Snider and Zeng
) 7.9), 7.45 (d, 1, J ) 7.9), 5.51 (br d, 1, J ) 6.1, NH), 5.30 (d,
1, J ) 12.2), 5.10 (d, 1, J ) 12.2), 4.47 (m, 1), 3.90-3.79 (m,
1), 2.90-2.78 (m, 1), 2.36-2.27 (m, 1), 2.10-1.93 (m, 3), 0.96
(br d, 3, J ) 6.7); 13C NMR (major rotamer) 173.5, 168.8, 154.2,
153.8, 136.0, 135.7, 135.4, 130.8, 128.8 (3 C),128.7 (2 C), 127.2,
125.6, 116.2, 95.0, 89.6, 83.6, 74.8, 68.4, 62.3, 51.8, 40.0, 35.2,
24.1, 23.5, 22.0; 13C NMR (minor rotamer, partial) 129.6, 129.1,
127.4, 125.1, 116.7, 89.9, 63.0, 51.4, 37.9, 22.3; IR (KBr) 3333,
1797, 1728, 1710, 1678, 1608. Anal. Calcd for C28H28Cl3N3O7:
C, 53.82; H, 4.52; N, 6.72. Found: C, 54.06; H, 4.50; N, 6.52.
An ilin e 51. To a solution of 43b (200 mg, 0.32 mmol) in
acetic acid (3.0 mL) was added zinc dust (600 mg). The mixture
was stirred at room temperature for 30 min. The zinc dust
was filtered off and the filtrate was concentrated. The residue
was dissolved in EtOAc (10 mL), which was washed with
saturated NaHCO3 solution and brine, dried (Na2SO4), and
evaporated under reduced pressure to give the crude amine.
13C NMR (minor rotamer, partial) 171.2, 139.3, 135.0, 133.4,
131.2, 129.5, 119.2, 91.7, 84.2, 24.5; IR (KBr) 3347 (br), 1794,
1707, 1647, 1602. Anal. Calcd for C50H47N5O9: C, 69.67; H,
5.50; N, 8.12. Found: C, 69.44; H, 5.41; N, 7.92.
Im in oben zoxa zin e fr om 52. To a solution of Ph3P (78 mg,
0.3 mmol, 2.0 equiv) in dry CH2Cl2 (5 mL) was added a Br2
solution in CH2Cl2 (1.0 M, 0.29 mmol, 1.95 equiv) under N2.
The resulting solution was stirred at room temperature for
15 min, and Et3N (0.10 mL, 3 equiv) and 52 (130 mg, 0.15
mmol) were added. The resulting mixture was stirred at room
temperature for 15 min and concentrated. The residue was
shaken with anhydrous benzene (5 mL) and the triethylamine
hydrobromide was filtered off. The filtrate was concentrated
to give a light brown residue. Flash chromatography on silica
gel (30:1 CH2Cl2/EtOAc) gave 98 mg (77%) of the iminoben-
zoxazine as a light-yellow solid: mp 129-131 °C; [R]D +86.9
(c 0.17, CHCl3); 1H NMR (3:1 mixture of rotamers, major
rotamer) 8.13 (d, 1, J ) 8.0), 7.78-7.72 (m, 2), 7.68-7.56 (m,
3), 7.56-7.48 (m, 2), 7.48-7.23 (m, 13), 6.03 (s, 1), 5.76 (d, 1,
J ) 8.5, NH), 5.40 (br d, 1, J ) 12.2), 5.21 (d, 1, J ) 12.2),
5.02 (dd, 1, J ) 9.2, 7.9), 4.66-4.53 (m, 2), 4.44-4.31 (m, 2),
4.27-4.16 (m, 1), 2.99 (dd, 1, J ) 13.8, 9.2), 2.22 (dd, 1, J )
13.8, 7.9), 2.16-1.75 (m, 3), 1.62 (br d, 3, J ) 6.7), 0.93 (br d,
To a mixture of the crude amine and EDAC (150 mg, 0.76
mmol) in MeCN (2 mL) was added anthranilic acid (102 mg,
0.74 mmol) in several portions over 60 min at room temper-
ature with stirring. The reaction mixture was stirred for an
additional 20 min, and concentrated under reduced pressure.
The residue was dissolved in CH2Cl2 (10 mL), which was
washed with water and saturated NaHCO3, dried (Na2SO4),
and concentrated. Flash chromatography on silica gel (50:1
CH2Cl2/EtOAc) gave 154 mg (85%) of aniline 51 as a white
1
3, J ) 6.7), 0.83 (br d, 3, J ) 6.7); H NMR (minor rotamer,
partial) 7.93 (d, 1, J ) 8.0), 7.78 (d, 2, J ) 8.0), 5.98 (s, 1),
5.86 (d, 1, J ) 8.5, NH), 5.45 (d, 1, J ) 12.2), 5.30 (m, 1), 4.50
(m, 1), 4.19 (m, 1), 2.90 (m, 1), 2.12 (m, 1), 2.16-1.75 (m, 3),
1.58 (br d, 3, J ) 6.7), 0.98 (br d, 3, J ) 6.7), 0.85 (br d, 3, J
) 6.7); 13C NMR (major rotamer) 174.4, 169.0, 159.4, 155.7,
154.2, 149.7, 143.8 (2 C), 141.3 (2 C), 136.1, 135.2, 133.8, 130.7,
129.2, 128.8, 128.5 (2 C), 128.5 (2 C), 127.9, 127.7 (2 C), 127.1,
127.0 (2 C), 126.4, 126.2, 125.9, 125.4, 125.2 (2 C), 124.9, 119.9
(2 C), 119.0, 116.2, 90.2, 83.6, 68.2, 67.0, 55.4, 49.1, 47.1, 40.0,
38.0, 24.1, 23.5, 22.0, 19.4; 13C NMR (minor rotamer, partial)
144.0, 143.2, 141.2 (2 C), 134.0, 120.0 (2 C), 119.0, 118.4, 115.0,
89.9, 83.1, 72.2, 68.0, 62.9, 54.8, 49.4, 46.7, 37.5, 22.3, 19.2;
IR (KBr) 3413 (br), 1793, 1725, 1717, 1676, 1654, 1607; HRMS
1
solid: mp 191-194 °C; [R]D +176.6 (c 0.24, CHCl3); H NMR
(5:1 mixture of rotamers) 8.00 (d, 1, J ) 7.9), 7.49 (d, 1, J )
8.0), 7.45-7.36 (m, 5), 7.37 (td, 1, J ) 8.0, 1.0), 7.29 (d, 1, J )
8.0), 7.25 (t, 1, J ) 8.0), 7.17 (t, J ) 8.0), 6.74 (d, 1, J ) 6.7,
NH), 6.66-6.56 (m, 2), 5.95 (br, 1), 5.57 (br, 2, NH), 5.27 (d, 1,
J ) 12.2), 5.18 (d, 1, J ) 12.2), 4.48-4.00 (m, 1), 4.16 (m, 1),
2.74 (dd, 1, J ) 14.0, 10.4), 2.29 (dd, 1, J ) 14.0, 9.1), 2.01-
1
1.73 (m, 3), 0.93 (br d, 3, J ) 6.7), 0.85 (br d, 3, J ) 6.7); H
NMR (minor rotamer, partial) 7.91 (d, 1, J ) 8.0), 7.45 (d, 1,
J ) 8.0), 6.78 (d, 1, J ) 6.7, NH), 6.63-6.52 (m, 2), 5.93 (s, 1),
5.35 (d, 1, J ) 12.2), 5.07 (d, 1, J ) 12.2), 4.39 (m, 1), 3.98 (m,
1), 2.83 (dd, 1, J ) 13.4, 9.8), 2.50-2.40 (m, 1), 2.14-1.96 (m,
3), 0.98 (d, 3, J ) 6.7); 13C NMR (major rotamer) 174.6, 168.95,
168.90, 154.1, 149.2, 136.0, 135.6, 132.9, 130.6, 129.5, 128.70
(2 C), 128.68 (2 C), 128.5, 127.4, 127.2, 126.1, 117.4, 116. 5,
116.1, 113.8, 89.7, 83.7, 68.3, 62.2, 51.3, 39.9, 35.1, 24.1, 23.5,
22.0; 13C NMR (minor rotamer, partial) 174.1, 165.9, 128.9,
125.7, 113.8, 90.1, 64.0, 51.0, 37.9, 35.6, 24.2, 22.3; IR (KBr)
3460 (br, NH), 3358 (br, NH), 1788, 1702, 1642, 1610.
(CI) calcd for C50H46N5O8 (MH+) 844.3346, found 844.3378.
+
N-19-Cbz-fu m iqu in a zolin e I (53). To a solution of the
iminobenzoxazine (84 mg, 0.10 mmol) in dry EtOAc (0.5 mL)
was added dry piperidine (0.1 mL, 10 equiv). The resulting
mixture was stirred at room temperature for 10 min, and
concentrated under reduced pressure to the give crude ami-
dine, which was dissolved in dry MeCN (4 mL). The solution
was refluxed for 2 h, cooled, and concentrated to give a light
red residue. Flash chromatography on silica gel (5:1 CH2Cl2/
EtOAc) gave 43 mg (70%) of 53 as a white solid: mp 161-162
°C; [R]D -21.8 (c 0.25, CHCl3); 1H NMR (3:1 mixture of
rotamers, major rotamer) 8.20 (d, 1, J ) 7.9), 7.75 (t, 2, J )
7.9), 7.69 (d, 1, J ) 7.9), 7.48 (d, 1, J ) 7.9), 7.47 (d, 1, J )
7.9), 7.43-7.32 (m, 6), 7.03 (t, 1, J ) 7.9), 6.71 (s, 1, NH), 5.74
(s, 1), 5.59 (dd, 1, J ) 7.7, 5.5), 5.24 (s, 2), 4.59 (q, 1, J ) 6.7),
4.53 (m, 1), 4.30 (s, 1, OH), 2.29 (dd, 1, J ) 14.6, 7.7), 2.20
(dd, 1, J ) 14.6, 5.5), 2.16-2.05 (m, 1), 2.00-1.79 (m, 2), 1.68
Dia m id e 52. To a solution of aniline 51 (125 mg, 0.22 mmol)
and EDAC (93 mg, 0.48 mmol) in MeCN (2 mL) was added
N-Fmoc-L-alanine (150 mg, 0.48 mmol). The resulting mixture
was stirred at room temperature for 1.5 h and concentrated.
The residue was dissolved in CH2Cl2 (10 mL), which was
washed with water and saturated NaHCO3, dried (Na2SO4),
and concentrated. Flash chromatography on silica gel (20:1
CH2Cl2/EtOAc) gave 165 mg (87%) of 52 as a white solid: mp
141-143 °C; [R]D +145.3 (c 0.22, CHCl3); 1H NMR (10:1
mixture of rotamers, major rotamer) 11.25 (br s, 1, NH), 8.38
(br d, 1, J ) 7.9), 8.01 (d, 1, J ) 8.0), 7.72 (d, 2, J ) 8.0), 7.70-
7.61 (m, 2), 7.53-7.43 (m, 3), 7.42-7.30 (m, 8), 7.30-7.17 (m,
3), 7.03 (t, 1, J ) 8.0), 5.91 (br s, 1), 5.79 (br d, 1, J ) 7.1,
NH), 5.23 (d, 1, J ) 12.2), 5.17 (d, 1, J ) 12.2), 4.46 (m, 1),
4.43-4.26 (m, 4), 4.18 (dd, 1, J ) 11.7, 9.4), 2.73 (dd, 1, J )
13.8, 11.7), 2.25 (dd, 1, J ) 13.8, 9.4), 1.95-1.72 (m, 3), 1.51
(br d, 3, J ) 6.7), 0.91 (br d, 3, J ) 6.7), 0.83 (br d, 3, J ) 6.7);
1H NMR (minor rotamer, partial) 11.07 (br s, 1, NH), 8.42 (br
d, 1, J ) 7.9), 7.89 (d, 1, J ) 8.0), 5.84 (br s, 1), 5.74 (br d, 1,
J ) 7.1, NH), 5.35 (d, 1, J ) 12.2), 4.99 (d, 1, J ) 12.2), 4.09
(m, 3), 4.02 (m, 1), 2.87 (m, 1), 2.03 (m, 1), 1.37 (br, 3), 0.95
(br d, 3, J ) 6.7), 0.81 (br d, 3, J ) 6.7); 13C NMR (major
rotamer) 175.0, 171.0, 168.85, 168.79, 155.9, 154.2, 144.0, 143.6
(2 C), 141.2 (2 C), 139.0, 136.1, 135.7, 135.4, 133.2, 130.9, 128.8
(2 C), 128.6 (3 C), 127.6 (2 C), 127.0 (2 C), 126.8, 125.9, 125.3,
125.1 (2 C), 123.3, 121.7, 119.9 (2 C), 116.2, 90.2, 83.6, 68.3,
67.1, 62.2, 51.7 (2 C), 47.0, 40.0, 34.7, 24.1, 23.5, 22.0, 19.0;
1
(br d, 3, J ) 6.7), 0.93 (d, 3, J ) 6.7), 0.85 (d, 3, J ) 6.7); H
NMR (minor rotamer, partial) 8.26 (d, 1, J ) 7.9), 7.82 (t, 1, J
) 7.9), 7.74 (t, 1, J ) 7.9), 7.18 (t, 1, J ) 7.9), 7.14 (t, 1, J )
7.9), 6.65 (s, 1, NH), 5.85 (s, 1), 5.22 (d, 1, J ) 12.2), 5.09 (d,
1, J ) 12.2), 4.64 (br, 1), 4.35 (s, 1, OH), 1.70 (br d, 3, J ) 6.7),
1.02 (d, 3, J ) 6.7), 0.90 (d, 3, J ) 6.7); 13C NMR (major
rotamer) 169.2, 167.3, 160.8, 154.9, 151.2, 146.7, 136.5, 135.5,
135.2, 134.6, 129.8, 128.7 (2 C), 128.6 (3 C), 127.32, 127.26,
127.1, 126.2, 125.4, 120.4, 116.5, 86.7, 81.0, 68.3, 62.9, 52.3,
49.4, 39.9, 35.5, 24.2, 23.6, 22.1, 17.9; 13C NMR (minor rotamer,
partial) 168.8, 168.2, 161.3, 152.5, 150.5, 146.8, 137.1, 135.0,
130.1, 128.7, 128.5, 127.9, 127.8, 127.6, 127.5, 126.4, 120.1,
116.7, 86.4, 81.2, 68.0, 63.0, 52.3, 49.1, 38.3, 37.1, 22.3, 17.2;
IR (KBr) 3460 (br), 3285 (br), 1701, 1686, 1654, 1607. Anal.
Calcd for C35H35N5O6‚H2O: 65.72; H, 5.79; N, 10.95. Found:
C, 65.48; H, 5.52; N, 10.71.
F u m iqu in a zolin e I (9). To a solution of 53 (29 mg, 0.047
mmol) in MeOH (2 mL) was added 5% Pd/C (15 mg). The
560 J . Org. Chem., Vol. 68, No. 2, 2003