Convenient synthesis of 2-benzazepines via radical cyclization

Article abstract of DOI:10.1021/jo030052h

Synthesis of 2-benzazepines was readily achieved via 7-endo radical cyclization of N-o-bromobenzylitaconamides or N-o-bromobenzylmethacrylamides which were prepared in two steps from commercially available benzaldehydes, amines, and α,β-unsaturated acids.

Full text of DOI:10.1021/jo030052h

TABLE 1. P r ep a r a tion of P r ecu r sor s 3
Con ven ien t Syn th esis of 2-Ben za zep in es
via Ra d ica l Cycliza tion
entry R1
R2
2
yielda (%)
R3
3
yielda (%)
1
2
3
4
5
6
7
8
9
MeO CF3 2a
MeO CF3 2a
MeO CF3 2a
87
87
87
83
83
77
84
84
84
CH2CO2Et 3a
77
81
84
78
80
79
80
79
75
Akio Kamimura,*,† Yohei Taguchi,‡ Yoji Omata,† and
Masahiko Hagihara‡
Me
H
3b
3c
MeO Ph
MeO Ph
2b
2b
CH2CO2Me 3d
Me 3e
CH2CO2Me 3f
CH2CO2Me 3g
Department of Applied Chemistry, Faculty of Engineering,
Yamaguchi University, Ube 755-8611 J apan, and
Ube Laboratory, Ube Industries Ltd., Ube 755-8633 J apan
MeO C3H7 2c
H
H
H
CF3 2d
CF3 2d
CF3 2d
Me
H
3h
3i
ak10@yamaguchi-u.ac.jp
Received February 13, 2003
a
Isolated yield.
SCHEME 1
Abstr a ct: Synthesis of 2-benzazepines was readily achieved
via 7-endo radical cyclization of N-o-bromobenzylitacona-
mides or N-o-bromobenzylmethacrylamides which were
prepared in two steps from commercially available benzal-
dehydes, amines, and R,â-unsaturated acids.
Integrins are recognized as pivotal proteins that play
a key role in cell-cell adhesion, signaling, and apotosis.1
Due to their biological importance, searching for a novel
antagonist of integrins has been of interest to medicinal
chemists because it is a promising candidate for a new
drug. RGD sequence is the most well-known peptide
sequence that interacts with Rvâ3 integrin and acts as
its antagonist. Recently, it has been reported that 2-ben-
zazepine derivatives work as a non-peptide mimic for the
RGD sequence,2 and their binding site has been inves-
tigated with use of trifluoromethyl-substituted 2-benza-
zepines.3 So far, however, the preparation of 2-benza-
zepines requires relatively long synthetic steps, and so
development of a shorter, more efficient preparation has
been desired.2 Elaboration of medium-sized heterocyclic
rings sometimes poses a challenging problem in organic
synthesis.4 Radical cyclization has been used as a power-
ful method for the preparation of carbocyclic or hetero-
cyclic compounds.5 In this paper, we report a convenient
three-step synthesis of 2-benzazepine derivatives from
commercially available aromatic aldehydes, amines, and
R,â-unsaturated acids. The key reaction of the present
procedure is a 7-endo-mode radical cyclization to R,â-
unsaturated amides.6 A multigram scale of preparation
was also accomplished through this method.
Preparation of cyclization precursors 3 was carried out
through the reductive amination and subsequent acyla-
tion reaction with acyl halide (Scheme 1).7 The results
are summarized in Table 1. R,â-Unsaturated amides 3
were prepared in good yields.
Conversion of 3a into 2-benzazepine 4a was attempted.
Initially, 3a was exposed under the standard Heck
reaction conditions,8 but no 2-benzazepine 4a was ob-
served in the reaction mixture.6d,e Treatment of 3a with
Bu3SnH, on the other hand, induced a 7-endo radical
cyclization to give the desired 4a along with small
amounts of reduced product (Scheme 2). The results are
summarized in Table 2.
A mixture of Bu3SnH, AIBN, and 3a in toluene at 110
°C gave 4a in 39% yield (Table 2, entry 1). The slow-
addition technique improved the yield of 4a to 47% (Table
2, entry 2). The reaction performed at 0 °C with photo-
initiation decreased the yield of 4a ; this might be due to
† Yamaguchi University.
‡ Ube Industries Ltd.
(1) (a) Haubner, R.; Finsinger, D.; Kessler, H. Angew. Chem., Int.
Ed. Engl. 1997, 36, 1374. (b) Gottschalk, K.-E.; Kessler, H. Angew.
Chem., Int. Ed. 2002, 41, 3767.
(2) Miller, W. H.; Alberts, D. P.; Bhatnagar, P. K.; Bondinell, W.
E.; Callahan, J . F.; Calvo, R. R.; Cousins, R. D.; Erhard, K. F.;
Heerding, D. A.; Keenan, R. M.; Kwon, C.; Manley, P. J .; Newlander,
K. A.; Ross, S. T.; Samanen, J . M.; Uzinskas, I. N.; Venslavsky, J . W.;
Yuan, C. C.-K.; Haltiwanger, R. C.; Gowen, M.; Hwang, S.-M.; J ames,
I. E.; Lark, M. W.; Rieman, D. J .; Stroup, G. B.; Azzarano, L. M.;
Salyers, K. L.; Smith, B. R.; Ward, K. W.; J ohanson, K. O.; Huffman,
W. F. J . Med. Chem. 2000, 43, 22.
(6) (a) Sato, T.; Ishida, S.; Ishibashi, H.; Ikeda, M. J . Chem. Soc.,
Perkin Trans. 1 1991, 353. (b) Clark, A. J .; J ones, K.; McCarthy, C.;
Storey, J . M. D. Tetrahedron Lett. 1991, 32, 2829. (c) Ghosh, A. K.;
Ghosh, K.; Pal, S.; Chatak, U. R. J . Chem. Soc., Chem. Commun. 1993,
809. (d) Gibson, S. E.; Guillo, N.; Middleton, R. J .; Thuilliez, A.; Tozer,
M. J . J . Chem. Soc., Perkin Trans. 1 1997, 447. (e) Gibson, S. E.; Guillo,
N.; Tozer, M. J . Chem. Commun. 1997, 637. (f) Merritt, J . E.; Sasson,
M.; Kates, S. A.; Snider, B. B. Tetrahedron Lett. 1988, 29, 5209. (g)
Ishibashi, H.; Ishita, A.; Tamura, O. Tetrahedron Lett. 2002, 43, 473.
(7) (a) Borch, R. F.; Hassid, A. I. J . Org. Chem. 1972, 37, 1673.
Nelsen, S. F.; Weisman, G. R. Tetrahedron Lett. 1973, 2321. (b)
Giumanini, A. G.; Chiavari, G.; Musiani, M. M.; Rossi, P. Synthe-
sis,1980, 743. (c) Kim, S.; Oh, C. H.; Ko, J . S.; Ahn, K. H.; Kim, Y. J .
J . Org. Chem. 1985, 50, 1927.
(3) Feuston, B. P.; Culberson, J . C.; Duggan, M. E.; Harman, G. D.;
Leu, C.-T.; Rodan, S. B. J . Med. Chem. 2002, 45, 5640.
(4) Yet, L. Chem. Rev. 2000, 100, 2963.
(5) (a) Curran, D. P.; Porter, N. A.; Giese, B. Stereochemistry of
Radical Reactions; VCH Verlagsgesellschaft mbH.; Weinheim, 1996.
(b) Curran, D. P. In Comprehensive Organic Synthesis; Trost, B. M.,
Flemming, I., Semmelhack, M. F., Eds.; Pergamon: Oxford, 1991; Vol.
4, Chapter 4.2. (c) Curran, D. P. Synthesis 1988, 417-439. (d) Curran,
D. P. Synthesis 1988, 489-513. (e) Giese, B. Radicals in Organic
Synthesis. Formation of Carbon-Carbon Bonds; Pergamon: Oxford,
1986. (f) Yet, L. Tetrahedron 1999, 55, 9349. (g) Bowman. W. R.; Bridge,
C. F.; Brookes, P. J . Chem. Soc., Perkin Trans. 1 2000, 1. (h) Bowman.
W. R.; Cloonan, M. O.; Krintel, S. L. J . Chem. Soc., Perkin Trans. 1
2001, 2885. (i) Bowman, W. R.; Fletcher, A. J .; Potts, G. B. S. J . Chem.
Soc., Perkin Trans. 1 2002, 2747.
(8) Hegedus, L. S. In Organometallics in Synthesis, A Manual;
Schlosser, M., Ed.; J ohn Wiley and Sons: New York, 2002; p 1173.
10.1021/jo030052h CCC: $25.00 © 2003 American Chemical Society
Published on Web 05/16/2003
4996
J . Org. Chem. 2003, 68, 4996-4998

TABLE 2. Op tim iza tion of Ra d ica l Cycliza tion of 3a
SCHEME 4
time
4a ,
entry solvent
conditions
(h) yield (%)
1
2
3
4
toluene 110 °C
toluene slow addition for 4 h, 80 °C
toluene slow addition for 4 h, hν, 0 °C 13
benzene slow addition for 6 h, 80 °C 15
8
27
39
47
32
57
TABLE 3. Ra d ica l Cycliza tion for Va r iou s P r ecu r sor s 3
yielda
(%)
yielda
(%)
entry
3
R1
R2
R3
4
5
1
2
3
4
5
6
7
8
9
3a MeO CF3
3b MeO CF3
3c MeO CF3
3d MeO Ph
3e MeO Ph
CH2CO2Et 4a
57
48
0
18
28
56
64
49
0
5a
5b
5c
5d
5e
5f
5g
5h
5i
0
0
50
0
0
0
0
0
51
Me
H
4b
4c
CH2CO2Me 4d
Me 4e
3f MeO C3H7 CH2CO2Me 4f
3g
3h
3i
H
H
H
CF3
CF3
CF3
CH2CO2Me 4g
Me
H
4h
4i
a
Isolated yield.
SCHEME 2
7-Endo cyclization occurred when some alkyl group
occupied the R3 position, while the absence of the sub-
stituent at R3 exclusively caused 6-exo cyclization to
produce 5.
SCHEME 3
Treatment of benzyl amide 3d with Bu3SnH resulted
in a poor yield of 2-benzazepine 4d along with the
formation of side product 6 that was isolated in a 56%
yield. The structural elucidation based on NMR data
revealed that compound 6 contained a 2-pyrrolidone
structure. Compound 6 consisted of a pair of diastereo-
mers whose ratio was about 7:3.9 The formation of 6 from
3d suggested that the 1,5-hydrogen transfer competed
with the desired 7-endo cyclization reaction. A plausible
reaction mechanism is depicted in Scheme 4.
First, the tributyltin radical abstracts the bromine
atom attached to the benzene ring to generate an aryl
radical. If the radical directly attacks the â-carbon of the
unsaturated amide unit, 2-benzazepine 4d is formed. The
aryl radical, however, is reactive enough to abstract the
benzylic hydrogen in the benzyl amide unit to give a
benzyl radical,10 which then attacks the â-carbon of the
amide in the 5-endo mode and 2-pyrrolidine 6 is formed.11
Considering the present product ratio, the 7-endo mode
cyclization should be much slower than the abstraction
of benzylic hydrogen.
the restriction of the rotation between the C-N bond in
the tertiary amide (Table 2, entry 3). Finally the best
yield of 4a was obtained in the reaction carried out in
benzene with the slow-addition technique (Table 2, entry
4). This procedure was useful in the multigram scale of
the preparation of 4a (see the Experimental Section).
With these optimized conditions in hand, radical cy-
clization with various 3 was examined (Scheme 3). The
results are summarized in Table 3.
Treatment of itaconamide 3a and methacrylamide 3b
with Bu3SnH produced 2-benzazepine 4a and 4b in good
yields (Table 3, entries 1 and 2), while exposure of
acrylamide 3c under the same conditions resulted in
6-exo cyclization to give 5c exclusively (Table 3, entry
3). In both cases, the formation of a small amount of
reduced produced product was observed. Other unsatur-
ated amides 3 showed similar results; itaconamides and
methacrylamides preferred 7-endo cyclization to selec-
tively give 2-benzazepine 4 (Table 3, entries 4-8),
whereas acrylamides gave only 2H-isoquinolin-3-one 5
(Table 3, entry 9). This change of the cyclization selectiv-
ity depended on the presence or absence of R3 substituent.
(9) The NOE experiments for the major-6 indicated the two sub-
stituents in the 2-pyrrolidone ring occupied a cis configuration because
2.3% signal enhancement between H3 and H5 was observed.
(10) (a) Sniekus, V.; Cuevas, J .-C.; Slaon, C. P.; Liu, H.; Curran, D.
P. J . Am. Chem. Soc. 1990, 112, 896. (b) Brown, C. D. S.; Dishington,
A. P.; Shishkin, O.; Simpkins, N. S. Synlett 1995, 943. (c) Bogen, S.;
Malacria, M. J . Am. Chem. Soc. 1996, 118, 3992. (d) Van Dort, P. C.;
Fuchs, P. L. J . Org. Chem. 1997, 62, 7142. (e) Delouvire´, B.; Lacoˆte,
E.; Fensterbank, L.; Malacria, M. Angew. Chem., Int. Ed. 1998, 37,
2116. (f) Imboden, C.; Villar, F.; Renaud, P. Org. Lett., 1999, 1, 873.
(g) Delouvire´, B.; Lacoˆte, E.; Fensterbank, L.; Malacria, M. Tetrahedron
Lett. 1999, 40, 3565. (h) Kamimura, A.; Mitsudera, H. Tetrahedron
Lett. 2001, 42, 7457.
J . Org. Chem, Vol. 68, No. 12, 2003 4997

(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