Friedel-crafts chemistry. Part 39. unprecedented facile route to the synthesis of benzo[b][1]benzazepines via intramolecular friedel-crafts cyclialkylations

Article abstract of DOI:10.1071/CH12548

A series of six pharmaceutically promising 5,6-dihydro-11H-benzo[b][1] benzazepine derivatives (1c-h) were cleanly prepared by Friedel-Crafts cyclialkylations of nitrogen-containing alkanols in the presence of AlCl3, 85% H₂SO₄ or polyphosphoric acid catalysts. The precursor alkanols (13a-f) were readily prepared by reaction of two synthesized carboxylic acid esters (12a, b) with different Grignard reagents. Also, two dibenzo[b,f]azepinones (15a, b) were prepared by Friedel-Crafts cycliacylation and reduced to the corresponding 5,6-dihydro-11H-benzo[b][1]benzazepines (1a, b). Overall, this approach allows easy and efficient access to polytricyclic amines from easily synthesized alkanols or cycloketones. A plausible carbocation mechanism is proposed to account for the results.

Full text of DOI:10.1071/CH12548

CSIRO PUBLISHING
Aust. J. Chem. 2013, 66, 635–645
Full Paper
http://dx.doi.org/10.1071/CH12548
Friedel Crafts Chemistry. Part 39. Unprecedented Facile
]
Route to the Synthesis of Benzo[b][1]benzazepines via
Intramolecular Friedel Crafts Cyclialkylations
]
A B
,
A
Hassan A. K. Abd El-Aal
and Ali A. Khalaf
A
Chemistry Department, Faculty of Science, Assiut University, Assiut, 71516, Egypt.
Corresponding author. Email: hassankotb33@yahoo.com
B
A series of six pharmaceutically promising 5,6-dihydro-11H-benzo[b][1]benzazepine derivatives (1c–h) were cleanly
prepared by Friedel–Crafts cyclialkylations of nitrogen-containing alkanols in the presence of AlCl3, 85 % H2SO4 or
polyphosphoric acid catalysts. The precursor alkanols (13a–f) were readily prepared by reaction of two synthesized
carboxylic acid esters (12a, b) with different Grignard reagents. Also, two dibenzo[b,f]azepinones (15a, b) were prepared
by Friedel–Crafts cycliacylation and reduced to the corresponding 5,6-dihydro-11H-benzo[b][1]benzazepines (1a, b).
Overall, this approach allows easy and efficient access to polytricyclic amines from easily synthesized alkanols or
cycloketones. A plausible carbocation mechanism is proposed to account for the results.
Manuscript received: 15 December 2012.
Manuscript accepted: 7 February 2013.
Published online: 1 March 2013.
Introduction
synthesis of dihydro-dibenzazepine counterparts. Some of the
few methods that have been reported for the synthesis of
dibenzazepines are summarized in the following. In an early
report, Thiele and Holzinger[14] reported the synthesis of diben-
zazepine 1 by initial oxidative Wurtz coupling of o-nitrotoluene
and reduction of the nitro groups followed by polyphosphoric
acid (PPA)-promoted cyclization. This procedure was modified
later by Schindler and Ha¨fliger.[15] Later approaches to the
syntheses of dibenzazepine derivatives were achieved by
Wagner–Meerwein rearrangement of 9,10-dihydroacridines,[16]
by coupling of o,o0-di(bromomethy1)diphenylamine with
excess PhLi,[17,18] by the ring closure of diphenylamine-o,o0-
dialdehyde with hydrazine in acetic acid,[19] and by the base-
mediated ring expansion of the mesylated 9,10-dihydroacridine
alcohols with potassium tert-butoxide in DMSO.[20] Further,
Palma and coworkers[21] reported the synthesis of
Among different azepine heteropolycycles, 5,6-dihydro-11H-
benzo[b][1]benzazepine or iminodibenzyl (1) derivatives
constitute a class of special interest. Apart from natural occur-
rence,[1] synthetic usage[2] and applications in the syntheses of
dyes,[3] polymers,[4] and organic semiconductors,[5] they are
also famous for their versatile biological[6] and pharmaceu-
ticals[7] activities. For example, scaffold 1 is the only precursor
for present-day construction of tricyclic antidepressant (TCA)[8]
drugs such as imipramine, clomipramine, and desipramine
(Fig. 1). Further, they also exhibit antiviral, antiepileptic, anti-
seizure, anticonvulsant, antimicrobial, antimalarial, anticancer,
antioxidant, and sirtuin-2-inhibitory activities.[9]
On searching the chemical literature, one finds that much
attention has been given to the synthesis of 5H-dibenzo[b, f]
azepine derivatives (e.g. 3, Fig. 1)[10–13] as compared with the
5
6
7
4
8
3
N
H
N
9
11
2
R1
10
1
R2
5,6-Dihydrobenzo[b][1]-benzazepine
1
(Iminodibenzyl)
R3
N
Me
2a–d
a: Imipramine; R1 ϭ R2 ϭ H, R3 ϭ Me
b: Desipramine; R1 ϭ R2 ϭ R3 ϭ H
N
c: Clomipramine; R1 ϭ Cl, R2 ϭ H, R3 ϭ Me
d: Trimipramine; R1 ϭ H, R2 ϭ R3 ϭ Me
O
NH2
Carbamazepine
3
Fig. 1. Benzo[b][1]benzazepine template-containing pharmaceuticals.
Journal compilation Ó CSIRO 2013
www.publish.csiro.au/journals/ajc

636
H. A. K. Abd El-Aal and A. A. Khalaf
COOEt
OH
Cl
ii
iii
Yield [%]
NH
Ar
NH
Ar
NH
Ar
8a
8b
91.5
85.7
92.0
90.4
88.2
90.8
Path A
Path B
Path C
6a, b
5a, b
7a, b
a: Ar ϭ Ph
b: Ar ϭ 2-MePh
iv
Path A
i
COOH
CN
CN
CN
v
vi
Path B
Path C
NH
Ar
Br
NH2
NH
Ar
9
10
8a, b
4a, b
Scheme 1. Reagents and conditions: (i) EtOH/H2SO4, 8 h, reflux. (ii) LiAlH4/THF/Et2O, 2 h, NaOH. (iii) SOCl2/
pyridine, 60–708C, 3 h. (iv) KCN/EtOH, 5 h, reflux. (v) (PhBr or 2-BrC6H4Me), KOH/DMSO, 1208C, 12 h, NH4Cl.
(vi) (PhNH2 or o-toluidine), CuCl, K2CO3, dichlorobenzene (DCB), 1708C, 15 h.
dihydromorphanthridines by acid-catalyzed intramolecular
Friedel–Crafts alkylations of substituted 2-allyl-N-
benzylanilines, which in turn, were prepared from N-allyl-N-
benzylanilines by aromatic amino-Claisen rearrangement.
Even more recently, Lohse et al.[22] reported the formation
of 10-ketoiminodibenzyl series via the remote metalation and
cyclization of N-alkyl-N-(o-tolyl)anthranilic esters synthesized
by palladium-mediated Buchwald–Hartwig coupling of
o-bromobenzamides with o-toluidine. MacNeil et al.[23] applied
the same methodology of Buchwald–Hartwig C–N cross-
coupling in the synthesis of dibenzo[b,f]azepinones by treat-
ment of N-methyl diarylamines with lithium diisopropylamide
(LDA).
In recent years, we have devoted part of our Friedel–Crafts
cyclialkylation research[24–26] to develop facile alternative
routes to the building of novel and known heteropolycyclic
systems[27,28] via cyclialkylations of suitably synthesized nitro-
gen-containing alkanols. In this paper, we apply the same
methodology for the generation of some new substituted 5,6-
dihydro-11H-benzo[b][1]benzazepines via cyclialkylation of
suitably synthesized nitrogen-containing alkanols. Compared
with earlier approaches, the present cycliakylation pathways are
not only easier but also more economical and more general. In
fact, the results showed that several difficult substituted hetero-
cyclic skeletons can be easily obtained with the advantages of
shorter reaction times and higher yields.
with bromobenzene and with 2-bromotoluene in the presence
of KOH/DMSO to afford 2-(2-phenylamino)phenyl)acetonitrile
(8a) and 2-(2-(o-toluidino)phenyl)acetonitrile (8b) respective-
ly. The third route comprised the reaction of aniline and
o-toluidine with 2-(2-bromophenyl)acetonitrile (10)[34] to give
8a and 8b respectively.
Once key intermediates 8a, b were formed, they were
converted into ethyl 2-(2-(arylamino)phenyl)acetate esters
11a, b by ethanolysis with ethanol and H2SO4, and then to
N-tosylated esters 12a, b by reaction with tosyl chloride in
pyridine. The resulting esters 12a, b were converted into
cyclialkylating alcohol substrates 13a–f by addition of two
equivalents of the corresponding Grignard reagents[35]
(Scheme 2) and to cycliacylating acid substrates 14a, b by
hydrolysis with KOH in methanol (Scheme 3). The conditions
and results for the synthesis of alkanols 13a–f are listed in
Table 1. The structures of all new alcohols were appropriately
established by both elemental and spectral analyses.
Cyclialkylation as a Pathway to the Synthesis of Parent
5,6-Dihydro-11H-benzo[b][1]benzazepine 1a and its
1-Methyl Analogue 1b
Knowing that primary alkanols can hardly close to either a five-
or seven-membered ring, we abandoned the cyclialkylation
pathway for synthesizing the parent 5,6-dihydro-11H-benzo[b]
[1]benzazepine 1a and its 1-methyl analogue 1b. Rather, the
best results to make them were obtained by cycliacylation of the
corresponding acids. Thus, the tosylated esters 12a, b were
hydrolyzed with KOH in methanol to furnish acids 14a, b. Ring
closure of the latter tosylated acids to dibenzo[b,f]azepinones
(15a, b)[36] was carried out in the presence of AlCl3, 85 %
H2SO4 or PPA. Wolff–Kishner reduction[37] of the resulting
ketones gave the corresponding 5,6-dihydro-11H-benzo[b][1]
benzazepines 1a, b[38] in high yields (Scheme 3, Table 2, entries
1 and 2).
Results and Discussion
Synthetic Plan for the Desired Cyclialkylation
and Cycliacylation Substrates
Both of the cyclialkylation substrates (13a–f) and the cyclia-
cylation substrates (14a, b) were obtained through 2-(2-
phenylamino)phenyl)acetonitrile (8a) and 2-(2-(o-toluidino)
phenyl)acetonitrile (8b) as common key intermediates. These
key intermediates were prepared by the three alternative routes
formulated in Scheme 1. The first route involved esterifica-
tion[29] of 2-(2-(arylamino)phenyl)acetic acids (4a, b) with
ethanol and H2SO4 to give the corresponding ethyl 2-(2-
(arylamino)phenyl)acetate (5a, b).[30] Reduction[31a] of the lat-
ter esters with LiAlH4 gave alcohols 6a[31b,c], 6b, which were
converted into chlorides 7a, b with SOCl2 in pyridine and then to
nitriles 8a–b by reaction with KCN in ethanol.
Cyclialkylation of Alkanols 13a–f to 5,5-Disubstituted-
5,6-dihydro-11H-benzo[b][1]benzazepines (1c–h)
Examination of Scheme 3 and Table 2 reveals that Friedel–
Crafts cyclialkylation of tosylated alkanols 13a–f in the
presence of AlCl3, 85 % H2SO4 or PPA gave a new series of
5,5-disubstituted-5,6-dihydro-11H-benzo[b][1]benzazepines
(1c–h).
The second route encompassed the catalyzed Ullmann[32]
N-coupling reaction of 2-(2-aminophenyl)acetonitrile (9)[33]
Except for alkanols 13c and 13f, most cyclialkylations of
alcohols 13a, b, e, d could easily achieved at room temperature

Friedel–Crafts Chemistry
637
in the presence of AlCl3, 85 % H2SO4, or PPA at 210–2308C
(Scheme 4; Table 2, entries 3, 4, 6, and 7). The results with these
catalysts gave similar products whose elemental, spectral, and
chromatographic data confirmed the formation of tricyclic
dibenzazepines 1c, d, f, g.
A plausible carbocation mechanism accounting for the
results is based on the generation of a tertiary carbocation by
loss of water on treatment of such alcohols with acidic catalysts.
The resulting carbocation underwent ring closure to substituted
5,6-dihydro-11H-benzo[b][1]benzazepines (1c–h) in overall
high reaction yields. The removal of the tosyl group occurred
concurrently with the closure step, as noted in other reported
cases.[39] In almost all cases, yields were over 80 %.
Ring closure of highly sterically hindered alcohols 13c and
13f was achieved using AlCl3, 85 % H2SO4 or PPA catalysts
under more severe conditions to give diphenylazepines 1e and
1h respectively (Scheme 4). The doubly benzylic nature of the
resulting tertiary benzylic carbocations 16c, f (hence their
stability and lower reactivity) coupled with the steric effect
exerted by the two bulky phenyl groups retards the ring closure.
Therefore, these factors can be overcome using more forcing
conditions in the cyclialkylations of these alcohols 13c and 13f.
That of course, like in similar cases,[24,25,40] raises the activation
energy for the ring closure. As evident from Table 2 (entries 5
and 8), cyclialkylations of 13c and 13f could be easily achieved
with AlCl3 for 20 h in dichloromethane (DCM) solution
under reflux condition, or with 85 % H2SO4 for 48 h at room
CN
COOEt
COOEt
Ts
ii
i
NH
Ar
N
NH
Ar
a: Ar ϭ Ph
b: Ar ϭ 2-MePh
Ar
iii
8a, b
11a, b
12a, b
OH
13a: R1 ϭ Me, Ar ϭ Ph
13b: R1 ϭ Et, Ar ϭ Ph
R1
R1
Ts
13c: R1 ϭ Ph, Ar
ϭ Ph
N
Ar
13d: R1 ϭ Me, Ar ϭ 2-MePh
13e: R1 ϭ Et, Ar ϭ 2-MePh
13f: R1 ϭ Ph, Ar ϭ 2-MePh
13a–f
Scheme 2. Reagents and conditions: (i) EtOH/H2SO4, 12 h, reflux. (ii) p-
Toluenesulfonyl chloride (p-TosCl)/pyridine, 70–808C, 4 h. (iii) RMgX,
THF/Et2O, NH4Cl solution (Table 1).
O
COOEt
COOH
ii
Ts
i
Ts
N
N
N
H
a: Ar ϭ Ph
b: Ar ϭ 2-MePh
Ar
Ar
R
14a, b
12a, b
15a, b
iii
a: R ϭ H
b: R ϭ Me
R1
OH
R1
R1
R1
ii
Ts
N
N
H
Ar
R
13a–f
1a–h
1e: R ϭ H, R1 ϭ Ph
1f: R ϭ Me, R1 ϭ Me
1g: R ϭ Me, R1 ϭ Et
1a: R ϭ R1 ϭ H
1b: R ϭ Me, R1 ϭ H
1c: R ϭ H, R1 ϭ Me
1d: R ϭ H, R1 ϭ Et
1h: R ϭ Me, R1 ϭ Ph
Scheme 3. Reagents and conditions: (i) KOH/MeOH, room temperature, 15 h. (ii) AlCl3, 85 % H2SO4 or PPA
catalysts (Table 2). (iii) KOH, N2H4ꢀH2O, EtOH/diethylene glycol (DEG), 13 h, reflux.
Table 1. Conditions and results for the synthesis of alkanols 13a f
]
Entry
Starting material
Product
ConditionsA
Mp [8C] (n2D5
)
Product [%]B
Ar
R1
1
2
3
4
5
6
12a
12a
12a
12b
12b
12b
Ph
Ph
Ph
Me
Et
MeMgI, Et2O, rt, 5 h
118
(1.594)
(1.566)
147
13a (91)
13b (87)
13c (82)
13d (93)
13e (89)
13f (85)
EtMgBr, Et2O, rt, 5 h
Ph
Me
Et
PhMgBr, Et2O, rt, 10 h
MeMgI, THF/Et2O, rt, 5 h
EtMgBr, Et2O, rt, 6 h
2-MePh
2-MePh
2-MePh
(1.602)
82
Ph
PhMgBr, THF/Et2O, rt, 11 h
AAll reactions were performed using 0.3 equiv. excess of RMgX.
BIsolated yield relative to substrate.

638
H. A. K. Abd El-Aal and A. A. Khalaf
Table 2. Friedel Crafts cycliacylations and cyclialkylations producing dibenzo[b, f ]azepinones 15a, b and benzo[b][1]benzazepines 1c h
]
]
Entry
Substrate
COOH
Product
Conditions
Product [%]A
O
AlCl3,B DCM,C 6 h, reflux
85 % H2SO4,D 8 h, rt
PPA,E 5 h, 2208C
15a (80)
15a (82)
15a (77)
Ts
N
1
14a
14b
N
H
COOH
Ts
O
AlCl3, DCM, 5 h, reflux
85 % H2SO4, 8 h, rt
PPA, 6 h, 2208C
15b (85)
15b (84)
15b (79)
N
2
N
H
OH
Me
Me
Ts
Me
Me
AlCl3, DCM, 2 h, rt
85 % H2SO4, 15 h, rt
PPA, 2 h, 2208C
1c (90)
1c (87)
1c (81)
N
3
N
H
13a
13b
13c
OH
Et
Et
Et
AlCl3, DCM, 2 h, rt
85 % H2SO4, 10 h, rt
PPA, 2 h, 2208C
1d (84)
1d (81)
1d (75)
Et
Ts
N
4
5
6
7
N
H
OH
Ph
Ph
Me
Et
Ph
Me
Et
AlCl3, DCM, 20 h, reflux
85 % H2SO4, 48 h, rt
PPA, 13 h, 2308C
1e (89)
1e (84)
1e (78)
Ph
Ts
N
N
N
N
N
H
OH
Me
Me
Ts
AlCl3, DCM, 2 h, rt
85 % H2SO4, 14 h, rt
PPA, 2 h, 2108C
1f (92)
1f (90)
1f (80)
N
H
13d
13e
OH
Et
AlCl3, DCM, 2 h, rt
85 % H2SO4, 12 h, rt
PPA, 2 h, 2208C
1g (86)
1g (83)
1g (80)
Et
Ts
N
H
OH
Ph
Ph
Ph
Ph
AlCl3, DCM, 20 h, reflux
85 % H2SO4, 48 h, rt
PPA, 12 h, 2308C
1h (91)
1h (88)
1h (82)
Ts
8
N
H
13f
AIsolated yield relative to substrate.
BWith AlCl3 catalyst, reactant proportions were: carbinol (3 mmol), AlCl3 (6 mmol), solvent (10 mL).
CDichloromethane.
DWith H2SO4 catalyst, reactant proportions were: carbinol (0.4 g) and 85 % H2SO4 (4 mL).
EWith PPA catalyst, reactant proportions were: carbinol (0.5 g) and PPA (5 g).

Friedel–Crafts Chemistry
639
Ph
OH
Ph
Ph
Ts
ϩ
Ph
Ph
Ph
Catalyst
Hϩ,
H2O
Ϫ
Hϩ
TsOH
Ts
N
N
Ϫ
Ϫ
N
H
R
R
1e:
1h:
R
R
ϭ
ϭ
H
13c:
13f:
R
ϭ
ϭ
H
R
Me
R
Me
1e, h
13c, f
16a, b
Scheme 4. Cyclialkylations of alkanols 13a–f.
temperature. However, on using PPA catalyst, cyclization of
alcohols was accomplished by heating for 12–13 h at 2308C.
whose analytical, physical, and spectroscopic data are as
follows:
Ethyl 2-(Phenylamino)benzoate 5a
Conclusion
Brownish viscous oil, 94 % (lit.[30a] bp 184–1878C/6 mmHg).
n2D5 1.572. nmax (film)/cmꢁ1 3345, 3050, 2985, 1745, 1600, 1570,
1490, 1455, 1330, 1275, 745. dH (90 MHz, CDCl3) 1.30 (3H, t,
J 7.5, CH3), 4.2 (2H, t, J 7.5, CH2), 4.8 (1H, s, NH), 6.45–7.70
(9H, m, Ar–H). m/z (EI, 70 eV) (%) 241 (Mþ, 42), 196 (100), 168
(35), 149 (63), 104 (16), 90 (12), 76 (7), 66 (5). Anal. calc. for
C15H15NO2 (241): C 74.68, H 6.22, N 5.80. Found: C 74.53,
H 6.45, N 6.13 %.
This work introduces the synthesis of eight 5,6-dihydrobenzo[b]
[1]benzazepine derivatives via intramolecular Friedel–Crafts
cyclialkylation reactions of suitably substituted nitrogen-
containing alkanols catalyzed by AlCl3, 85 % H2SO4 or PPA.
The work represents an extension of our continued efforts
towards the efficient synthesis of medicinally important
heteropolycycles by facile, economic, and simple modern
Friedel–Crafts pathways.
Ethyl 2-(o-Tolylamino)benzoate 5b
Experimental
Reddish viscous oil, 89 %. n2D5 1.595. nmax (film)/cmꢁ1 3340,
3043, 2990, 1740, 1590, 1550, 1460, 1450, 1335, 1285, 750. dH
(90 MHz, CDCl3) 1.30 (3H, t, J 7.5, CH3), 2.3 (3H, s, CH3), 4.2
(2H, t, J 7.5, CH2), 4.8 (1H, s, NH), 6.50–7.70 (8H, m, Ar–H).
m/z (EI) (%) 255 (Mþ, 66), 240 (52), 210 (100), 195 (34), 149
(82), 105 (35), 91 (15), 76 (12), 66 (7). Anal. calc. for
C16H17NO2 (255): C 75.29, H 6.66, N 5.49. Found: C 75.52,
H 6.48, N 5.62 %.
General
All reagents were purchased from Merck, Sigma or Aldrich
Chemical Co. and were used without further purification.
Melting points were measured on a digital Gallenkamp capillary
melting point apparatus and are uncorrected. The IR spectra
were determined with a Shimadzu 470 infrared spectropho-
tometer using KBr wafer and thin film techniques. The 1H NMR
and 13C NMR spectra were recorded on Jeol LA 400 MHz
FT-NMR (400 MHz for H, 100 MHz for 13C) and on Varian
1
General Procedure for the Synthesis of (2-(Arylamino)
NMR (90 MHz) spectrometers using CDCl3 solvent with TMS
as internal standard. Chemical shifts (d) and J values are
reported in ppm and Hz respectively. Elemental analyses were
performed on a Perkin–Elmer 2400 Series II analyser. The mass
spectra were recorded on a JEOL JMS 600 spectrometer at an
ionizing potential of 70 eV electron impact (EI) ionization mode
using the direct inlet system. Reactions were monitored by thin-
layer chromatography (TLC) using precoated silica plates and
visualized with UV light. Flash column chromatography was
performed on silica gel and basic alumina.
phenyl)methanols 6a, b
A solution of ethyl 2-(arylamino)benzoates 5a or 5b (20 mmol)
in THF (35 mL) was added over 30 min to an ice-cold (08C)
suspension of LiAlH4 (LAH) (2.7 g, 22 mmol)[31a] in ether
(40 mL). The reduction was complete after stirring for 2 h at
room temperature. The cold reaction mixture was quenched at
08C by the sequential addition of water (5 mL), NaOH solution
(25 mL, 20 %) and water (25 mL); then, it was warmed to room
temperature. Suction filtration removed the white precipitate of
aluminium compounds, which were thoroughly triturated with
ethyl acetate. The organic layer was separated, washed with
water, dried over anhydrous Mg2SO4 and the solvent was
evaporated under vacuum to afford crude alcohols 6a, b. Puri-
fication of the crude products by flash column chromatography
(basic alumina, EtOAc/n-hexane, 2 : 3) gave the pure alcohols.
The yields and spectral data are given below:
Synthesis of 2-(2-(Arylamino)phenyl)acetonitrile 8a, b
These compounds were synthesized via three different path-
ways: Path A, starting from N-arylanthranilic acids 4a, b;
Path B, starting from 2-(2-aminophenyl)acetonitrile 9; and
Path C, starting from 2-(2-bromophenyl)acetonitrile 10.
Path A comprises four reaction steps starting from arylan-
thranilic acids 4a, b.
(2-(Phenylamino)phenyl)methanol 6a[31b,c]
Yellow needles, 85 %; mp 96–988C (acetone). nmax (KBr)/
cmꢁ1 3550, 3320, 3080, 2965, 1590, 1470, 1460, 1445, 1330,
760. dH (90 MHz, CDCl3) 2.7 (1H, s, OH exchangeable with
D2O), 4.6 (2H, s, CH2), 4.9 (1H, s, NH), 6.40–7.90 (9H, m,
Ar–H). m/z (EI) (%) 199 (Mþ, 10), 182 (84), 181 (100), 168 (43),
107 (25), 90 (11), 76 (8). Anal. calc. for C13H13NO (199):
C 78.39, H 6.53, N 7.03. Found: C 78.52, H 6.37, N 6.88 %.
General Procedure for the Synthesis of N-Arylanthranilic
Acid Esters 5a, b
Esterification of N-arylanthranilic acids 4a, b was carried out
with ethanol and H2SO4 following standard procedures.[29]
Purification of the crude esters by flash column chromatography
(basic alumina, EtOAc/n-hexane, 1 : 1) gave pure esters 5a, b

640
H. A. K. Abd El-Aal and A. A. Khalaf
(2-(o-Toluidino)phenyl)methanol 6b
NH), 6.4–7.50 (9H, m, Ar–H). m/z (EI) (%) 209 ([Mþ þ 1], 20),
208 (100), 207 (24), 181 (35), 168 (72), 131 (23), 116 (44), 91
(13), 76 (6). Anal. calc. for C14H12N2 (208), C 80.76, H 5.77, N
13.46. Found: C 80.72, H 5.85, N 13.43 %.
White plates, 88 %; mp 102–103.58C (methanol). nmax
(KBr)/cmꢁ1 3540, 3340, 3090, 2985, 1590, 1460, 1445, 1360,
755. dH (90 MHz, CDCl3) 2.3 (3H, s, CH3), 2.6 (1H, s, OH
exchangeable with D2O), 4.6 (2H, s, CH2) 4.8 (1H, s, NH),
6.40–7.80 (8H, m, Ar–H). m/z (EI) (%) 213 (Mþ, 12), 198 (22),
196 (38), 195 (100), 182 (52), 167 (31), 106 (29), 91 (12), 76 (9).
Anal. calc. for C14H15NO (213): C 78.87, H 7.04, N 6.57. Found:
C 79.05, H 7.10, N 6.44 %.
2-(2-(o-Toluidino)phenyl)acetonitrile 8b
White plates; mp 58–598C (n-hexane). nmax (KBr)/cmꢁ1
3330, 3010, 2980, 2240, 1590, 1490, 1450, 1360, 1283, 750.
dH (90 MHz, CDCl3) 2.3 (3H, s, CH3), 3.6 (2H, s, CH2), 5.2 (1H,
s, NH), 6.4–7.70 (8H, m, Ar–H). m/z (EI) (%) 223 ([Mþ þ 1],
16), 222 (100), 207 (31), 195 (43), 131 (26), 105 (23), 91 (11), 90
(15), 76 (6). Anal. calc. for C15H14N2 (222), C 81.08, H 6.30, N
12.61. Found: C 81.25, H 6.13, N 12.62 %.
General Procedure for the Synthesis of N-(2-(Chloromethyl)
phenyl)benzenamines 7a, b
A solution of (2-(arylamino)phenyl)methanols 6a, b (15 mmol)
in pyridine (1.18 g, 15 mmol) was cooled to 5–108C while
freshly distilled thionyl chloride (3.6 g, 30 mmol) was added
dropwise over a period of 25 min. The reaction mixture was then
heated for 3 h on a water bath and finally decomposed by
addition of cold water (10 mL) and NaOH solution (15 mL,
10 %). The resulting chlorides were extracted with diethyl ether,
washed with water, and dried over MgSO4. The solvent was
distilled off on a water bath, leaving the crude products, which
were purified by flash column chromatography (basic alumina,
light petroleum (60–808C)/EtOAc, 3 : 1) to give the desired pure
chlorides 7a, b. The yields and spectral data are given below:
Path B: General Procedure for Arylation[32]
of 2-(2-Aminophenyl)acetonitrile 9
A mixture of 2-(2-aminophenyl)acetonitrile (9)[33] (3.3 g,
25 mmol), KOH (0.14 g, 2.5 mmol), haloarenes (bromobenzene
or o-bromotoluene) (25 mmol), and dry DMSO (15 mL) was
stirred in an oil bath for 12 h at 1208C. The mixture was cooled,
quenched with a saturated aq. NH4Cl (20 mL) and then extracted
with ethyl acetate (2 ꢂ 10 mL). The combined organic phases
were washed with water, dried over anhydrous MgSO4 and the
solvent was evaporated. The residues were purified by flash
column chromatography (basic alumina, EtOAc/n-hexane,
1 : 2). Physical and spectral data of compounds 8a, b are similar
to those obtained through Path A.
N-(2-(Chloromethyl)phenyl)benzenamine 7a
Cream crystals, 89 %; mp 75–768C (benzene). nmax (KBr)/
cmꢁ1 3350, 3020, 2977, 1585, 1470, 1450, 1380, 760. dH
(90 MHz, CDCl3) 4.6 (2H, s, CH2), 4.8 (1H, s, NH), 6.40–7.70
(9H, m, Ar–H). m/z (EI) (%) 219.5 ([Mþ þ 2], 13), 217.5 (42),
182 (100), 140 (51), 125 (15), 90 (86), 76 (13). Anal. calc. for
C13H12ClN (217.5): C 71.72, H 5.51, Cl 16.32, N 6.43. Found:
C 71.52, H 5.45, Cl 16.37, N 6.65 %.
Path C: General Procedure for Arylation
of 2-(2-Bromophenyl)acetonitrile 10
A mixture of 2-(2-bromophenyl)acetonitrile 10[34] (3.0 g,
15 mmol), amines (aniline or o-toludine) (45 mmol), CuCl
(0ꢀ05 g, 0.5 mmol), and K2CO3 (6.2 g, 45 mmol) in dichloro-
benzene (15 mL) was heated with continuous stirring for 15 h at
1708C. After removal of the solvent under vacuum, ammonia
solution (50 mL) was added and the mixture was left to stand for
2 h. Ethyl acetate (100 mL) and water (50 mL) were added. The
organic phase was separated, washed with water (2 ꢂ 100 mL)
and brine solution (50 mL), dried over anhydrous MgSO4, fil-
tered, and the solvent was removed under vacuum. The crude
nitriles 8a, b were purified by flash chromatography (basic
alumina, EtOAc/n-hexane, 1 : 2). Physical and spectral data of
compounds 8a, b are similar to those obtained through Path A.
N-(2-(Chloromethyl)phenyl)-2-methylbenzenamine 7b
Pale yellow crystals, 83 %; mp 63–658C (light petroleum
60–808C). nmax (KBr)/cmꢁ1 3345, 3046, 2940, 1590, 1460,
1445, 1320, 764. dH (90 MHz, CDCl3) 2.3 (3H, s, CH3), 4.6
(2H, s, CH2), 4.8 (1H, s, NH), 6.3–7.4 (8H, m, Ar–H). m/z (EI)
(%) 233.5 ([Mþ þ 2], 21), 231.5 (58), 216 (30), 196 (100), 181
(62), 141 (25), 125 (20), 90 (71), 76 (11). Anal. calc. for
C14H14ClN (231.5): C 72.57, H 6.04, Cl 15.33, N 6.04. Found:
C 72.84, H 5.97, Cl 14.92, N 6.27 %.
General Procedure for the Synthesis of Ethyl
2-(2-(Arylamino)phenyl)acetate 11a, b
General Procedure for the Synthesis of 2-(2-(Arylamino)
phenyl)acetonitrile 8a, b
A mixture of 2-(2-(arylamino)phenyl)acetonitriles 8a, b (3.12 g,
15 mmol), absolute ethanol (25 mL), and concentrated sulfuric
acid (5 mL) was stirred under reflux for 12 h. The excess alcohol
removed by distillation and the residue was diluted with water
(50 mL), basified with Na2CO3 solution (20 mL, 30 %) and
extracted with ether. The ethereal layer was separated, washed
with water and dried over MgSO4. The solvent was evaporated
under vacuum and the crude esters were subjected to flash
column chromatography (basic alumina, EtOAc/n-hexane, 2 : 3)
to give the pure esters 11a, b. The yields and spectral data are
given below:
To a solution of potassium cyanide (1.5 g, 24 mmol) in water
(10 mL) was added a solution of chlorides 7a or 7b (15 mmol) in
ethanol (30 mL) over a period of 30 min. The mixture was stirred
under reflux for 5 h, concentrated and then diluted with water
(40 mL). The residue was extracted with ether and washed
successively with saturated NaHCO3, water and dried over
anhydrous MgSO4. The ether solution was removed under
vacuum and the residues were purified by flash column
chromatography (basic alumina, EtOAc/n-hexane, 2 : 3) or
recrystallized from suitable solvents to give 8a, b. Analytical,
physical, and spectroscopic data are given below:
2-(2-(Phenylamino)phenyl)acetonitrile 8a
Ethyl 2-(2-(Phenylamino)phenyl)acetate 11a
White crystals; mp 72–738C (n-hexane/benzene). nmax
(KBr)/cmꢁ1 3345, 3030, 2950, 2230, 1600, 1480, 1445, 1375,
1290, 755. dH (90 MHz, CDCl3) 3.6 (2H, s, CH2), 4.9 (1H, s,
Yellowish oil, 93 %. n2D5 1.584. nmax (film)/cmꢁ1 3386, 3065,
2970, 1745, 1600, 1560, 1490, 1455, 1340, 1170, 745. dH
(90 MHz, CDCl3) 1.30 (3H, t, J 7.5, CH3), 3.5 (2H, s, CH2),

Friedel–Crafts Chemistry
641
4.2 (2H, s, J 7.5, CH2), 4.8 (1H, s, NH), 6.30–7.20 (9H, m,
Ar–H). m/z (EI) (%) 255 (Mþ, 25), 240 (27), 210 (100), 195 (33),
164 (19), 148 (37), 119 (12), 91 (8), 90 (16), 77 (5). Anal. calc.
for C16H17NO2 (255): C 75.29, H 6.66, N 5.49. Found: C 75.48,
H 6.72, N 5.21 %.
over anhydrous MgSO4. The solvent was removed under vac-
uum and the residue was purified by flash column chromato-
graphy (basic alumina, EtOAc/n-hexane, 1 : 1), yielding the
pure alcohols 13a–f. The conditions and yields are shown in
Table 2 and spectral data are given below:
Ethyl 2-(2-(o-Tolylamino)phenyl)acetate 11b
1-(2-(N-Phenyl-N-tosylamino)phenyl)-2-methylpropan-
2-ol 13a
Brownish viscous oil, 89 %. n2D5 1.617. nmax (film)/cmꢁ1
3365, 3060, 2990, 1750, 1605, 1570, 1495, 1440, 1335, 1160,
745. dH (90 MHz, CDCl3) 1.30 (3H, t, J 7.5, CH3), 2.3 (3H, s,
CH3), 3.5 (2H, s, CH2), 4.1 (2H, s, J 7.5, CH2), 4.7 (1H, s, NH),
6.20–7.15 (8H, m, Ar–H). m/z (EI) (%) 270 ([Mþ þ 1], 5), 269
(38), 254 (16), 224 (100), 209 (23), 163 (23), 118 (14), 90 (20),
77 (4). Anal. calc. for C17H19NO2 (269): C 75.83, H 7.06, N
5.20. Found: C 75.59, H 6.92, N 5.47 %.
White needles; mp 118–1208C (benzene). nmax (KBr)/cmꢁ1
3340, 3060, 2975, 1610, 1560, 1450, 1445, 1375, 1330, 760. dH
(400 MHz, CDCl3) 1.10 (6H, s, 2CH3), 2.1 (1H, s, OH exchange-
able with D2O), 2.30 (3H, s, CH3), 2.55 (2H, s, CH2), 6.40–7.60
(13H, m, Ar–H). m/z (EI) (%) 395 (Mþ, 9), 380 (38), 377 (100),
365 (47), 340 (91), 300 (25), 225 (43), 222 (28), 191 (25),
180 (62), 177 (20), 168 (9), 163 (43), 91 (12), 90 (8), 77 (6).
Anal. calc. for C23H25NO3S (395): C 69.87, H 6.32, N 3.54,
S 8.10. Found: C 69.66, H 6.19, N 3.72, S 8.27 %.
General Procedure for the Tosylation of Esters 11a, b
Ester 11a or 11b (12 mmol) was dissolved in a mixture of
chloroform (15 mL) and pyridine (4.5 mL, 57.7 mmol). The
solution was cooled to 08C, and p-toluenesulfonyl chloride
(5.75 g, 30.2 mmol) was added in portions over 5 min. The
resulting solution was stirred for 2 h at room temperature and
further heated for 2 h in a water bath at 70–808C. After cooling,
water (100 mL) was added and the mixture was extracted with
ether. The ether layer was washed thoroughly with HCl solution
(30 mL, 10 %), then with saturated NaHCO3 solution (30 mL)
and water. The solvent was evaporated under vacuum, and the
residue was chromatographed using basic alumina (EtOAc/
n-hexane, 2 : 3) to give the pure product. The yields and spectral
data are given below:
3-(2-(N-Phenyl-N-tosylamino)benzyl)pentan-3-ol 13b
Reddish viscous oil. n2D5 1.594. nmax (film)/cmꢁ1 3320, 3040,
2977, 1600, 1560, 1455, 1430, 1390, 1330, 750. dH (400 MHz,
CDCl3) 0.90 (6H, t, J 7.5, 2CH3), 1.40 (4H, q, J 7.5, 2CH2), 2.10
(1H, s, OH exchangeable with D2O), 2.30 (3H, s, CH3), 2.6 (2H,
s, CH2), 6.45–7.60 (13H, m, Ar–H). m/z (EI) (%) 423 (Mþ, 15),
405 (100), 376 (74), 347 (31), 288 (76), 270 (41), 268 (59),
239 (20), 210 (47), 190 (55), 181 (39), 178 (19), 168 (12),
91 (16), 90 (10), 77 (8). Anal. calc. for C25H29NO3S (423):
C 70.92, H 6.85, N 3.30, S 7.56. Found: C 70.94, H 6.75, N 3.52,
S 7.43 %.
2-(2-(N-Phenyl-N-tosylamino)phenyl)-1,1-
diphenylethanol 13c
Ethyl 2-(2-(N-Phenyl-N-tosylamino)phenyl)acetate 12a
Reddish-brown viscous oil. n2D5 1.566. nmax (film)/cmꢁ1
3450, 3085, 2974, 1600, 1480, 1460, 1445, 1370, 1345, 740.
dH (400 MHz, CDCl3) 2.2 (1H, s, OH exchangeable with D2O),
2.30 (3H, s, CH3), 3.3 (2H, s, CH2), 6.40–7.80 (21H, m, Ar–H).
m/z (EI) (%) 519 (Mþ, 8), 501 (100), 442 (64), 424 (20),
365 (24), 364 (72), 287 (45), 210 (71), 191 (42), 180 (35), 177
(18), 168 (14), 133 (17), 90 (12), 90 (8), 77 (8). Anal. calc. for
C33H29NO3S (519) C 76.30, H 5.58, N 2.69, S 6.16. Found:
C 76.42, H 5.47, N 2.88, S 6.31 %.
White crystals, 92 %; mp 152–1538C (benzene). nmax (KBr)/
cmꢁ1 3070, 2980, 1740, 1590, 1520, 1450, 1440, 1390, 1320,
1160, 747. dH (90 MHz, CDCl3) 1.30 (3H, t, J 7.5, CH3), 2.30
(3H, s, CH3), 3.55 (2H, s, CH2), 4.1 (2H, s, J 7.5, CH2), 6.45–
7.50 (13H, m, Ar–H). m/z (EI) (%) 410 ([Mþ þ 1], 12), 409 (Mþ,
31), 364 (100), 254 (83), 209 (50), 181 (66), 163 (31), 118 (17),
90 (24) 77 (9). Anal. calc. for C23H23NO4S (409) C 67.48,
H 5.62, N 3.42, S 7.82. Found: C 67.58, H 5.84, N 3.41, S 7.74 %.
Ethyl 2-(2-(N-o-Tolyl-N-tosylamino)phenyl)acetate 12b
1-(2-(N-o-Tolyl-N-tosylamino)phenyl)-2-methylpropan-
2-ol 13d
Pale yellow crystals, 90 %; mp 127–128.58C (benzene). nmax
(KBr)/cmꢁ1 3068, 2950, 1750, 1585, 1560, 1450, 1440, 1385,
1340, 1170, 745. dH (90 MHz, CDCl3) 1.30 (3H, t, J 7.5, CH3),
2.30 (6H, s, 2CH3), 3.5 (3H, s, CH2), 4.1 (2H, s, J 7.5, CH2),
6.35–7.50 (12H, m, Ar–H). m/z (EI) (%) 424 ([Mþ þ 1], 9), 423
(Mþ, 41), 378 (100), 363 (49), 332 (61), 268 (42), 253 (33), 208
(20), 177 (39), 118 (22), 91 (12), 90 (18), 77 (9). Anal. calc. for
C24H25NO4S (423): C 68.08, H 5.91, N 3.30, S 7.56. Found:
C 68.26, H 5.89, N 3.42, S 7.57 %.
White plates; mp 147–1498C (cyclohexane). nmax (KBr)/
cmꢁ1 3420, 3040, 2960, 2850, 1580, 1470, 1450, 1440, 1395,
1330, 750, 670. dH (400 MHz, CDCl3) 1.20 (6H, s, 2CH3),
2.3 (6H, s, 2CH3), 2.10 (1H, s, OH exchangeable with D2O),
2.60 (2H, S, CH2), 6.55–7.90 (20H, m, Ar–H). m/z (EI) (%) 409
(Mþ, 12), 394 (35), 391 (100), 364 (42), 350 (92), 335(12), 320
(22), 318 (20), 303 (31), 254 (55), 238 (37), 224 (14), 209 (23),
190 (21), 177 (18), 168 (9), 148 (29), 90 (15), 77 (4). Anal. calc.
for C24H27NO3S (409) C 70.41, H 6.60, N 3.42, S 7.82. Found:
C 70.27, H 6.53, N 3.66, S 7.76 %.
General Procedure for the Synthesis of Alcohols 13a–f
To an ice-cold Grignard reagent solution obtained as usual[35]
from Mg turnings (0.32 g, 13 mmol) and alkyl or aryl halide
(13 mmol) in ether (40 mL), was added a solution of esters 12a
or 12b (5 mmol) in ether or THF (30 mL). The reaction mixture
was stirred at the required temperature for the appointed time
(Table 2), followed by decomposition with saturated aq. NH4Cl
soln. The product was extracted with ether (3 ꢂ 30 mL) and the
combined organic phases were washed with water and dried
3-(2-(N-o-Tolyl-N-tosylamino)benzyl)pentan-3-ol 13e
Pale yellow viscous oil. n2D5 1.602. nmax (film)/cmꢁ1 3480,
3090, 2970, 1590, 1480, 1455, 1440, 1400, 1345, 745. dH
(400 MHz, CDCl3) 0.90 (6H, t, J 7.5, 2CH3), 1.35 (4H, q,
J 7.5, 2CH2), 2.10 (1H, s, OH exchangeable with D2O), 2.30
(6H, s, 2CH3), 2.6 (2H, s, CH2), 6.45–7.80 (13H, m, Ar–H). m/z

642
H. A. K. Abd El-Aal and A. A. Khalaf
(EI) (%) 437 (Mþ, 9), 436 (78), 419 (100), 422 (62), 408 (52),
393 (16), 379 (27), 364 (15), 330 (51), 282 (33), 253 (20),
224 (37), 208 (49), 191 (36), 180 (30), 177 (22), 168 (15),
91 (19), 90 (11), 77 (6). Anal. calc. for C26H31NO3S (437)
C 71.39, H 7.09, N 3.20, S 7.32. Found: C 71.24, H 7.18, N 3.37,
S 7.55 %.
EtOAc/n-hexane, 1 : 1) to give the pure products 15a, b and
1c–h. The conditions and yields for the cyclic products are
shown in Table 2 and the physical and spectral data of the
products are given below.
Procedure A: Cyclialkylations Using AlCl3 Catalyst
To a stirred suspension of AlCl3 (6 mmol) in DCM (5 mL)
was added a solution of acid 14a, b or carbinol 13a–f (3 mmol) in
DCM (5 mL) dropwise with stirring over 10 min. The reaction
mixture was further stirred for a certain time at the desired
temperature (Table 2), then cooled in an ice-bath. Decomposi-
tion of the reaction complex was carried out by careful addition
of ice-cold HCl solution (20 mL, 5 %). The residue was
extracted with EtOAc (3 ꢂ 20 mL). The combined organic
phases were washed Na2CO3 (20 mL, 10 %) and water, and
dried over anhydrous MgSO4. The solvent was evaporated under
reduced pressure to afford the crude product.
2-(2-(N-o-Tolyl-N-tosylamino)phenyl)-1,1-
diphenylethanol 13f
Cream plates; mp 82–848C (benzene). nmax (KBr)/cmꢁ1
3490, 3075, 2990, 1610, 1490, 1450, 1430, 1386, 1355, 1020,
745. dH (400 MHz, CDCl3) 1.70 (1H, s, OH exchangeable with
D2O), 1.60 (3H, s, CH3), 2.30 (3H, s, CH3), 2.30 (3H, s, CH3),
3.35 (2H, s, CH2), 6.33–7.95 (20H, m, Ar–H). m/z (EI) (%) 533
(Mþ, 11), 515 (100), 456 (61), 441 (32), 438 (41), 378 (77),
364 (21), 361 (50), 350 (10), 300 (61), 272 (17), 223 (35), 206
(28), 191 (33), 180 (27), 178 (22), 168 (10), 90 (10), 77 (4). Anal.
calc. for C34H31NO3S (533) C 76.54, H 5.81, N 2.62, S 6.00.
Found: C 76.62, H 5.75, N 2.77, S 6.17 %.
Procedure B: Cyclialkylations Using 85 % H2SO4
Catalyst
A mixture of acid 14a, b or carbinol 13a–f (0.4 g) and 85 %
H2SO4 (4 mL) was stirred for a certain time (Table 2) at room
temperature. Afterwards, the reaction mixture was cooled in an
ice-bath, diluted with water (30 mL), basified by addition of
Na2CO3 solution (20 mL, 30 %) and finally extracted with ether
(3 ꢂ 20 mL). The combined organic layers were washed succes-
sively with water and dried over MgSO4. The solvent was
evaporated under reduced pressure to afford the crude product.
General Procedure for the Synthesis of 2-(2-(Arylamino)
phenyl)acetic Acid 14a, b
To a solution of tosylated ester 12a or 12b (8 mmol) in methanol
(20 mL) was added in small increments with swirling KOH
solution (7 mL, 10 %). After 15 h at room temperature, the clear
solution was diluted with water (500 mL) and then poured with
stirring into an ice-cold dilute HCl solution (25 mL, 15 %). The
solid acid was filtered off and dissolved with slight warming in
NaHCO3 solution (40 mL, 20 %), filtered and acidified. The
precipitated acid was filtered off, washed successively with
water and left to dry. The yields and spectral data are given
below:
Procedure C: Cyclialkylations Using PPA Catalyst
A stirred mixture of acid 14a, b or carbinol 13a–f (0.5 g) and
freshly prepared PPA (5 g) was heated in an oil bath and kept at
the required temperature for a certain time (Table 2). After-
wards, the flask was cooled to room temperature and basified by
addition of NaHCO3 solution (25 mL, 30 %). The residue was
extracted with ether (3 ꢂ 20 mL) and the combined organic
phases were washed with water, dried over anhydrous Na2SO4
and the solvent was evaporated under vacuum to give the crude
residue.
2-(2-(N-Phenyl-N-tosylamino)phenyl)acetic Acid 14a
White crystals, 86 %; mp 152–1548C (benzene). nmax (KBr)/
cmꢁ1 3100, 2977, 2700–2535, 1715, 1585, 1460, 1435, 1395,
1225, 745. dH (400 MHz, CDCl3) 2.30 (3H, s, CH3), 3.40 (2H, s,
CH2), 6.30–7.80 (13H, m, Ar–H), 11.00 (s, 1, COOH). m/z (EI)
(%) 381 (Mþ, 32), 364 (24), 363 (43), 336 (100), 304 (31),
260 (57), 259 (27), 226 (75), 206 (34), 183 (82), 178 (17),
168 (13), 104 (18), 91 (9), 77 (5). Anal. calc. for C21H19NO4S
(381) C 66.14, H 4.98, N 3.67, S 8.39. Found: C 66.25, H 4.77,
N 3.92, S 8.50 %.
5,6-Dihydro-11H-benzo[b][1]benzazepin-5-one 15a
White needles; mp 141–1438C (lit.[36] mp 145–1468C) (light
petroleum 60–808C/benzene). nmax (KBr)/cmꢁ1 3380, 3060,
2975, 1745, 1590, 1470, 1450, 1385, 1285, 1070, 750, 695. dH
(400 MHz, CDCl3) 3.8 (2H, s, CH2), 6.40–7.62 (8H, m, Ar–H),
9.6 (1H, s, NH). dC (100 MHz, CDCl3) 55.2, 118.4, 119.0, 119.5,
119.8, 123.0, 128.2, 128.8, 129.3, 132.2, 136.8, 140.7, 145.6,
198.5. m/z (EI) (%) 210 ([Mþ þ 1], 28), 209 (Mþ, 19), 208 (100),
194 (62), 181 (83), 177 (27), 167 (48), 151 (31), 109 (57),
91 (35), 77 (15). Anal. calc. for C14H11NO (209): C 80.38, H
5.26, N 6.69. Found: C 80.50, H 5.25, N 6.72 %.
2-(2-(N-o-Tolyl-N-tosylamino)phenyl)acetic Acid 14b
White crystals, 90 %; mp 165–166.58C (ethanol). nmax (KBr)/
cmꢁ1 3090, 2955, 2690–2520, 1718, 1600, 1520, 1430, 1370,
1235, 748. dH (400 MHz, CDCl3) 2.30 (6H, s, 2CH3), 3.45 (2H,
s, CH2), 6.40–7.80 (13H, m, Ar–H), 10.8 (s, 1, COOH). m/z (EI)
(%) 395 (Mþ, 20), 380 (18), 363 (38), 351 (100), 336 (33), 287
(40), 260 (18), 259 (71), 240 (83), 225 (27), 204 (20), 183 (62),
178 (11), 168 (10), 104 (8), 90 (11), 77 (9). Anal. calc. for
C22H21NO4S (395): C 66.83, H 5.31, N 3.54, S 8.10. Found:
C 66.82, H 5.42, N 3.55, S 7.82 %.
1-Methyl-5,6-dihydro-11H-benzo[b][1]benzazepin-
5-one 15b
White needles; mp 161–1628C (benzene). nmax (KBr)/cmꢁ1
3395, 3070, 2978, 1740, 1585, 1463, 1450, 1385, 1280, 1075,
745, 700. dH (400 MHz, CDCl3) 2.35 (3H, s, CH3), 3.80 (2H, s,
CH2), 6.40–7.55 (7H, m, Ar–H), 10.32 (1H, s, NH). dC
(100 MHz, CDCl3) 18.4, 53.2, 118.4, 118.8, 119.4, 122.7,
126.4, 127.6, 129.8, 131.4, 133.7, 134.6, 139.2, 143.2, 198.5.
m/z (EI) (%) 224 ([Mþ þ 1], 34), 223 (Mþ, 22), 208 (100), 193
(55), 182 (89), 177 (21), 165 (92), 151 (28), 119 (49), 109 (57),
Friedel–Crafts Cyclialkylation and Cycliacylation
Procedures
The procedures described earlier for cyclialkylation of hetero-
arylalkanols with AlCl3, 85 % H2SO4 or PPA[25] were essen-
tially followed. In all reactions, the crude oily or solid products
were purified by flash column chromatography (basic alumina,

Friedel–Crafts Chemistry
643
91 (25), 90 (31), 77 (15). Anal. calc. for C15H13NO (223):
C 80.71, H 5.82, N 6.27. Found: C 80.76, H 5.94, N 6.15 %.
0.90 (6H, t, J 7.5, 2CH3), 1.45 (4H, q, J 7.5, 2CH2), 2.3 (3H, s,
CH3), 2.70 (2H, s, CH2), 6.30–7.54 (7H, m, Ar–H), 10.35 (1H, s,
NH). dC (100 MHz, CDCl3) 9.3 (2CH3, –Et), 16.8, 33.0 (2CH2,
–Et), 34.6, 36.2, 117.6, 118.4, 118.9, 123.0, 126.9 (2CH, Ar),
128.5, 129.5, 129.6, 131.5, 138.7, 139.4. m/z (EI) (%) 266
([Mþ þ 1], 38), 265 (Mþ, 52), 264 (100), 250 (31), 221 (18),
207 (47), 191 (46), 190 (32), 178 (15), 176 (18), 167 (44),
161 (20), 148 (49), 109 (14), 104 (38), 90 (12), 77 (9). Anal. calc.
for C19H23N (265): C 86.03, H 8.67, N 5.28. Found: C 86.17,
H 8.82, N 5.07 %.
5,5-Dimethyl-5,6-dihydro-11H-benzo[b][1]
benzazepine 1c
White plates; mp 147–1498C (ethanol). nmax (KBr)/cmꢁ1
3420, 3075, 2988, 1600, 1480, 1460, 1435, 1355, 1220, 748. dH
(400 MHz, CDCl3) 1.25 (6H, s, 2CH3), 2.7 (2H, s, CH2), 6.35–
7.40 (8H, m, Ar–H), 9.25 (1H, s, NH). dC (100 MHz, CDCl3)
32.4 (2CH3), 35.5, 46.2, 116.9, 117.4, 118.4, 124.6, 126.5,
126.8, 127.6, 128.2, 130.5, 133.6, 138.6, 140.1. m/z (EI) (%)
224 ([Mþ þ 1], 18), 223 (Mþ, 35), 222 (100), 209 (24), 193 (93),
192 (35), 190 (23), 178 (18), 167 (11), 151 (11), 109 (22),
104 (51), 90 (26), 77 (24). Anal. calc. for C16H17N (223):
C 86.09, H 7.62, N 6.27. Found: C 86.25, H 7.54, N 6.21 %.
1-Methyl-5,5-diphenyl-5,6-dihydro-11H-benzo[b][1]
benzazepine 1h
White solid; mp 117–1188C (light petroleum 60–808C). nmax
(KBr)/cmꢁ1 3460, 3092, 2965, 1600, 1590 1480, 1445, 1338,
749. dH (400 MHz, CDCl3) 2.25 (3H, s, CH3), 3.40 (2H, s, CH2),
6.25–7.58 (17H, m, Ar–H), 9.94 (1H, s, NH). dC (100 MHz,
CDCl3) 17.8, 41.6, 42.2, 118.2, 118.7, 119.0, 126.3 (2CH, Ph),
126.4, 126.9, 127.9, 128.3 (4CH, Ph), 128.6, 128.7, 129.3 (4CH,
Ph), 135.3, 146.6 (2CH, Ph), 133.4, 132.6, 138.3. m/z (EI) (%)
362 ([Mþ þ 1], 7), 361 (Mþ, 22), 359 (100), 346 (52), 283 (91),
243 (54), 207 (30), 192 (64), 191 (32), 190 (15), 176 (25),
166 (20), 150 (8), 118 (32), 90 (26), 77 (11). Anal. calc. for
C27H23N (361) C 89.75, H 6.37, N 3.87. Found: C 89.74, H 6.52,
N 3.74 %.
5,5-Diethyl-5,6-dihydro-11H-benzo[b][1]
benzazepine 1d
Pale yellow solid; mp 94–958C (ethanol). nmax (KBr)/cmꢁ1
3435, 3090, 2980, 1610, 1485, 1465, 1440, 1350, 750. dH
(400 MHz, CDCl3) 0.90 (6H, t, J 7.5, 2CH3), 1.40 (4H, q,
J 7.5, 2CH2), 2.70 (2H, s, CH2), 6.25–7.60 (8H, m, Ar–H), 9.2
(1H, s, NH). dC (100 MHz, CDCl3) 12.3 (2CH3, –Et), 33.0
(2CH2, –Et), 35.8, 41.4, 117.6, 118.5, 118.7, 122.9, 125.2,
126.8, 127.6, 128.2, 129.1, 136.6, 137.7, 138.6. m/z (EI) (%)
252 ([Mþ þ 1], 10), 251 (Mþ, 37), 250 (100), 236 (41), 222 (30),
221 (17), 193 (84), 190 (37), 177 (28), 166 (21), 151 (7), 109
(18), 104 (38), 91 (22), 76 (13). Anal. calc. for C18H21N (251):
C 86.05, H 8.36, N 5.57. Found: C 86.27, H 8.37, N 5.36 %.
General Procedure for the Synthesis of Benzo[b][1]
benzazepines 1a, b
A mixture of ketone 15a or 15b (5 mmol), absolute ethyl alcohol
(6 mL), hydrazine hydrate[37] (10 mL, 90 %), and diethylene
glycol (20 mL) was refluxed for 8 h, then excess alcohol, water,
and hydrazine hydrate were distilled off. The residue was then
cooled and KOH (0.7 g, 12 mmol) was added and the reaction
mixture was refluxed for additional 5 h. Cold water (40 mL) was
added with shaking and the product was extracted with ether
(50 mL), washed with water and dried over MgSO4. The ether
solution was decanted and ether was removed under vacuum to
give the crude product. The yields and spectral data are given
below.
5,5-Diphenyl-5,6-dihydro-11H-benzo[b][1]
benzazepine 1e
Yellowish viscous oil. n2D5 1.575. nmax (film)/cmꢁ1 3445,
3085, 2955, 1590, 1490, 1470, 1440, 1345, 745. dH (400 MHz,
CDCl3) 3.35 (2H, s, CH2), 6.3–7.50 (18H, m, Ar–H), 9.6 (1H, s,
NH). dC (100 MHz, CDCl3) 41.4, 43.6, 118.5, 118.2, 119.2,
121.6, 126.3 (2CH, Ph), 126.9, 127.7, 128.3 (4CH, Ph), 128.2,
128.4, 128.9, 129.3 (4CH, Ph), 134.4, 137.5, 138.6, 143.6 (2CH,
Ph). m/z (EI) (%) 348 ([Mþ þ 1], 34), 347 (Mþ, 50), 345 (100),
332 (18), 270 (62), 243 (64), 193 (79), 191 (22), 190 (13),
177 (5), 165 (20), 151 (8), 106 (44), 91 (33), 77 (16). Anal. calc.
for C26H21N (347): C 89.91, H 6.05, N 4.03. Found: C 90.17,
H 5.86, N 3.95 %.
5,6-Dihydro-11H-benzo[b][1]benzazepine 1a
Orange solid; mp 110–1118C (light petroleum 60–808C)
(lit.[38] mp 107–1088C). nmax (KBr)/cmꢁ1 3425, 3065, 2950,
1590, 1465, 1440, 1375, 1280, 745. dH (400 MHz, CDCl3) 2.8
(4H, s, 2CH2), 6.30–7.75 (8H, m, Ar–H), 9.82 (1H, s, NH). dC
(100 MHz, CDCl3) 34.1 (2CH2, cyclic), 121.6, 123.6, 126.8,
128.9, 129.1, 138.4. m/z (EI) (%) 195 (Mþ, 30), 194 (100), 180
(92), 191 (43), 178 (18), 165 (12), 151 (15), 109 (25), 105 (80),
91 (56), 77 (22). Anal. calc. for C14H13N (195): C 86.15, H 6.66,
N 7.17. Found: C 86.22, H 6.56, N 7.21 %.
1,5,5-Trimethyl-5,6-dihydro-11H-benzo[b][1]
benzazepine 1f
White solid; mp 138–1408C (ethanol). nmax (KBr)/cmꢁ1
3435, 3055, 2990, 1605, 1580, 1480, 1465, 1345, 746. dH
(400 MHz, CDCl3) 1.25 (6H, s, 2CH3), 2.3 (3H, s, CH3), 2.75
(2H, s, CH2), 6.40–7.63 (7H, m, Ar–H), 9.55 (1H, s, NH). dC
(100 MHz, CDCl3) 17.6, 27.8 (2CH3), 31.5, 41.8, 117.9, 118.8,
120.2, 123.4, 126.5, 127.3, 128.2, 129.5, 129.8, 131.4, 137.9,
138.2. m/z (EI) (%) 238 ([Mþ þ 1], 12), 223 (Mþ, 29), 236 (100),
222 (84), 207 (45), 192 (36), 191 (85), 190 (63), 177 (11), 166
(9), 151 (3), 109 (15), 104 (22), 91 (14), 77 (13). Anal. calc. for
C17H19N (237): C 86.07, H 8.01, N 5.90. Found: C 86.10,
H 8.24, N 5.66 %.
1-Methyl-5,6-dihydro-11H-benzo[b][1]benzazepine 1b
Cream yellow solid; mp 64–65.58C (benzene). nmax (KBr)/
cmꢁ1 3415, 3080, 2975, 1585, 1480, 1445, 1375, 1235, 744. dH
(400 MHz, CDCl3) 2.3 (3H, s, CH3), 2.8 (4H, s, 2CH2), 6.35–
7.10 (7H, m, Ar–H), 9.75 (1H, s, NH). dC (100 MHz, CDCl3)
18.4, 34.6, 35.1, 118.2, 118.5, 122.0, 125.2, 126.0, 127.2, 128.5,
128.6, 128.9, 134.2, 136.8, 140.1. m/z (EI) (%) 210 ([Mþ þ 1],
24), 209 (Mþ, 35), 207 (80), 194 (100), 190 (18), 181 (42), 179
(77), 177 (12), 166 (19), 151 (11), 109 (19), 104 (72), 90 (32), 77
5,5-Diethyl-1-methyl-5,6-dihydro-11H-benzo[b][1]
benzazepine 1g
Reddish viscous oil. n2D5 1.583. nmax (film)/cmꢁ1 3450, 3084,
2977, 1600, 1575, 1460, 1445, 1337, 748. dH (400 MHz, CDCl3)

644
H. A. K. Abd El-Aal and A. A. Khalaf
(14). Anal. calc. for C15H15N (209): C 86.12, H 7.17, N 6.69.
Found: C 86.33, H 7.05, N 6.62 %.
(d) D. Bolten, M. Tu¨rk, J. Supercrit. Fluids 2012, 66, 389. doi:10.1016/
J.SUPFLU.2012.04.010
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Acknowledgement
The authors are grateful to the Chemistry Department, Faculty of Science,
Assiut University, for financial support and use of facilities while carrying
out and writing this work.
(e) M. Oetken, G. Nentwig, D. Lc¸ffler, T. Ternes, J. Oehlmann, Arch.
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