(dd, 1 H, J ) 2.6, 8.6 Hz), 7.01 (d, 1 H, J ) 8.6 Hz), 7.18-7.31
(m, 5 H); 13C NMR (CDCl3) δ 34.6, 36.7, 37.0, 50.4, 51.3, 51.7,
55.2, 113.3, 114.0, 127.3, 127.9, 128.3, 128.5, 131.5, 135.0, 137.1,
157.3, 172.9, 173.9.
In conclusion, the present procedure provides a con-
venient method to construct a 2-benzazepine ring which
is of interest as a Gly-Asp mimic in the RGD sequence.
It should be mentioned that the procedure could be
applied in a multigram scale and 2-benzazepine 4a was
prepared in up to 5 g in a short time. As all of the starting
materials were either commercially available or ready
to be prepared, the present method will provide a
convenient method to prepare these heterocyclic com-
pounds.
[1-(3-Meth oxyben zyl)-2-oxo-5-p h en ylp yr r olid in -3-yl]a ce-
tic a cid m eth yl ester (6): 1H NMR (270 MHz, CDCl3) δ 1.70
(td, 1 H, J ) 9.6, 13.8 Hz), 2.57 (dd, 1 H, J ) 8.9, 16.5 Hz), 2.69
(td, 1 H, J ) 6.9, 12.5 Hz), 2.87-2.95 (m, 1 H), 3.02 (dd, 1 H, J
) 4.0, 16.4 Hz), 3.47 (d, 1 H, J ) 14.2 Hz), 3.70 (s, 3 H), 3.73 (s,
3 H), 4.33 (dd, 1 H, J ) 7.2, 9.2 Hz), 5.02 (d, 1 H, J ) 14.5 Hz),
6.53 (d, 1 H, J ) 2.0 Hz), 6.58 (d, 1 H, J ) 7.6 Hz), 6.79 (dd, 1
H, J ) 2.3, 7.9 Hz), 7.12-7.19 (m, 3 H), 7.32-7.40 (m, 3 H); 13
C
NMR (CDCl3) δ 35.3, 36.2, 38.7, 44.5, 51.8, 55.2, 60.0, 113.2,
113.9, 120.9, 127.4, 128.3, 129.0, 129.5, 137.7, 140.1, 159.7, 172.3,
175.5.
Exp er im en ta l Section
P r ep a r a tion of [8-Meth oxy-3-oxo-2-(2,2,2-tr iflu or oeth yl)-
2,3,4,5-tetr a h yd r o-1H-ben zo[c]a zep in -4-yl]a cetic Acid Eth -
yl Ester (4a ). Gen er a l P r oced u r e. A solution of Bu3SnH (11.6
mL, 42.75 mmol) and AIBN (0.87 g, 5.27 mmol) in benzene (100
mL) was added to a solution of 3a (11.34 g, 25.87 mmol) in
benzene (40 mL) at refluxing temperature over 6 h. The resulting
reaction mixture was allowed to stir at the same temperature
for an additional 9 h. Benzene was removed in vacuo, and the
crude residue was passed through flash chromatography (hexane
then hexanes-ethyl acetate) to give 4a in 57% yield (5.28 g):12
2-Ben zyl-8-m et h oxy-4-m et h yl-1,2,4,5-t et r a h yd r ob en zo-
[c]a zep in -3-on e (4e): mp 88 °C; 1H NMR (CDCl3) δ 1.31 (d, 3
H, J ) 6.3 Hz), 2.88 (dd, 1 H, J ) 12.5, 16.8 Hz), 3.00 (dd, 1 H,
J ) 4.9, 16.8 Hz), 3.42 (m, 1 H, J ) 6.3 Hz), 3.71 (s, 3 H), 3.76
(d, 1 H, J ) 16.5 Hz), 4.33 (d, 1 H, J ) 14.8 Hz), 4.98 (d, 2 H, J
) 15.2 Hz), 6.36 (d, 1 H, J ) 2.6 Hz), 6.74 (dd, 1 H, J ) 2.3, 8.6
Hz), 7.01 (d, 1 H, J ) 8.6 Hz), 7.19-7.31 (m, 5 H); 13C NMR
(CDCl3) δ 18.2, 35.5, 37.7, 50.9, 51.7, 55.7, 113.6, 114.4, 127.8,
128.9, 129.8, 131.9, 135.6, 138.0, 157.6, 176.2.
(2-Bu tyl-8-m eth oxy-3-oxo-2,3,4,5-tetr a h yd r o-1H-ben zo-
1
white solid; mp 91 °C; H NMR (CDCl3) δ 1.27 (t, 3 H, J ) 7.1
1
[c]a zep in -4-yl)a cetic a cid m eth yl ester (4f): mp 69 °C; H
Hz), 2.45 (dd, 1 H, J ) 5.6, 16.8 Hz), 2.90-3.06 (m, 3 H), 3.79
(s, 3 H), 3.83-4.00 (m, 3 H), 4.15 (q, 2 H, J ) 6.9 Hz), 4.02-
4.20 (m, 1 H), 5.34 (d, 1 H, J ) 16.5 Hz), 6.61 (d, 1 H, J ) 2.3
Hz), 6.79 (dd, 1 H, J ) 2.6, 8.6 Hz), 7.034 (d, 1 H, J ) 8.6 Hz);
13C NMR (CDCl3) δ 14.6, 34.9, 37.3, 48.1 (q, J ) 34.2 Hz), 53.6,
55.5, 61.1, 114.0, 114.8, 125.5 (q, J ) 280 Hz), 128.4, 132.2, 134.5,
158.0, 172.6, 175.3. Anal. Calcd for C17H20F3NO4: C, 56.82; H,
5.61; N, 3.90. Found: C, 56.78; H, 5.61; N, 3.88.
NMR (CDCl3) δ 0.84 (t, 3 H, J ) 7.3 Hz), 1.20 (m, 2 H, J ) 7.3
Hz), 1.43 (m, 2 H, J ) 7.3 Hz), 2.40 (dd, 1 H, J ) 5.4, 16.8 Hz),
2.87 (dd, 1 H, J ) 13.2, 16.8 Hz), 3.00 (dd, 1 H, J ) 8.3, 16.5
Hz), 2.81-3.05 (m, 1 H), 3.40 (m, 1 H, J ) 7.3 Hz), 3.51 (m, 1 H,
J ) 7.3 Hz), 3.70 (s, 3 H), 3.79 (s, 3 H), 3.82 (d, 1 H, J ) 17.5
Hz), 5.21 (d, 1 H, J ) 16.5 Hz), 6.62 (d, 1 H, J ) 2.6 Hz), 6.76
(dd, 1 H, J ) 2.6, 8.2 Hz), 7.01 (d, 1 H, J ) 8.3 Hz); 13C NMR
(CDCl3) δ 13.7, 19.9, 30.3, 34.7, 36.6, 37.0, 47.7, 51.6, 52.3, 55.3,
113.0, 114.1, 128.5, 131.6, 135.6, 157.5, 173.0, 173.5.
Radical cyclization for other 3 was performed in a similar
manner.
[3-Oxo-2-(2,2,2-tr iflu or oeth yl)-2,3,4,5-tetr a h yd r o-1H-ben -
zo[c]a zep in -4-yl]a cetic a cid m eth yl ester (4g): mp 89 °C;
1H NMR (CDCl3) δ 2.47 (dd, 1 H, J ) 5.3, 16.9 Hz), 2.91-3.12
(m, 3 H), 3.71 (s, 3 H), 3.80-4.20 (m, 4 H), 5.38 (d, 1 H, J ) 16.5
Hz), 7.07-7.27 (m, 4 H); 13C NMR (CDCl3) δ 35.2, 36.4, 36.7,
47.5 (q, J ) 32.9 Hz), 51.8, 53.0, 124.2 (q, J ) 280.8 Hz), 126.2,
128.2, 128.9, 130.6, 133.0, 136.1, 172.5, 174.7. Anal. Calcd for
C15H16F3NO3: C, 57.14; H, 5.12; N, 4.44. Found: C, 57.18; H,
5.14; N, 4.48.
4-Meth yl-2-(2,2,2-tr iflu or oeth yl)-1,2,4,5-tetr a h yd r oben -
zo[c]a zep in -3-on e (4h ): 1H NMR (CDCl3) δ 1.29 (d, 3 H, J )
6.3 Hz), 2.93 (dd, 1 H, J ) 12.9, 17.5 Hz), 3.08 (dd, 1 H, J ) 4.6,
17.5 Hz), 3.47 (m, 1 H, J ) 6.3 Hz), 3.88 (qd, 1 H, J ) 8.9, 15.1
Hz), 4.02 (d, 1 H, J ) 16.8 Hz), 4.26 (qd, 1 H, J ) 8.9, 15.2 Hz),
5.27 (d, 1 H, J ) 16.5 Hz), 7.05-7.34 (m, 4 H); 13C NMR (CDCl3)
δ 17.4, 34.6, 37.8, 47.4 (q, J ) 34.3 Hz), 52.9, 124.4 (q, J ) 279.6
Hz), 125.9, 128.1, 128.8, 130.5, 133.1, 137.0, 176.3. Anal. Calcd
for C13H14F3NO: C, 60.70; H, 5.49; N, 5.44. Found: C, 60.44; H,
5.54; N, 5.40.
8-Met h oxy-4-m et h yl-2-(2,2,2-t r iflu or oet h yl)-1,2,4,5-t et -
r a h yd r oben zo[c]a zep in -3-on e (4b): mp 94 °C; 1H NMR
(CDCl3) δ 1.27 (d, 3 H, J ) 6.6 Hz), 2.84 (dd, 1 H, J ) 6.9, 17.2
Hz), 3.00 (dd, 1 H, J ) 4.3, 17.2 Hz), 3.43 (m, 1 H), 3.79 (s, 3 H),
3.83-3.99 (m, 1 H), 3.96 (d, 1 H, J ) 16.9 Hz), 4.27 (qd, 1 H, J
) 9.2, 15.8 Hz), 5.24 (d, 1 H, J ) 16.8 Hz), 6.61 (d, 1 H, J ) 2.3
Hz), 6.79 (dd, 1 H, J ) 2.3, 8.2 Hz), 7.03 (d, 1 H, J ) 8.6 Hz);
13C NMR (CDCl3) δ 17.5, 34.8, 37.0, 47.5 (q, J ) 34.8 Hz), 53.0,
55.3, 113.4, 114.2, 124.4 (q, J ) 279.9 Hz), 128. 6, 131.6, 134.1,
157.4, 176.4. Anal. Calcd for C14H16F3NO2: C, 58.53; H, 5.61;
N, 4.88. Found: C, 58.69; H, 5.68; N, 4.88.
7-Meth oxy-4-m eth yl-2-(2,2,2-tr iflu or oeth yl)-1,4-d ih yd r o-
2H-isoqu in olin -3-on e (5c): mp 77 °C; 1H NMR (CDCl3) δ 1.50
(d, 3 H, J ) 7.3 Hz), 3.56 (q, 1 H, J ) 7.3 Hz), 3.80 (s, 3 H), 4.09
(qd, 1 H, J ) 9.2, 14.8 Hz), 4.21 (qd, 1 H, J ) 9.2, 15.2 Hz), 4.48
(d, 1 H, J ) 15.5 Hz), 4.61 (d, 1 H, J ) 15.5 Hz), 6.73 (d, 1 H, J
) 2.3 Hz), 6.86 (dd, 1 H, J ) 2.6, 8.6 Hz), 7.14 (d, 1 H, J ) 8.6
Hz); 13C NMR (CDCl3) δ 16.7, 40.7, 47.19, 47.4 (q, J ) 34.2 Hz),
51.5, 55.3, 110.7, 113.5, 124.4 (q, J ) 282.0 Hz), 127.0, 129.2,
132.0, 158.4, 173.3. Anal. Calcd for C13H14F3NO2: C, 57.14; H,
5.16; N, 5.13. Found: C, 57.09; H, 5.20; N, 5.10.
4-Meth yl-2-(2,2,2-tr iflu or oeth yl)-1,4-d ih yd r o-2H-isoqu in -
olin -3-on e (5i): 1H NMR (CDCl3) δ 1.53 (d, 3 H, J ) 7.6 Hz),
3.62 (q, 1 H, J ) 7.3 Hz), 4.10 (qd, 1 H, J ) 8.9, 15.2 Hz), 4.23
(qd, 1 H, J ) 8.9, 15.2 Hz), 4.53 (d, 1 H, J ) 15.2 Hz), 4.65 (d,
1 H, J ) 15.2 Hz), 7.18-7.36 (m, 4 H); 13C NMR (CDCl3) δ 16.3,
41.4, 47.4 (q, J ) 33.0 Hz), 51.4, 124.4 (q, J ) 280.8 Hz), 125.0,
125.8, 126.6, 128.1, 130.9, 137.1, 173.1.
(2-Ben zyl-8-m eth oxy-3-oxo-2,3,4,5-tetr a h yd r o-1H-ben zo-
1
[c]a zep in -4-yl)a cetic a cid m eth yl ester (4d ): mp 93 °C; H
NMR (CDCl3) δ 2.47 (dd, 1 H, J ) 5.3,16.8 Hz), 2.94 (dd, 1 H, J
) 7.1, 8.2 Hz), 3.08 (dd, 1 H, J ) 8.6, 16.8 Hz), 2.88-3.12 (m, 1
H), 3.72 (s, 3 H), 3.73 (s, 3 H). 3.76 (d, 1 H, J ) 14.5 Hz), 3.80-
3.90 (m, 1 H), 4.33 (d, 1 H, J ) 14.8 Hz), 5.01 (d, 1 H, J ) 14.9
Hz), 5.11 (d, 1 H, J ) 16.5 Hz), 6.37 (d, 1 H, J ) 2.3 Hz), 6.74
Su p p or tin g In for m a tion Ava ila ble: Experimental pro-
cedures for the preparation of compounds 2 and 3, and
spectroscopic charts for compounds 2a -d , 3a , 4d -f, 5i, and
6. This material is available free of charge via the Internet at
http://pubs.acs.org.
(11) (a) Ishibashi, H.; Sato, T.; Ikeda, M. Synthesis 2002, 695. (b)
Gribble, G. W.; Fraser, H. L.; Badenock, J . C. Chem. Commun. 2001,
805.
(12) Callman, J . F.; Cousins, R. D.; Keenan, R. M.; Kwon, C.; Miller,
W. H.; Uzinkans, I. N. U.S. Patent WO 98/14192.
J O030052H
4998 J . Org. Chem., Vol. 68, No. 12, 2003