A new synthesis of 2-benzazepines

Article abstract of DOI:10.1055/s-2002-23538

AlCl₃-mediated intramolecular cyclization of N,N-bis (1H-1,2,3-benzotriazol-1-ylmethyl)-3-phenyl-1-propanamine (5) gave 2-benzotriazolylmethyl-2,3,4,5-tetrahydro-1H-2-benzazepine (6). Subsequent nucleophilic substitution of the benzotriazolyl group in 6 with Grignard reagents, triethyl phosphite and sodium borohydride afforded 2,3,4,5-tetrahydro-1H-2-benzazepines 1a-e, 2 and 3. Similarly, TiCl₄-mediated cyclization of 8 and 10 gave 5,6,7,13b-tetrahydro-9H-isoindolo[1,2-a][2]benzazepin-9-one (9) and 1,2,5,6,7,11b-hexahydro-3H-pyrrolo[2,1-a][2]benzazepin-3-one (11), respectively.

Full text of DOI:10.1055/s-2002-23538

PAPER
601
A New Synthesis of 2-Benzazepines
S
ynthesis of 2-Ben
l
zazepi
a
Center for Heterocyclic Compounds, Department of Chemistry, University of Florida, Gainesville, Florida 32611–7200, USA
Fax +1(352)3929551; E-mail: katritzky@chem.ufl.edu
Received 27 November 2001; revised 18 February 2002
Recently, we reported the syntheses of 1,4-benzothia-
zepines and 1,4-benzoxazepines from
Abstract: AlCl3-mediated intramolecular cyclization of N,N-
bis(1H-1,2,3-benzotriazol-1-ylmethyl)-3-phenyl-1-propanamine
(5) gave 2-benzotriazolylmethyl-2,3,4,5-tetrahydro-1H-2-benza-
zepine (6). Subsequent nucleophilic substitution of the benzotriaz-
ArX(CH2)2NRCH2Bt (Bt = benzotriazole) using benzotri-
azole methodology.10 In the present work, we now report
olyl group in 6 with Grignard reagents, triethyl phosphite and an analogous approach to 2-benzazepines and explore the
sodium borohydride afforded 2,3,4,5-tetrahydro-1H-2-benza-
zepines 1a–e, 2 and 3. Similarly, TiCl4-mediated cyclization of 8
and 10 gave 5,6,7,13b-tetrahydro-9H-isoindolo[1,2-a][2]benza-
possibility of introducing different functional groups onto
the benzazepine moiety.
Condensation of 3-phenyl-1-propylamine (7), benzotria-
zole and formaldehyde in methanol–water at 20 °C gave
pure N,N-bis(1H-1,2,3-benzotriazol-1-ylmethyl)-3-phe-
nyl-1-propanamine (5). Compound 5 on heating with 4
equivalents of AlCl3 in anhydrous CH2Cl2 under reflux for
8–10 h gave 6 in 70% yield (Scheme 2). Although the
starting material 5 was only Bt1 (benzotriazol-1-yl) iso-
mer, equilibration occurred during the cyclization and
product 6 was obtained as a mixture of Bt1and Bt2 (benzo-
triazol-2-yl) isomers, in which Bt1 isomer predominated.
Preliminary attempts to separate the Bt1and Bt2 isomers
failed. Since both Bt1and Bt2 can be substituted by nucleo-
philes, the mixture was used as such in the subsequent re-
actions. We have reported the 1H and 13C NMR data of the
major Bt1 isomer in the experimental section. The ratio of
Bt1and Bt2 isomers was determined by 1H NMR spectrum
to be 4.4:1. The aliphatic region in the 1H NMR spectrum
of 5 showed one strong singlet ascribed to two BtCH2N at
zepin-9-one (9) and 1,2,5,6,7,11b-hexahydro-3H-pyrrolo[2,1-
a][2]benzazepin-3-one (11), respectively.
Key words: benzotriazole, 2-benzazepine, cyclization, synthesis
2-Benzazepines1 are of considerable interest due to their
diverse pharmacological properties.2a–c Known routes to
2-benzazepines include (Scheme 1): (i) cyclization of N-
(3-bromopropyl)arylamine hydrobromides with alum-
inum chloride at 130 °C in decalin;3 (ii) cyclization of 3-
arylpropylsulfonamides with formaldehyde and acid to
the N-sulfonyl-2-benzazepine;4 (iii) cyclization of 3-(2-
methoxycarbonylaryl)propylamines with sodium methox-
ide to 2-benzazepin-1-ones and subsequent reduction;5
(iv) Beckman6 or Schmidt rearrangements of 3,4-dihydro-
1(2H)-naphthalenone;7,8 and (v) ring enlargement of 2-
acetyl-7,8-dichloro-1,2-dihydroisoquinolines.9
Br-
+
NHSO2R
N
Br
H2
O
N
N
R
P
OEt
OEt
N+
-
1a-f
(see Table)
BH3
(ii)
N
2
(i)
3
CH3
CH2Cl2
AlCl3
N
Bt1,2
(iii)
Bt
N
R'
Bt
5
6
Cl
O
O
BtH CH2O
Cl
(v)
CO2H
CHO
BtH
N
N
(iv)
H3CO2C
Bt1
TiCl4
NAc
H2N
H2N
7
8
9
MeO
BtH
O
O
O
OMe
N
N
Bt1
=
=
N
O
Scheme 1
N
N
N
N
TiCl4
Bt1,2
Bt2
N
Synthesis 2002, No. 5, 08 04 2002. Article Identifier:
11
10
1437-210X,E;2002,0,05,0601,0604,ftx,en;M06101SS.pdf.
© Georg Thieme Verlag Stuttgart · New York
ISSN 0039-7881
Scheme 2

602
A. R. Katritzky et al.
PAPER
5.63 ppm. After the cyclization, two singlets were ob- hexahydro-3H-pyrrolo[2,1-a][2]benzazepin-3-one (11) in
served at 4.00 ppm and 5.42 ppm in the 1H NMR spectrum 52% yield (Scheme 2). No previous examples of the ring
of 6, which were ascribed to ArCH2N and BtCH2N frag- system of 11 could be located.
ments, respectively.
In conclusion, we have developed a new approach to 2-
The benzotriazole moiety in 6 could, as expected,11 be re- benzazepines via cyclization of N,N-bis(1H-1,2,3-benzo-
placed by various nucleophiles. Thus, reactions of 6 with triazol-1-ylmethyl)-3-phenyl-1-propanamine (5), 3-(1H-
the corresponding Grignard reagents 4a–f gave com- 1,2,3-benzotriazol-1-yl)-2-(3-phenylpropyl)-1-isoindoli-
pounds 1a–f, respectively, in 40–70% yields (Scheme 2). none (8), and 5-(benzotriazolyl)-2-(3-phenylpropyl)-2-
The results are listed in the Table.
pyrrolidinone (10). A series of N-substituted 2-benza-
zepines were obtained by nucleophilic substitution of ben-
zotriazolyl moiety in 6 using different nucleophiles.
Table Reaction of 6 with Grignard Reagents
Product 1 Nucleophile
R
Yield (%)
Melting points were determined on a Koefler hot stage apparatus
and are uncorrected. 1H and 13C NMR spectra were recorded at 300
MHz and 75 MHz, respectively, in CDCl3 referenced to Me4Si for
the 1H spectra and CDCl3 for the 13C spectra. THF was distilled un-
der N2 from sodium-benzophenone immediately before use. CH2Cl2
was distilled over CaH2 under N2. Column chromatography was
performed on silica gel (200–425 mesh, Fisher Scientific). All reac-
tions with moisture-sensitive compounds were carried out under dry
argon.
a
b
c
d
e
f
p-MeOC6H4MgCl
p-MeOC6H4
p-ClC6H4
C6H5C C
Et
70
47
43
71
69
78
p-ClC6H4MgCl
C6H5C CMgCl
EtMgBr
BuMgBr
Bu
p-MeC6H4MgCl
p-MeC6H4
N,N-Bis(1H-1,2,3-benzotriazol-1-ylmethyl)-3-phenyl-1-propan-
amine (5)
To a solution of 3-phenyl-1-propylamine (5 g, 37 mmol) and ben-
zotriazole (9.6 g, 81.2 mmol) in MeOH (60 mL) and H2O (15 mL)
was added formaldehyde (6.47 g, 81.4 mmol, 37% aq solution). The
reaction mixture was stirred for 24 h at 20 °C. Then, the white pre-
cipitates were filtered and washed with Et2O to give the desired
product (9.2 g, 62%), which was directly used in the subsequent re-
action without further purification. Pale yellow prisms (from
EtOAc–hexane); yield: 62%; mp 84–86 °C.
1H NMR (CDCl3): = 1.89 (quintet, 2 H, J = 7.2 Hz), 2.50 (t, 2 H,
J = 7.2 Hz), 2.87 (t, 2 H, J = 7.2 Hz), 5.63 (s, 4 H), 7.01 (d, 2 H,
J = 6.3 Hz), 7.14–7.26 (m, 3 H), 7.41 (dt, 2 H, J = 0.9, 7.5 Hz), 7.51
(dt, 2 H, J = 0.9, 6.9 Hz), 7.62 (d, 2 H, J = 8.4 Hz), 8.10 (d, 2 H,
J = 8.4 Hz).
Treatment of compound 6 with triethyl phosphite in the
presence of ZnBr2 in THF at 0 °C replaced the benzotria-
zolyl group to give the expected product diethyl 1,3,4,5-
tetrahydro-2H-2-benzazepin-2-ylmethylphosphonate (2)
in 87% yield (Scheme 2).
The reduction of 6 with sodium borohydride in methanol
failed; however, compound 6 was reduced in THF using
sodium borohydride in 4 hours at 20 °C to give 2-methyl-
2,3,4,5-tetrahydro-1H-2-benzazepine borane complex 3
in 83% yield (Scheme 2).
Heating 3-phenyl-1-propylamine (7), benzotriazole and
phthalaldehydic acid with a catalytic amount of p-toluene-
sulfonic acid monohydrate using a Dean–Stark apparatus
gave 3-(1H-1,2,3-benzotriazol-1-yl)-2-(3-phenylpropyl)-
1-isoindolinone (8) in 89% yield (Scheme 2). Heating 8
with aluminum chloride in CH2Cl2 gave traces of product
9, but TiCl4 (1.7 M solution CH2Cl2) afforded the desired
5,6,7,13b-tetrahydro-9H-isoindolo[1,2-a][2]benzazepin-
9-one (9) in 83% yield at 20 °C (Scheme 2). Compound 9
was previously prepared by the cyclization of 3-(3-phe-
nylpropylamine)phthalide in polyphosphoric acid at
95 °C in 30% yield.12
13C NMR (CDCl3): = 29.1, 32.8, 50.1, 64.4, 109.7, 120.0, 124.2,
126.0, 127.9, 128.2, 128.4, 133.2, 141.1, 146.0.
Anal. Calcd for C23H23N7: C, 69.50; H, 5.83; N, 24.67. Found: C,
69.56; H, 5.88; N, 25.02.
2-(Benzotriazolylmethyl)-2,3,4,5-tetrahydro-1H-2-benzazep-
ine (6)
AlCl3 (0.53 g, 16 mmol) was placed in a dry flask under argon with
a stirring bar, and a solution of the starting material 5 (1.59 g, 4
mmol) in anhyd CH2Cl2 (80 mL) was added and stirred. This mix-
ture was refluxed for 8–10 h, then cooled to r.t. and quenched with
2 M NaOH solution (10 mL). The organic layer was separated and
washed with 2 M NaOH solution and H2O. The organic layer was
collected and dried (MgSO4). Removal of the solvent gave a pale
yellow oil (0.23 g, 70%), which was used in the next step without
purification.
1H NMR (CDCl3): = 1.83 (quintet, 2 H, J = 5.1 Hz), 2.89 (t, 2 H,
J = 5.4 Hz), 3.19 (t, 2 H, J = 5.1 Hz), 4.00 (s, 2 H), 5.42 (s, 2 H),
7.10–7.20 (m, 4 H), 7.34–7.56 (m, 2 H), 7.65 (d, 1 H, J = 8.1 Hz),
8.09 (d, 1 H, J = 8.4 Hz).
In a slightly different procedure from the above, 3-phenyl-
1-propylamine (7) was heated with benzotriazole and 2,5-
dimethoxy-2,5-dihydrofuran in acetic acid at 60–70 °C
for 48 hours to give 10 as mixed Bt1 and Bt2 isomers in
56% yield. Separation by column chromatography afford-
ed the Bt1 isomer of 10 in 47% yield and the Bt2 isomer of
10 in 9% yield (Scheme 2). However, the unseparated
mixture was used in the subsequent reaction.
13C NMR (CDCl3): = 26.7, 35.4, 57.1, 58.2, 68.1, 110.3, 119.9,
123.9, 126.2, 127.3, 127.6, 129.2, 129.7, 133.2, 138.3, 142.5, 146.1.
Cyclization of 10 was more difficult than that of 8 using
1.7 M solution of TiCl4, and only a small amount of 10
was converted; however, TiCl4 (4 equiv) in CH2Cl2 for 36
hours at 20 °C cyclized 10 into the novel 1,2,5,6,7,11b-
Anal. Calcd for C17H18N4: N, 20.13. Found: N, 20.49.
HRMS-FAB: m/z (M – 1) calcd for C17H17N4: 277.1453; found:
277.1430.
Synthesis 2002, No. 5, 601–604 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
Synthesis of 2-Benzazepines
603
2-(4-Methoxybenzyl)-2,3,4,5-tetrahydro-1H-2-benzazepine
(1a); Typical Procedure
13C NMR (CDCl3): = 14.0, 22.6, 25.0, 27.2, 29.7, 36.2, 53.4, 59.1,
59.5, 125.8, 127.1, 128.7, 129.7, 139.4, 142.9.
Compound 6 (0.2 g, 0.72 mmol) was dissolved in THF (10 mL) un-
der argon in a round bottom flask containing a stirring bar, and
cooled to 0 °C in an ice-water bath. After 10 min, 4-methoxylphe-
nylmagnesium bromide (0.8 mL, 1.0 M, 0.86 mmol) was added
dropwise. The reaction mixture was stirred at 0 °C for 2 h. This was
then warmed up to r.t. and stirred for an additional 10 h. The reac-
tion was quenched with H2O (10 mL), the organic layer was sepa-
rated and washed with 2 M NaOH solution. The aqueous layer was
back-extracted with CH2Cl2. The combined organic layers were
dried (MgSO4), and concentrated to give a yellow solid. The prod-
uct was purified by column chromatography on silica gel using 30%
Et2O in pentane as eluent; micro-needles (Et2O–pentane); yield:
70%; mp 83–85 °C.
Anal. Calcd for C15H23N: C, 82.89; H, 10.67; N, 6.44. Found: C,
83.20; H, 11.08; N, 6.76.
2-(4-Methylbenzyl)-2,3,4,5-tetrahydro-1H-2-benzazepine (1f)
Yellow oil; yield: 78%.
1H NMR (CDCl3): = 1.75 (quintet, 2 H, J = 5.1 Hz), 2.34 (s, 2 H),
2.91(t, 2 H, J = 5.4 Hz), 3.10 (t, 2 H, J = 5.1 Hz), 3.49 (s, 2 H), 3.87
(s, 2 H), 6.95 (d, 1 H, J = 6.9 Hz), 7.05–7.20 (m, 7 H).
13C NMR (CDCl3): = 21.1, 25.2, 29.7, 36.1, 57.5, 58.7, 59.2,
125.8, 127.1, 128.7, 128.8, 128.9, 130.0, 136.1, 136.4, 139.4,
143.1.
Anal. Calcd. for C18H21N: C, 86.01; H, 8.42; N, 5.57. Found: C,
86.13; H, 8.37; N, 5.89.
1H NMR (CDCl3): = 1.75 (quintet, 2 H, J = 5.0 Hz), 2.92 (t, 2 H,
J = 5.1 Hz), 3.10 (t, 2 H, J = 5.1 Hz), 3.46 (s, 2 H), 3.81 (s, 3 H),
3.86 (s, 2 H), 6.85 (d, 2 H, J = 8.7 Hz), 6.95 (d, 1 H, J = 7.2 Hz),
7.00–7.26 (m, 5 H).
Diethyl 1,3,4,5-Tetrahydro-2H-2-benzazepin-2-ylmethylphos-
phonate (2)
13C NMR (CDCl3): = 25.2, 36.2, 55.2, 57.1, 58.7, 59.1, 113.5,
125.8, 127.1, 128.8, 130.0, 130.1, 131.3, 139.4, 143.1, 158.5.
To a solution of 6 (0.1 g, 0.36 mmol) in THF (5 mL), cooled to 0 °C
in ice-water bath, was added ZnBr2 (0.08 g, 0.36 mmol, oven dried)
followed by triethyl phosphite (0.07 mL, 0.4 mmol). The mixture
was stirred overnight, quenched with H2O, extracted with CH2Cl2,
and the organic layer was washed with aq 2 M NaOH (2 15 mL),
and dried (MgSO4). Removal of the solvent gave 0.12 g of oil which
was purified using 5% MeOH in CHCl3 as eluent; colorless oil;
yield: 90 mg, 87%.
1H NMR (CDCl3): = 1.32 (t, 6 H, J = 7.2 Hz), 1.64–1.74 (m, 2 H),
2.72 (d, 2 H, J = 10.5 Hz), 2.90 (t, 2 H, J = 5.1 Hz), 3.27 (t, 2 H,
J = 5.1 Hz), 4.06 (s, 2 H), 4.06–4.20 (m, 4 H), 7.02–7.20 (m, 4 H).
Anal. Calcd for C18H21NO: C, 80.86; H, 7.92; N, 5.24. Found: C,
80.43; H, 7.70; N, 5.07.
2-(4-Chlorobenzyl)-2,3,4,5-tetrahydro-1H-2-benzazepine (1b)
White needles (EtOAc–hexane); yield: 47%; mp 97–99 °C.
1H NMR (CDCl3): = 1.81 (quintet, 2 H, J = 5.0 Hz), 2.98 (t, 2 H,
J = 5.0 Hz), 3.17 (t, 2 H, J = 5.0 Hz,), 3.54 (s, 2 H), 3.90 (s, 2 H),
6.96 (d, 1 H, J = 7.2 Hz), 7.10–7.24 (m, 2 H), 7.25–7.36 (m, 5 H).
13C NMR (CDCl3): = 25.2, 36.1, 57.0, 58.9, 59.1, 125.8, 127.2,
128.3, 128.8, 129.9, 130.2, 132.5, 137.9, 139.2, 143.0.
13C NMR (CDCl3): = 16.5 (d, J = 5.7 Hz), 24.4, 36.1, 47.5 (d,
J = 167.2 Hz), 60.2 (d, J = 9.2 Hz), 60.4 (d, J = 8.0 Hz), 62.0 (d,
J = 6.9 Hz), 125.9, 127.4, 129.0, 130.4, 138.4, 143.0.
Anal. Calcd for C17H18ClN: C, 75.13; H, 6.68; N, 5.15. Found: C,
75.32; H, 7.09; N, 5.05.
Anal. Calcd. for C15H24NO3P: C, 60.59; H, 8.14; N, 4.71. Found: C,
60.16; H, 8.51; N, 5.07.
2-(3-Phenylprop-2-ynyl)-2,3,4,5-tetrahydro-1H-2-benzazepine
(1c)
2-Methyl-2,3,4,5-tetrahydro-1H-2-benzazepine Borane Com-
plex (3)
Yellow oil; yield: 43%.
1H NMR (CDCl3): = 1.80 (quintet, 2 H, J = 5.0 Hz), 2.91 (t, 2 H,
J = 5.0 Hz), 3.20 (t, 2 H, J = 5.0 Hz), 3.52 (s, 2 H), 3.98 (s, 2 H),
7.08–7.22 (m, 4 H), 7.27–7.34 (m, 3 H), 7.40–7.50 (m, 2 H).
13C NMR (CDCl3): = 26.3, 35.6, 45.8, 58.9, 59.7, 84.7, 85.5,
123.3, 126.1, 127.4, 128.0, 128.2, 128.8, 129.8, 131.7, 138.7, 142.8.
To a solution of 6 (0.28 g, 1 mmol) in THF (20 mL) was added
NaBH4 (0.15 g, 4 mmol) and stirred at r.t. for 4 h. The solvent was
evaporated, the residue was dissolved in CH2Cl2, and washed with
2 M NaOH solution. The organic layer was dried (MgSO4) and con-
centrated to give yellow solid, which was purified by column chro-
matography on silica gel using 20% EtOAc in hexane; yellow
prisms (EtOAc–hexane); yield: 83%; mp 67.6–68.8 °C.
Anal. Calcd for C19H19N: N, 5.36. Found: N, 5.67.
1H NMR (CDCl3): = 1.10–2.10 (m, 5 H), 2.32 (s, 3 H), 2.78–3.10
(m, 2 H), 3.15–3.40 (m, 2 H), 4.00 (d, 1 H, J = 14.7 Hz), 4.36 (d, 1
H, J = 14.4 Hz), 7.15–7.30 (m, 4 H).
13C NMR (CDCl3): = 23.7, 34.3, 45.2, 65.5, 65.9, 126.8, 128.9,
129.1, 131.6, 132.9, 142.4.
HRMS-FAB: Calcd for C19H20N (M + 1): 262.1596; Found:
262.1601.
2-Propyl-2,3,4,5-tetrahydro-1H-2-benzazepine (1d)
Yellow oil; yield: 71%.
1H NMR (CDCl3): = 0.85 (t, 3 H, J = 7.2 Hz), 1.45–1.57 (m, 2 H),
1.72 (quintet, 2 H, J = 5.1 Hz), 2.28–2.33 (m, 2 H), 2.89 (t, 2 H,
J = 5.4 Hz), 3.12 (t, 2 H, J = 5.4 Hz), 3.89 (s, 2 H), 7.12 (br s, 4 H).
Anal. Calcd. for C11H18BN: C, 74.46; H, 10.36; N, 8.00. Found: C,
75.56; H, 10.22; N, 7.95.
13C NMR (CDCl3): = 11.9, 20.6, 25.0, 36.2, 55.3, 59.0, 59.4,
125.9, 127.1, 128.8, 129.7, 139.3, 142.9.
3-(1H-1,2,3-Benzotriazol-1-yl)-2-(3-phenylpropyl)-1-isoindoli-
none (8)
3-Phenyl-1-propylamine (0.3 g, 2.2 mmol), BtH (0.28 g, 2.4 mmol),
phthalaldehydic acid (0.34 g, 2.2 mmol) and p-toluenesulfonic acid
monohydrate (0.04 g, 0.24 mmol) were dissolved in toluene (50
mL) and refluxed using a Dean–Stark apparatus. After 24 h, the re-
action mixture was cooled. After evaporating the solvent, the resi-
due was dissolved in CH2Cl2 and washed with aq 2 M NaOH and
brine. The organic layer was dried (Na2SO4), and concentrated to
give a yellow oil, which was purified by column chromatography on
Anal. Calcd for C13H19N: C, 82.48; H, 10.12; N, 7.40. Found: C,
82.61; H, 10.45; N, 7.65.
2-Pentyl-2,3,4,5-tetrahydro-1H-2-benzazepine (1e)
Brown oil; yield: 69%.
1H NMR (CDCl3): = 0.87 (t, 3 H, J = 7.2 Hz), 1.18–1.34 (m, 4 H),
1.46–1.58 (m, 2 H), 1.71–1.79 (m, 2 H,), 2.36–2.42 (m, 2 H), 2.90
(t, 2 H, J = 6.0 Hz), 3.15 (t, 2 H, J = 5.4 Hz), 3.95 (s, 2 H), 7.13 (br
s, 4 H).
Synthesis 2002, No. 5, 601–604 ISSN 0039-7881 © Thieme Stuttgart · New York

604
A. R. Katritzky et al.
PAPER
1,2,5,6,7,11b-Hexahydro-3H-pyrrolo[2,1-a][2]benzazepin-3-
silica gel using 30% EtOAC in hexane as eluent; yellow flakes
(EtOAc–hexane); yield: 89%; mp 92–93 °C.
one (11)
Compound 10 (0.4 g, 1.25 mmol) was placed in a dry flask, dis-
solved in anhyd CH2Cl2 (50 mL), TiCl4 (0.55 mL, 5 mmol) was add-
ed and and the mixture was stirred at 20 °C for 36 h. The reaction
was quenched with H2O. The aqueous layer was extracted with
CH2Cl2. The combined organic layer was washed with aq 2 M
NaOH, dried (Na2SO4), and concentrated to give 0.13 g of a brown
oil (52%) as the product: No further purification was needed.
1H NMR (CDCl3): = 1.64–1.82 (m, 1 H), 1.96–2.10 (m, 1 H),
2.12–2.28 (m, 1 H), 2.36–2.55 (m, 3 H), 2.60–2.74 (m, 1 H), 2.87–
3.40 (m, 2 H), 4.09–4.17 (m, 1 H), 4.84 (t, 1 H, J = 7.2 Hz), 7.10–
7.50 (m, 4 H).
1H NMR (CDCl3): = 1.75 (quintet, 2 H, J = 7.5 Hz), 2.25 (dt, 2 H,
J = 4.2, 2.7 Hz), 2.90–3.40 (m, 1 H), 3.72–3.84 (m, 1 H), 6.40 (d, 1
H, J = 8.4 Hz), 7.00 (d, 2H, J = 7.2 Hz), 7.06–7.22 (m, 4 H), 7.28–
7.36 (m, 2 H), 7.38 (s, 1 H), 7.58 (t, 1 H, J = 7.5 Hz), 7.67 (t, 1 H,
J = 7.5 Hz), 8.04 (d, 1 H, J = 7.5 Hz), 8.08 (d, 1 H, J = 8.4 Hz).
13C NMR (CDCl3): = 29.3, 33.0, 40.1, 72.7, 110.0, 120.5, 123.5,
124.2, 124.7, 125.9, 128.1, 128.2, 128.3, 130.5, 130.9, 132.0, 132.9,
138.9, 140.8, 147.0, 167.2.
Anal. Calcd. for C23H20N4O: C, 74.98; H, 5.47; N, 15.21. Found: C,
75.12; H, 5.70; N, 15.11.
13C NMR (CDCl3): = 25.7, 27.9, 31.0, 31.2, 39.6, 64.0, 126.5,
126.7, 127.9, 130.8, 138.6, 139.1, 174.3.
5,6,7,13b-Tetrahydro-9H-isoindolo[1,2-a][2]benzazepin-9-one
(9)
Compound 8 (0.31 g, 0.84 mmol) was dissolved in CH2Cl2 (9 mL),
TiCl4 (3.3 mmol, 1.7 M in CH2Cl2) was added, and the mixture was
stirred at r.t. for 10 h. Then, the reaction was quenched with H2O.
The organic layer was separated, washed with aq 2 M NaOH, brine,
and dried (MgSO4). Removal of the solvent gave a yellow solid,
which was purified by column chromatography on silica gel using
25% EtOAc in hexane as eluent. White micro prisms (EtOAc–hex-
ane); yield: 89%; mp 138–141 °C (Lit.12 mp 143–145 °C).
1H NMR (CDCl3): = 1.84–2.00 (m, 1 H), 2.10–2.28 (m, 1 H),
2.66–2.76 (m, 2 H), 3.31–3.41 (m, 1 H), 4.33–4.40 (m, 1 H), 5.75
(s, 1 H), 7.11–7.14 (m, 1 H), 7.23–7.32 (m, 3 H), 7.45–7.58 (m, 3
H), 7.90 (d, 1 H, J = 7.2 Hz).
HRMS: m/z (M + 1) calcd for C13H16NO: 202.1232; found:
202.1175
References
(1) Kasparek, S. In Advances in Heterocyclic Chemistry;
Katritzky, A. R.; Boulton, A. J., Eds.; Academic Press: New
York, 1974, 45.
(2) (a) Fuller, R. W.; Molloy, B. B.; Hemrick, S. K. Biochem.
Pharmacol. 1979, 28, 528. (b) Trybulski, E. J.; Benjamin,
L.; Vitone, S.; Walser, A.; Fryer, R. I. J. Med. Chem. 1983,
26, 367. (c) Trybulski, E. J.; Fryer, R. I.; Reeder, E.; Walser,
A.; Blount, J. J. Med. Chem. 1983, 26, 1596.
(3) Deady, L. W.; Pirzada, N. H.; Topsom, R. D. J. Chem. Soc.,
Perkin Trans 1 1973, 782.
13C NMR (CDCl3): = 25.4, 31.5, 41.0, 65.8, 123.3, 123.8, 126.8,
127.4, 128.3, 128.4, 130.5, 131.4, 132.2, 135.1, 139.9, 144.0, 168.9.
(4) Orazi, O. O.; Corral, R. A.; Giaccio, H. J. Chem. Soc., Perkin
Trans. 1 1986, 1977.
(5) Grunewald, G. L.; Paradkar, V. M.; Stillions, D. M.; Ching,
F. J. Heterocycl. Chem. 1991, 28, 1587.
(6) Jensen, B. L.; Chockalingam, K. J. Heterocycl. Chem. 1986,
23, 343.
(7) Molloy, B. B. Canadian Patent 1/119/592, 1982; Chem.
Abstr. 1982, 97, 388632.
(8) Grunewald, G. L.; Dahanukar, V. H.; Ching, P.; Criscione,
K. R. J. Med. Chem. 1996, 39, 3539.
(9) Perchonock, C. D.; Lantos, I.; Finkelstein, J. A.; Holden, K.
G. J. Org. Chem. 1980, 45, 1950.
(10) Katritzky, A. R.; Xu, Y.-J.; He, H.-Y.; Mehta, S. J. Org.
Chem. 2001, 66, 5590.
(11) Katritzky, A. R.; Lan, X.; Yang, J. Z.; Denisko, O. V. Chem.
Rev. 1998, 98, 409.
5-(Benzotriazolyl)-1-(3-phenylpropyl)-2-pyrrolidinone (10)
3-Phenyl-1-propylamine (1.37 g, 10 mmol), BtH (2.38 g, 20 mmol),
2,5-dimethoxy-2,5-dihydrofuran (1.43 g, 11 mmol) were dissolved
in HOAc (75 mL) and heated at 60-70 °C for 48 h. Then, the reac-
tion mixture was cooled and neutralized with NaOH. The mixture
was extracted with CH2Cl2, the organic layer was dried (Na2SO4),
and concentrated to give a yellow oil. The product was separated by
column chromatography using 30%–50% EtOAc in hexane as elu-
ent; yellow oil; yield: 56%.
1H NMR (CDCl3): = 1.56–1.84 (m, 2 H), 2.34–2.44 (m, 1 H),
2.46–2.72 (m, 5 H), 2.84–2.96 (m, 1 H), 3.54–3.65 (m, 1 H), 6.44
(dd, 1 H, J = 7.9, 2.4 Hz), 7.03 (d, 2 H, J = 6.9 Hz), 7.10–7.28 (m,
3 H), 7.32–7.54 (m, 3 H), 8.10 (d, 1 H, J = 8.1 Hz).
13C NMR (CDCl3): = 24.9, 28.0, 29.3, 32.9, 40.4, 72.4, 108.8,
120.5, 124.4, 125.9, 128.0, 128.1, 128.2, 131.2, 140.7, 146.3, 174.3.
(12) Walker, G. N.; Engle, A. R.; Kempton, R. J. J. Org. Chem.
1972, 37, 3755.
Anal. Calcd. for C19H20N4O: N, 17.49. Found: N, 17.02.
HRMS-FAB: m/z (M + 1) calcd for C19H21N4O: 321.1715; found:
321.1717.
Synthesis 2002, No. 5, 601–604 ISSN 0039-7881 © Thieme Stuttgart · New York