCl3); H NMR δ 2.16 (s, 3H), 3.38 (AB
D
dd, J ) 14.0, 4.4 Hz, 1H), 3.47 (AB dd, J ) 14.0, 4.4 Hz, 1H),
4.08 (br s, 1H), 5.34, 5.46 (AB, J ) 14.8 Hz, 2H), 5.82 (s, 1H,
NCHN), 6.84 (d, J ) 8.2 Hz, 2H), 6.88-6.96 (m, 4H), 7.13-
Da ta for (2R,5S)-5-ben zyl-3-(4-m eth ylp h en yl)-2-p h en -
ylt et r a h yd r o-4H -im id a zol-4-on e (16a ): yellowish micro-
7.36 (m, 4H), 7.40-7.50 (m, 7H), 8.11 (d, J ) 8.1 Hz, 1H); 13
C
crystals; yield 38%; mp 106-107 °C; [R]25 -52.5 (c 1.86,
NMR δ 20.9, 36.9, 58.9, 61.6, 77.8, 108.8, 120.2, 124.2, 124.5,
126.8, 128.0, 128.4, 128.5, 128.9, 129.3, 129.4, 130.5, 132.5,
134.0, 136.3, 136.7, 137.1, 145.6, 169.5. Anal. Calcd for
D
CHCl3); 1H NMR δ 1.70 (br s, 1H), 2.24 (s, 3H), 3.09-3.21(m,
2H), 4.13 (t, J ) 5.5 Hz, 1H), 5.55 (s, 1H), 7.03, 7.11 (AB, J )
8.5 Hz, 4H), 7.22-7.32 (m, 10H); 13C NMR δ 20.8, 38.0, 60.2,
77.1, 122.0, 126.4, 126.8, 128.5, 128.8, 128.9, 129.4, 129.8,
134.2, 135.1, 137.3, 139.4, 173.7. Anal. Calcd for C23H22N2O:
C, 80.67; H, 6.48; N, 8.18. Found: C, 80.39; H, 6.51; N, 7.94.
Da ta for (2S,5S)-5-ben zyl-3-(4-m eth ylp h en yl)-2-p h en -
ylt et r a h yd r o-4H -im id a zol-4-on e (16′a ): yellowish micro-
C
30H27N5O: C, 76.09; H, 5.75; N, 14.79. Found: C, 75.84; H,
5.96; N, 14.54.
(2R,5S)-1-(Ben zotr iazolylm eth yl)-5-ben zyl-3-cycloh exyl-
2-p h en yltetr a h yd r o-4H-im id a zol-4-on e (17b): obtained as
a mixture of Bt1 and Bt2 isomers in 10:1 ratio, and NMR data
are reported for the major Bt1 isomer; yellowish oil; yield 94%;
8228 J . Org. Chem., Vol. 67, No. 23, 2002