A Simple and practical approach to the dibenzo[ c, f ]thiazolo[3,2- a ]azepines: A novel fused tetracyclic azepine system

Article abstract of DOI:10.1055/s-0029-1218674

A novel set of functionalized dibenzo[c,f]thiazolo[3,2-a]azepines, which is a new ring system, were successfully synthesized in a four-step protocol starting from readily available substituted N-allyl-N-benzylanilines. The synthesis of the title compounds

Full text of DOI:10.1055/s-0029-1218674

PAPER
1291
A Simple and Practical Approach to the Dibenzo[c,f]thiazolo[3,2-a]azepines:
A Novel Fused Tetracyclic Azepine System
Synthesis of
D
iben
l
zo[
c
,
f
]
i
thiazol
r
a
]a
i
zepine
o
s
Palma,*a Nelson Galeano,a Ali Bahsasb
a
Laboratorio de Síntesis Orgánica, Escuela de Química, Universidad Industrial de Santander, A.A. 678, Bucaramanga, Colombia
Fax +57(76)349069; E-mail: apalma@uis.edu.co
b
Laboratorio de RMN, Grupo de Productos Naturales, Departamento de Química, Universidad de los Andes, Mérida 5101, Venezuela
Received 7 September 2009; revised 15 December 2009
no prior literature reports that describe the fusion of the
dibenz[b,e]azepine nucleus to a thiazolidin-4-one ring,
also a core structure in important synthetic molecules with
significant biological activity, including antibacterial, an-
Abstract: A novel set of functionalized dibenzo[c,f]thiazolo[3,2-
a]azepines, which is a new ring system, were successfully synthe-
sized in a four-step protocol starting from readily available substi-
tuted N-allyl-N-benzylanilines. The synthesis of the title
compounds was accomplished through cyclocondensation of mor- tifungal, anticancer, anti-HIV, antiparasitic, and antipsy-
chotic activities among others.8
phanthridines with mercaptoacetic acid. Morphanthridines were
prepared by selective oxidation of dihydromorphanthridines with
pyridinium chlorochromate in dichloromethane. The dihydromor-
phanthridines were obtained by acid-catalyzed intramolecular
Friedel–Crafts alkylation of substituted 2-allyl-N-benzylanilines,
which in turn, were prepared from N-allyl-N-benzylanilines by aro-
matic amino-Claisen rearrangement. The structural elucidation of
all synthesized compounds by high resolution NMR is also report-
ed.
N
N
N
R1
N
N
R2
Me
II
I
Key words: amino-Claisen rearrangement, intramolecular Friedel–
Crafts alkylation, 2-allyl-N-benzylanilines, dihydromorphan-
thridines, dibenzo[c,f]thiazolo[3,2-a]azepines
N
N
O
The dibenz[b,e]azepine ring is a commonly observed
structural moiety in the molecular structures of important
fused tetracyclic azepines with pharmacological potential,
as shown by the examples in Figure 1. Thus, mianserin
(Tolvon) and its N-substituted derivatives I as well as mir-
tazapine (azamianserin, Remeron) analogue II are well
documented in the literature as antidepressants1 and anti-
serotoninergic agents.2 2-(Aminoalkyl)-2,3,3a,8-tetrahy-
drodibenz[c,f]oxazolo[2,3-a]azepine derivatives III were
synthesized and evaluated as potent and selective 5-
HT2A/2C receptor antagonists with oral activity and,
therefore, could be considered as potential anxiolytic/an-
tidepressant agents.3 Some of these compounds may also
be used as therapeutic agents in the treatment or the pre-
vention of cardiovascular disorders or gastrointestinal dis-
orders.3,4 Epinastine (IV) was initially patented as an anti-
allergenic and antihistaminergic agent,5 but it is also used
for pain treatment and prophylaxis, especially, for chronic
or inflammation-induced pain, in particular, in migraine.6
N
H2N
( )n
R2
IV
N
R1
III
Figure 1 Molecular structures of some bioactive-fused tetracyclic
azepines
Among the classical methodologies, the intramolecular
Friedel–Crafts alkylation has been particularly useful in
synthetic organic chemistry, since this reaction results in
the construction of an extra ring by generation of a new
C–C bond,9 including the central azepine ring of the
dibenz[b,e]azepine system.3,7g,j,10 In this context, several
years ago our laboratory became interested in using the
acid-catalyzed intramolecular Friedel–Crafts alkylation
of ortho-amino-substituted allylarenes V to prepare
dihydrodibenz[b,e]azepines VI and dihydroben-
zo[e]naphth[b]azepines VII (Scheme 1).11
On the other hand, knowing that the cyclocondensation
reaction of an imine and a-mercaptoalkanoic acid is the
most convenient method for the preparation of many thia-
zolidin-4-one derivatives,12 and having in our hands an
expedient synthetic route to build the dihydrodi-
benz[b,e]azepine ring, we decided to extend our investi-
gation to the synthesis of the novel compounds with the
general structure 5 as shown retrosynthetically in
Scheme 2.
The unique structural features and biological properties of
tetracyclic azepine derivatives have resulted in consider-
able synthetic efforts to develop efficient methods for the
synthesis of bioactive derivatives in which the tricyclic
dibenz[b,e]azepine ring is fused at the N5–C6 bond with
different heterocycles.1a,2–4,5b,d,e,7 Surprisingly, there are
SYNTHESIS 2010, No. 8, pp 1291–1302
x
x
.
x
x
.2
0
1
0
Advanced online publication: 11.02.2010
DOI: 10.1055/s-0029-1218674; Art ID: M05209SS
© Georg Thieme Verlag Stuttgart · New York

1292
A. Palma et al.
PAPER
R2
R2
R1
R1
R1
R2
ref. 11b
ref. 11a
N
R
N
N
H
O
VII
V
VI
Scheme 1 ortho-Amino-substituted allylarenes in the construction of dihydrodibenz[b,e]azepine and dihydrobenzo[e]naphth[b]azepine rings
R2
R2
R2
R1
R1
R1
R3
R3
R3
N
N
N
S
H
O
3
4
5
Scheme 2 Retrosynthetic analysis of title compounds 5
To the best of our knowledge, the facile construction of As previously reported,11a under acidic conditions the al-
this new tetraheterocyclic system using the classical cy- lylic fragment of the rearranged products 2 can be used as
clocondensation reaction of an imine and mercaptoacetic potential electrophilic center to be exploited in the con-
acid in the morphanthridine series has not been previously struction of the dihydrodibenz[b,e]azepine ring. Taking
explored. It is the purpose of this paper to describe the into account this result, we initially examined the intramo-
successful synthesis of novel tetrahydrodibenzo[c,f]thia- lecular cyclization of 2a using various Brönsted acids in
zolo[3,2-a]azepine derivatives 5, using as the main trans- excess, including sulfuric (95%), polyphosphoric, 4-tolu-
formations the intramolecular Friedel–Crafts alkylation of enesulfonic, trifluoroacetic, tetrafluoroboric (54% HBF4
substituted 2-allyl-N-benzylanilines and boron trifluo- in Et2O), and perchloric (70%) acids, for varying temper-
ride–diethyl ether complex catalyzed cyclocondensation atures and times.
reaction of morphanthridines and mercaptoacetic acid.
TLC and GC-MS analysis indicated formation of the ex-
The synthesis of the tricyclic precursors, 6,11-dihydro- pected dihydromorphanthridine 3a with several of these
5H-dibenz[b,e]azepines 3, was achieved using our previ- acids and the best results were obtained with sulfuric and
ously reported multistep reaction protocol (Scheme 3).11a perchloric acids. We found that the progress of the reac-
Initially, the key intermediates, substituted 2-allyl-N-ben- tion became very slow when carried out with polyphos-
zylanilines 2, were easily obtained by thermal-induced phoric acid; heating the reaction mixture at 100–110 °C
aromatic amino-Claisen rearrangement of the correspond- for 1.5 hours gave 3a together with complex mixtures of
ing N-allyl-N-benzylanilines 1 using our previous report- undesirable products. Control experiments also indicated
ed experimental conditions.13 Thus, heating synthetically that cyclization reaction did not take place when carried
available substituted N-allyl-N-benzylanilines 1 with 1.5 out with 4-toluenesulfonic acid, trifluoroacetic acid in
equiv of boron trifluoride–diethyl ether complex at 138– acetic acid, or tetrafluoroboric acid, even at high temper-
145 °C for 3–5 hours produced rearranged compounds atures (100–120 °C) and for long reaction times (1–4 h);
2a–i, which after chromatographic purification were iso- in each case unchanged starting material was recovered.
lated as viscous maroon oils in good to excellent yields
Based on these preliminary results, we chose both sulfuric
(74–88%). The yields were not significantly affected by
and perchloric acids to perform the intramolecular cy-
the nature and positions of substituents on either benzene
clization of the remaining 2-allyl-N-benzylanilines 2b–i.
Under the reaction conditions employed, all the 2-allyla-
ring of precursors 1.
R1
R1
R2
ii
i
R1
R3
N
N
H
R2
R2
N
R3
R3
H
3a–i
1a–i
a R1 = R2 = R3 = H;
d R1 = Me, R2 = R3 = H;
g R1 = Cl, R2 = H, R3 = Me; h R1 = R2 = Me, R3 = H;
2a–i
b R1 = F, R2 = R3 = H;
e R1 = OMe, R2 = R3 = H;
c R1 = Cl, R2 = R3 = H;
f R1 = R3 = H, R2 = Me;
i R1 = R3 = Me, R2 = H
Scheme 3 Synthesis of dihydromorphanthridines 3. Reagents and conditions: (i) BF3·OEt2 (1.5 equiv), 138–145 °C, 3–5 h, 74–88% ; (ii) 95%
H2SO4, 70–90 °C, 5–60 min or 70% HClO4, 85–120 °C, 30–60 min (see Table 1).
Synthesis 2010, No. 8, 1291–1302 © Thieme Stuttgart · New York

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Synthesis of Dibenzo[c,f]thiazolo[3,2-a]azepines
1293
nilines were transferred, through a 7-exo-trig cyclization
route, to the corresponding substituted dihydromorphan-
thridines in moderate to good yields (Table 1).
Table 1 Preparation of Dihydromorphanthridines 3 by Intramolec-
ular Friedel–Crafts Alkylation of Substituted 2-Allylanilines 2 with
Sulfuric and Perchloric Acids
The obtained results indicated that the cyclization reaction
can take place over a wide range of temperatures. In gen-
eral, we find it convenient to carry out the reaction at a
temperature range from 70 to 90 °C in the presence of sul-
furic acid, and at a temperature of 85 to 120 °C with per-
chloric acid. The required time for the reaction (5–60 min)
may also vary widely, depending on the reaction temper-
ature, the nature of the substituents, and, notably, the acid
used. We also found that the conditions employed for the
cyclization of 2e with concentrated sulfuric acid led to the
formation of the expected dihydromorphanthridine 3e in
very low quantities (5%) along with a large amount of in-
separable byproducts. In this case, it is probable that the
increased nucleophilicity of the benzene ring in 2e by the
presence of both the methoxy and the amino groups facil-
itates the sulfonation of the activated benzene instead of
the intramolecular alkylation of the benzylic benzene; it is
also probable that the double bond of the allylic fragment
undergoes sulfonation in the presence of sulfuric acid to
form the respective sulfonic acid derivatives.14 However,
using perchloric acid instead of sulfuric acid increased the
yield of 3e to 65%, especially when the reaction was car-
ried out at 85–90 °C for 60 minutes (Table 1, entry 10).
Entry
2
Acid
Time Temp
(min) (°C)
Product Yielda
(%)
1
2
2a
2a
2b
2b
2c
2c
2d
2d
2e
2e
2f
H2SO4
HClO4
H2SO4
HClO4
H2SO4
HClO4
H2SO4
HClO4
H2SO4
HClO4
H2SO4
HClO4
H2SO4
HClO4
H2SO4
HClO4
H2SO4
HClO4
30
60
30
45
30
45
5
70–75
3a
3a
3b
3b
3c
3c
3d
3d
3e
3e
3f
75
70
65
73
62
68
75
72
5b
105–110
75–80
115–120
75–80
115–120
90
3
4
5
6
7
8
30
100–105
60–70
85–90
90
9
2–5
10
11
12
13
14
15
16
17
18
60
5
65
73
70
75
66
73
68
84
75
2f
30
5
100–105
90
3f
2g
2g
2h
2h
2i
3g
2g
3h
3h
3i
30
5
85–90
90
It should also be noted that in the cases of 2g and 2i with
a methyl group in the meta position of the benzylic frag-
ment, the cyclization occurred with complete regioselec-
tivity to give only one of the two possible regioisomers, 8-
substituted dihydromorphanthridines 3g and 3i (Table 1,
entries 13, 14, 17, and 18). The complete regioselectivity
observed with 2g and 2i could be readily explained by the
differences in the stabilities of the two possible Wheland
intermediates A and B, that can be formed during the cy-
clization process (Figure 2).15 The generation of the inter-
mediate B is more difficult because of the unfavorable
steric interactions between the hydrogen atom at C10a and
the methyl substituent at C10, an interaction that is not
present in the intermediate A.
30
5
100–105
90
2i
60
110
3i
a Yields are for isolated, chromatographically pure products.
b Plus byproducts.
and two-dimensional NMR spectroscopy. The assign-
ments of all the signals to individual H and C atoms (see
experimental) have been made from their chemical shift
values, coupling constants, and confirmed on the basis of
COSY, HMQC and HMBC spectra as well as by compar-
ing with the reference spectra of previously reported ana-
logues.11a
H
H
R
R
+
+
Having in hand the required tricyclic precursors 3, we
then turned our attention to the synthesis of their oxidized
analogues 4. Dihydromorphanthridines 3a–i were easily
converted into the corresponding morphanthridines 4a–i
by oxidation with equimolar amounts of pyridinium chlo-
rochromate in dichloromethane at 0 °C (Scheme 4). When
the reactions were complete, usually in 30–40 minutes,
the dehydrogenated compounds 4 were isolated by silica
gel column chromatography in excellent yields (85–95%)
as high-viscosity yellow oils.
N+
N+
H
H
H
H
A
B
Figure 2 Wheland complexes A and B as potential intermediates in
the intramolecular Friedel–Crafts alkylation of 2g and 2i
In general, the use of sulfuric acid as a promoter of the in-
tramolecular Friedel–Crafts alkylation of all the key inter-
mediates 2 examined, with the exception of 2e, proved to
be more efficient in terms of yields, lower temperatures,
and shorter reaction times, compared to perchloric acid.
MS spectral data for 4a–i were in full agreement with the
expected compounds (see experimental). The IR spectra
displayed absorption bands at ca. 1618–1609 cm–1 charac-
teristic for N=CH stretching vibration (endocyclic imine
group). The 1H NMR spectra showed the same set of sig-
The structures of all the 6,11-dihydro-5H-
dibenz[b,e]azepines 3 obtained were determined by one-
Synthesis 2010, No. 8, 1291–1302 © Thieme Stuttgart · New York

1294
A. Palma et al.
PAPER
R2
R2
11
R2
15
14
13
12
10
10
9
8
5
1
R1
R1
7
R1
8
i
ii
2
R3
R3
9
R3
11
12
13
7
5
6
6
3
13b
4
N
N
4
N
S
3
4a–i
2
H
1
O
3a–i
5a–i
Scheme 4 Synthesis of title compounds 5. Reagents and conditions: (iii) PCC (1 equiv), CH2Cl2, 0°C, 30–40 min, 85–95%; (ii) Dean–Stark
trap, HSCH2CO2H (3 equiv), BF3·OEt2 (trace), toluene, reflux, 24–40 h, 50–65%.
nals in the aliphatic region (triplet for H11, d = 3.69–3.58, signed for methylene (C2), methine (C13b) and carbonyl
J = 8.0 Hz; multiplet for 12-CH2, d = 1.69–1.65, and trip- (C3) carbons, respectively. Furthermore, long range cou-
let for 13-CH3, d = 0.71–0.69, J = 7.4–7.2 Hz) as those re- plings from the proton attached to C13b to C2, C9a, C13a,
ported for 3a–i, except for the disappearance of signals and C13 were observed in their HMBC spectra. Addition-
originated from the 6-CHAHB and N–H protons. In addi- al support was obtained from the 1H NMR spectra, where
tion, the appearance in the 1H NMR spectra of a singlet at the iminic proton (N=CH) signal was absent, but the res-
d = 8.79–8.67 as well as a signal at d = 160.6–158.1 in the onances at d = 6.23–6.15, 3.99–3.97, and 3.64–3.62 at-
13C NMR spectra unambiguously confirmed the forma- tributed to 13b-CH, 2-CHAHB, and 2-CHAHB protons of
tion of the CH=N group.
the thiazolidin-4-one ring were clearly identified. The two
diastereotopic hydrogens at C2 displayed two signals ap-
pearing as doublet (2J = 15.6–15.2 Hz) or double doublet
In the last step of our approach, the construction of the
thiazolidinone ring and. consequently, the formation of
the new tetracyclic system 5 was accomplished through a
cyclocondensation of 4 with a threefold excess of mercap-
toacetic acid. The reaction was carried out in dry toluene
at reflux using a Dean–Stark water separator, and in the
presence of a trace of boron trifluoride–diethyl ether com-
plex (Scheme 4). In this way, and after heating 24–40
4
(2J = 15.5 Hz and Jtrans = 0.7 Hz) for proton H2A, and
double doublet (2J = 15.6–15.2 Hz and 4Jcis = 2.0–1.8 Hz)
for proton H2B due to geminal coupling and coupling with
tertiary proton H13b. All the above signals in the 1H and
13C NMR spectra were fully assigned on the basis of
COSY and HMQC as well as HMBC experiments.
hours, the desired title compounds, dibenzo[c,f]thiazo- In conclusion, we have successfully extended the classical
lo[3,2-a]azepines 5a–i, were chromatographically isolat- cyclocondensation of an imine and mercaptoacetic acid to
ed in 50–65% yields together with significant amounts of the synthesis of previously unknown dibenzo[c,f]thiazo-
unreacted starting materials (20–45%). It is worthy of lo[3,2-a]azepine derivatives. Our synthetic procedure
note that in the absence of boron trifluoride–diethyl ether proved to be attractive due to its simplicity and of great
the cyclocondensation required longer reaction times practical value; it could provide a new approach to the
(>60 h) and the yields of the expected compounds dramat- synthesis of potential antiparasitic agents against Trypa-
ically decreased (<20%). Unfortunately, all attempts to nosoma cruzi and Leishmania chagasi parasites as well as
further improve the yields of 5 either by heating in the CNS active molecules in the group of dibenzo[c,f]thiazo-
presence
of
cyclohexylcarbodiimide
in
dry lo[3,2-a]azepines. Their anxiolytic and anti-parasitic ac-
tetrahydrofuran16 or by extending the reaction time (60 h) tivities are currently investigated and the detailed results
in the presence of molecular sieves (4 Å) in benzene or from these studies will be reported in the near future else-
toluene were unsuccessful. The construction of the thia- where.
zolidinone ring in compounds 5 is assumed to proceed via
initial attack by the sulfur nucleophile to the iminic carbon
All the reagents and solvents were purchased from commercial sup-
activated by boron trifluoride–diethyl ether, followed by
intramolecular cyclization between amino and carboxylic
groups with the elimination of a water molecule.
pliers (Aldrich, Merck), and used without further purification. Ana-
lytical TLC was performed on Merck precoated silica gel (60 F254
)
plates and column chromatography was accomplished on Merck
Kieselgel 60 70–230 mesh (ASTM). Melting points were deter-
mined on a MEL-TEMP 1201D capillary apparatus and are uncor-
rected. IR spectra were recorded on a Nicolet Avatar 360-FTIR
spectrophotometer and referenced to polystyrene standard, using
The structure elucidation of the new compounds 5 was
based on spectral data (IR, MS, 1H NMR, and 13C NMR)
and elemental analysis. Thus, the presence in the IR spec-
tra of the characteristic absorption band at about 1711– cells equipped with KBr windows. 1H (400.13 MHz) and 13C NMR
1690 cm–1 associated with a lactam C=O provided the first
(100.6 MHz) spectra were acquired on a Bruker AM-400 spectrom-
eter using CDCl3 as the solvent and chemical shifts relative to the
evidence for ring closure. In the EI-MS, their molecular
solvent peaks used as reference [CDCl3: dH = 7.26, and dC = 77.0].
ion peaks of high intensity (36–57%) were observed to-
MS were obtained by electron impact at 70 eV on a Hewlett-
Packard (HP) 5890 A series II Gas Chromatograph interfaced to a
HP 5972 Mass Selective Detector with a HP MS ChemStation Data.
Elemental analyses (C, H, N) were performed on a Perkin-Elmer
2400 Series II analyzer. The synthesis and structural characteriza-
tion of 2a–c and 3a–c were previously reported.11a
gether with their fragment ion peaks M+ – SCHCHO –
C2H5 as base peaks (see experimental).
The formation of the thiazolidinone ring in 5 was also
clearly evident from the signals around d = 33.9–33.5,
13
64.8–64.4, and 172.1–171.6 in the C NMR spectra, as-
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Synthesis of Dibenzo[c,f]thiazolo[3,2-a]azepines
1295
2-Allyl-N-benzylanilines 2; General Procedure
2-Allyl-N-benzyl-4-methylaniline (2d)
Time: 4.5 h; maroon oil; yield: 88%.
A mixture of N-allyl-N-benzylaniline 1 (0.10 mmol) and BF3·OEt2
(0.15 mmol) was heated at 138–145 °C for 3–5 h under N2. The
mixture was cooled to r.t. and then it was poured into ice-H2O (30
mL), treated with sat. Na2CO3 soln to pH 8, and extracted with
CH2Cl2 (3 × 50 mL). The combined organic extracts were dried (an-
hyd Na2SO4), filtered, and concentrated in vacuo. The crude mate-
rial was purified by column chromatography (silica gel, heptane–
EtOAc, 30:1, 20:1).
IR (KBr): 3434 (N–H), 3027 (C–H Ar), 1635 (C=C allyl), 1513
(C=C Ar), 913 cm–1 (=C–H allyl).
1H NMR (400 MHz, CDCl3): d = 2.35 (s, 3 H, 4-CH3), 3.40 (d,
J = 6.0 Hz, 2 H, CH2CH=), 4.42 (s, 2 H, NCH2), 5.18 (dq, J = 18.0,
1.6 Hz, 1 H, =CHAHB), 5.21 (dq, J = 10.0, 1.6 Hz, 1 H, =CHAHB),
6.06 (ddt, J = 18.0, 10.0, 6.0 Hz, 1 H, =CH), 6.65 (d, J = 8.0 Hz, 1
H, H6), 7.0 (br s, 1 H, H3), 7.03 (dd, J = 8.0, 1.2 Hz, 1 H, H5), 7.36
(t, J = 8.0 Hz, 1 H, H4¢), 7.42 (t, J = 8.0 Hz, 2 H, H3¢, H5¢), 7.45 (d,
J = 8.0 Hz, 2 H, H2¢, H6¢).
2-Allyl-N-benzylaniline (2a)
Time: 3 h; maroon oil; yield: 75%.
13C NMR (100 MHz, CDCl3): d = 20.5 (4-CH3), 36.6 (CH2CH=),
48.6 (NCH2), 111.2 (C6), 116.3 (=CH2), 123.9 (C2), 126.7 (C4),
127.2 (C4¢), 127.5 (C2¢, C6¢), 128.1 (C5), 128.7 (C3¢, C5¢), 130.8
(C3), 136.3 (=CH), 139.7 (C1¢), 143.9 (C1).
MS (EI, 70 eV): m/z (%) = 237 (76) [M+], 208 (13), 160 (15), 146
(100), 132 (25), 131 (60), 91 (86), 77 (13).
IR (KBr): 3439 (N–H), 3028 (C–H Ar), 1634 (C=C allyl), 1510
(C=C Ar), 914 cm–1 (=C–H allyl).
1H NMR (400 MHz, CDCl3): d = 3.37 (d, J = 6.0 Hz, 2 H,
CH2CH=), 4.16 (br s, 1 H, NH), 4.40 (s, 2 H, NCH2), 5.12 (dq,
J = 16.0, 1.6 Hz, 1 H, =CHAHB), 5.17 (dq, J = 10.0, 1.6 Hz, 1 H,
=CHAHB), 6.02 (ddt, J = 16.0, 10.0, 6.0 Hz, 1 H, =CH), 6.69 (dd,
J = 7.2, 0.8 Hz, 1 H, H6), 6.77 (td, J = 7.2, 0.8 Hz, 1 H, H4), 7.13
(dd, J = 7.2, 1.4 Hz, 1 H, H3), 7.18 (td, J = 7.6, 1.4 Hz, 1 H, H5),
7.30–7.42 (m, 5 H, H2¢, H3¢, H4¢, H5¢, H6¢).
2-Allyl-N-benzyl-4-methoxyaniline (2e)
Time: 4.5 h; maroon oil; yield: 74%.
13C NMR (100 MHz, CDCl3): d = 36.5 (CH2CH=), 48.2 (NCH2),
110.7 (C6), 116.3 (=CH2), 117.4 (C4), 123.5 (C2), 127.1 (C5),
127.4 (C2¢, C6¢), 127.7 (C4¢), 128.6 (C3¢, C5¢), 129.8 (C3), 136.0
(CH=), 139.5 (C1¢), 146.1 (C1).
MS (EI, 70 eV): m/z (%) = 223 (35) [M+], 146 (12), 132 (100), 117
(24), 91 (87), 77 (16), 65 (28).
IR (KBr): 3430 (N–H), 3028 (C–H Ar), 1636 (C=C allyl), 1510
(C=C Ar), 913 cm–1 (=C–H allyl).
1H NMR (400 MHz, CDCl3): d = 3.35 (d, J = 6.0 Hz, 2 H,
CH2CH=), 3.78 (s, 3 H, 4-OCH3), 4.35 (s, 2 H, NCH2), 5.13 (dq,
J = 17.2, 1.6 Hz, 1 H, =CHAHB), 5.17 (dq, J = 10.0, 1.6 Hz, 1 H,
=CHAHB), 6.01 (ddt, J = 17.2, 10.0, 6.0 Hz, 1 H, =CH), 6.63 (d,
J = 8.8 Hz, 1 H, H6), 6.76 (dd, J = 8.8, 3.0 Hz, 1 H, H5), 6.78 (d,
J = 3.0 Hz, 1 H, H3), 7.32–7.42 (m, 5 H, H2¢, H3¢, H4¢, H5¢, H6¢).
2-Allyl-N-benzyl-4-fluoroaniline (2b)
13C NMR (100 MHz, CDCl3): d = 36.1 (CH2CH=), 48.5 (NCH2),
55.3 (4-OCH3), 111.6 (C5, C6), 116.0 (=CH2), 116.2 (C3), 125.1
(C2), 126.7 (C4¢), 127.0 (C2¢, C6¢), 128.1 (C3¢, C5¢), 135.3 (=CH),
139.3 (C1¢), 139.9 (C1), 151.6 (C4).
MS (EI, 70 eV): m/z (%) = 253 (100) [M+], 224 (3), 176 (6), 162
(72), 148 (8), 147 (21), 91 (75), 65 (15).
Time: 4.5 h; maroon oil; yield: 76%.
IR (KBr): 3440 (N–H), 3029 (C–H Ar), 1643 (C=C allyl), 1511
(C=C Ar), 916 cm–1 (=C–H allyl).
1H NMR (400 MHz, CDCl3): d = 3.32 (d, J = 6.4 Hz, 2 H,
CH2CH=), 4.06 (br s, 1 H, NH), 4.34 (s, 2 H, NCH2), 5.12 (dq,
J = 18.0, 1.6 Hz, 1 H, =CHAHB), 5.19 (dq, J = 10.0, 1.6 Hz, 1 H,
=CHAHB), 5.97 (ddt, J = 18.0, 10.0, 6.4 Hz, 1 H, =CH), 6.56 (dd,
J = 9.0, 5.0 Hz, 1 H, H6), 6.83 (d, J = 3.0 Hz, 1 H, H3), 6.85 (dd,
J = 9.0, 3.0 Hz, 1 H, H5), 7.30–7.39 (m, 5 H, H2¢, H3¢, H4¢, H5¢,
H6¢).
2-Allyl-N-(4-methylbenzyl)aniline (2f)
Time: 5 h; maroon oil; yield: 85%.
IR (KBr): 3435 (N–H), 3008 (C–H Ar), 1635 (C=C allyl), 1511
(C=C Ar), 915 cm–1 (=C–H allyl).
13C NMR (100 MHz, CDCl3): d = 36.2 (CH2CH=), 48.7 (NCH2),
111.5 (d, 3JC,F = 10.0 Hz, C6), 113.4 (d, 2JC,F = 20.0 Hz, C3), 116.5
1H NMR (400 MHz, CDCl3): d = 2.43 (s, 3 H, 4¢-CH3), 3.39 (d,
J = 6.0 Hz, 2 H, CH2CH=), 4.38 (s, 2 H, NCH2), 5.16 (dq, J = 17.0,
2.0 Hz, 1 H, =CHAHB), 5.20 (dq, J = 10.0, 2.0 Hz, 1 H, =CHAHB),
6.03 (ddt, J = 17.0, 10.0, 6.0 Hz, 1 H, =CH), 6.73 (d, J = 8.0 Hz, 1
H, H6), 6.80 (td, J = 8.0, 1.0 Hz, 1 H, H4), 7.15 (dd, J = 8.0, 1.0 Hz,
1 H, H3), 7.22 (td, J = 8.0, 1.0 Hz, 1 H, H5), 7.23 (d, J = 8.0 Hz, 2
H, H3¢, H5¢), 7.33 (d, J = 8.0 Hz, 2 H, H2¢, H6¢).
2
3
(d, JC,F = 20.0 Hz, C5), 116.9 (=CH2), 125.3 (d, JC,F = 10.0 Hz,
C2), 127.2 (C4¢), 127.5 (C2¢, C6¢), 128.5 (C3¢, C5¢), 135.1 (CH=),
139.3 (C1¢), 142.3 (C1), 155.6 (d, 1JC,F = 206.1 Hz, C4).
MS (EI, 70 eV): m/z (%) = 241 (23) [M+], 164 (10), 150 (71), 135
(20), 91 (100), 77 (6), 65 (21).
13C NMR (100 MHz, CDCl3): d = 21.2 (4¢-CH3), 36.6 (CH2CH=),
48.1 (NCH2), 110.9 (C6), 116.4 (=CH2), 117.5 (C4), 123.7 (C2),
127.5 (C2¢, C6¢), 127.8 (C5), 129.4 (C3¢, C5¢), 129.9 (C3), 136.1
(=CH), 136.5 (C1¢), 136.9 (C4¢), 146.3 (C1).
MS (EI, 70 eV): m/z (%) = 237 (35) [M+], 208 (8), 146 (7), 132 (71),
118 (17), 117 (12), 105 (100), 91 (8), 79 (13).
2-Allyl-N-benzyl-4-chloroaniline (2c)
Time: 3.5 h; maroon oil; yield: 77%.
IR (KBr): 3426 (N–H), 3029 (C–H Ar), 1638 (C=C allyl), 1503
(C=C Ar), 919 cm–1 (=C–H allyl).
1H NMR (400 MHz, CDCl3): d = 3.29 (d, J = 6.0 Hz, 2 H,
CH2CH=), 4.10 (br s, 1 H, NH), 4.34 (s, 2 H, NCH2), 5.11 (dq,
J = 17.0, 1.6 Hz, 1 H, =CHAHB), 5.17 (dq, J = 10.0, 1.6 Hz, 1 H,
=CHAHB), 5.95 (ddt, J = 17.0, 10.0, 6.0 Hz, 1 H, =CH), 6.54 (d,
J = 8.0 Hz, 1 H, H6), 7.06 (d, J = 2.0 Hz, 1 H, H3), 7.08 (dd, J = 8.0,
2.0 Hz, 1 H, H5), 7.30–7.43 (m, 5 H, H2¢, H3¢, H4¢, H5¢, H6¢).
13C NMR (100 MHz, CDCl3): d = 36.1 (CH2CH=), 48.2 (NCH2),
111.8 (C6), 116.9 (=CH2), 122.0 (C4), 125.2 (C2), 127.3 (C2¢, C6¢),
127.4 (C5), 128.7 (C3), 129.0 (C4¢), 129.5 (C3¢, C5¢), 135.0 (CH=),
139.0 (C1¢), 144.6 (C1).
2-Allyl-4-chloro-N-(3-methylbenzyl)aniline (2g)
Time: 5 h; maroon oil; yield: 74%.
IR (KBr): 3437 (N–H), 3019 (C–H Ar), 1639 (C=C allyl), 1503
(C=C Ar), 919 cm–1 (=C–H allyl).
1H NMR (400 MHz, CDCl3): d = 2.40 (s, 3 H, 3¢-CH3), 3.31 (d,
J = 6.0 Hz, 2 H, CH2CH=), 4.32 (s, 2 H, NCH2), 5.14 (dq, J = 17.2,
1.6 Hz, 1 H, =CHAHB), 5.20 (dq, J = 10.4, 1.6 Hz, 1 H, =CHAHB),
5.97 (ddt, J = 17.2, 10.4, 6.0 Hz, 1 H, =CH), 6.58 (d, J = 8.4 Hz, 1
MS (EI, 70 eV): m/z (%) = 257 (35Cl, 20) [M+], 180 (7), 166 (26),
151 (4), 131 (40), 91 (100), 65 (26).
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A. Palma et al.
PAPER
H, H6), 7.08 (d, J = 2.4 Hz, 1 H, H3), 7.11 (dd, J = 8.4, 2.4 Hz, 1 H,
H5), 7.17–7.28 (m, 4 H, H2¢, H4¢, H5¢, H6¢).
13C NMR (100 MHz, CDCl3): d = 21.5 (3¢-CH3), 36.2 (CH2CH=),
48.4 (NCH2), 112.0 (C6), 117.1 (=CH2), 122.1 (C4), 124.5 (C6¢),
125.4 (C2), 127.4 (C5), 128.2 (C2¢), 128.3 (C4¢), 128.7 (C5¢), 129.6
(C3), 135.2 (=CH), 138.4 (C3¢), 139.0 (C1¢), 144.8 (C1).
with CH2Cl2 (3 × 50 mL). The combined organic extracts were
dried (anhyd Na2SO4), filtered, and evaporated to dryness in vacuo.
The crude material was purified by column chromatography (silica
gel, heptane–EtOAc, 20:1, 15:1, and 10:1).
11-Ethyl-6,11-dihydro-5H-dibenz[b,e]azepine (3a)
IR (KBr): 3416 (N–H), 2963 (C–H Ar), 1598 (N–H), 1497 cm–1
(C=C Ar).
1H NMR (400 MHz, CDCl3): d = 0.91 (t, J = 7.4 Hz, 3 H, 13-CH3),
2.15–2.25 (m, 2 H, 12-CH2), 3.45 (br s, 1 H, NH), 3.69 (t, J = 7.3
Hz, 1 H, H11), 4.00 (d, J = 14.8 Hz, 1 H, H6A), 4.95 (d, J = 14.8 Hz,
1 H, H6B), 6.53 (d, J = 8.0 Hz, 1 H, H4), 6.72 (td, J = 8.0, 1.0 Hz, 1
H, H2), 7.01 (td, J = 8.0, 1.0 Hz, 1 H, H3), 7.10 (dd, J = 8.0, 1.0 Hz,
1 H, H1), 7.15 (dd, J = 8.0, 2.0 Hz, 1 H, H7), 7.20–7.24 (m, 2 H, H8,
H9), 7.26 (dd, J = 8.0, 2.0 Hz, 1 H, H10).
13C NMR (100 MHz, CDCl3): d = 13.0 (13-CH3), 31.6 (12-CH2),
51.1 (C6), 54.8 (C11), 117.9 (C4), 118.2 (C2), 126.8 (C10), 127.2
(C3), 127.4 (C9), 128.3 (C8), 129.0 (C7), 130.2 (C11a), 130.8 (C1),
136.5 (C6a), 142.1 (C10a), 146.2 (C4a).
MS (EI, 70 eV): m/z (%) = 271 (35Cl, 29) [M+], 243 (1), 230 (1), 180
(9), 166 (35), 151 (3), 105 (100), 79 (12).
2-Allyl-4-methyl-N-(4-methylbenzyl)aniline (2h)
Time: 5 h; maroon oil; yield: 87%.
IR (KBr): 3430 (N–H), 3003 (C–H Ar), 1635 (C=C allyl), 1514
(C=C Ar), 913 cm–1 (=C–H allyl).
1H NMR (400 MHz, CDCl3): d = 2.33 (s, 3 H, 4-CH3), 2.42 (s, 3 H,
4¢-CH3), 3.37 (d, J = 6.0 Hz, 2 H, CH2CH=), 4.36 (s, 2 H, NCH2),
5.15 (dq, J = 17.2, 1.6 Hz, 1 H, =CHAHB), 5.19 (dq, J = 10.0, 1.2
Hz, 1 H, =CHAHB), 6.03 (ddt, J = 17.2, 10.0, 6.0 Hz, 1 H, =CH),
6.65 (d, J = 8.0 Hz, 1 H, H6), 6.97 (d, J = 1.6 Hz, 1 H, H3), 7.02 (dd,
J = 8.4, 1.6 Hz, 1 H, H5), 7.22 (d, J = 8.0 Hz, 2 H, H3¢, H5¢), 7.32
(d, J = 8.0 Hz, 2 H, H2¢, H6¢).
13C NMR (100 MHz, CDCl3): d = 20.5 (4-CH3), 21.2 (4¢-CH3), 36.6
(CH2CH=), 48.4 (NCH2), 111.2 (C6), 116.3 (=CH2), 123.9 (C2),
126.7 (C4), 127.6 (C2¢, C6¢), 128.1 (C5), 129.4 (C3¢, C5¢), 130.7
(C3), 136.3 (=CH), 136.6 (C1¢), 136.8 (C4¢), 144.0 (C1).
MS (EI, 70 eV): m/z (%): 223 (14) [M+], 194 (100), 178 (8), 165
(11), 116 (10), 96 (10).
Anal. Calcd for C16H17N: C, 86.05; H, 7.67; N, 6.27. Found: C,
86.13; H, 7.81; N, 6.05.
11-Ethyl-2-fluoro-6,11-dihydro-5H-dibenz[b,e]azepine (3b)
IR (KBr): 3412 (N–H), 2963 (C–H Ar), 1607 (N–H), 1503 cm–1
(C=C Ar).
MS (EI, 70 eV): m/z (%) = 251 (56) [M+], 222 (9), 160 (7), 146 (72),
132 (17), 131 (23), 105 (100), 91 (8).
1H NMR (400 MHz, CDCl3): d = 0.91 (t, J = 7.1 Hz, 3 H, 13-CH3),
2.04–2.26 (m, 2 H, 12-CH2), 3.44 (br s, 1 H, NH), 3.71 (t, J = 7.6
Hz, 1 H, H11), 4.20 (d, J = 14.6 Hz, 1 H, H6A), 4.72 (d, J = 14.6 Hz,
1 H, H6B), 6.49 (dd, J = 8.0, 5.0 Hz, 1 H, H4), 6.72 (dd, J = 8.0, 3.0
Hz, 1 H, H3), 6.82 (dd, J = 10.0, 3.0 Hz, 1 H, H1), 7.14 (dd, J = 8.0,
2.0 Hz, 1 H, H7), 7.20 (dd, J = 8.0, 2.0 Hz, 1 H, H10), 7.22–7.25 (m,
2 H, H8, H9).
2-Allyl-4-methyl-N-(3-methylbenzyl)aniline (2i)
Time: 5 h; maroon oil; yield: 80%.
IR (KBr): 3430 (N–H), 3004 (C–H Ar), 1635 (C=C allyl), 1514
(C=C Ar), 913 cm–1 (=C–H allyl).
1H NMR (400 MHz, CDCl3): d = 2.29 (s, 3 H, 4-CH3), 2.38 (s, 3 H,
3¢-CH3), 3.34 (d, J = 6.2 Hz, 2 H, CH2CH=), 4.32 (s, 2 H, NCH2),
5.11 (dq, J = 17.4, 1.7 Hz, 1 H, =CHAHB), 5.15 (dq, J = 10.2, 1.7
Hz, 1 H, =CHAHB), 5.99 (ddt, J = 17.4, 10.2, 6.2 Hz, 1 H, =CH),
6.62 (d, J = 8.1 Hz, 1 H, H6), 6.94 (d, J = 1.7 Hz, 1 H, H3), 6.98 (dd,
J = 8.1, 1.7 Hz, 1 H, H5), 7.12 (d, J = 7.3 Hz, 1 H, H4¢), 7.19 (d,
J = 7.6 Hz, 1 H, H6¢), 7.23 (d, J = 1.6 Hz, 1 H, H2¢), 7.26 (t, J = 7.5
Hz, 1 H, H5¢).
13C NMR (100 MHz, CDCl3): d = 20.6 (4-CH3), 21.7 (3¢-CH3), 36.7
(CH2CH=), 49.1 (NCH2), 112.2 (C6), 117.0 (=CH2), 124.9 (C2),
125.4 (C6¢), 126.9 (C4), 128.8 (C5), 128.9 (C2¢), 129.2 (C4¢), 129.4
(C5¢), 131.5 (C3), 137.1 (=CH), 137.1 (C3¢), 139.1 (C1¢), 143.9
(C1).
13C NMR (100 MHz, CDCl3): d = 12.9 (13-CH3), 30.8 (12-CH2),
2
49.7 (C6), 53.1 (C11), 113.7 (d, JC,F = 20.0 Hz, C3), 116.7 (d,
3
2JC,F = 20.0 Hz, C1), 119.5 (d, JC,F = 10.0 Hz, C4), 126.8 (C8),
127.4 (C9), 128.2 (C7), 129.1 (C10), 130.0 (C11a), 136.5 (C6a),
141.3 (C10a), 142.5 (C4a), 156.4 (d, 1JC,F = 230.0 Hz, C2).
MS (EI, 70 eV): m/z (%) = 241 (17) [M+], 212 (100), 196 (15), 183
(17), 165 (10), 116 (9).
Anal. Calcd for C16H16FN: C, 79.64; H, 6.68; N, 5.80. Found: C,
79.70; H, 6.80; N, 5.65.
2-Chloro-11-ethyl-6,11-dihydro-5H-dibenz[b,e]azepine (3c)
IR (KBr): 3414 (N–H), 2962 (C–H Ar), 1602 (N–H), 1503 cm–1
(C=C Ar).
MS (EI, 70 eV): m/z (%) = 251(56) [M+], 222 (10), 160 (13), 146
(100), 132 (23), 131 (44), 105 (71), 79 (15).
1H NMR (400 MHz, CDCl3): d = 0.91 (t, J = 7.3 Hz, 3 H, 13-CH3),
2.15–2.23 (m, 2 H, 12-CH2), 3.63 (t, J = 7.3 Hz, 1 H, H11), 3.91 (br
s, 1 H, NH), 4.17 (d, J = 14.4 Hz, 1 H, H6A), 4.77 (d, J = 14.4 Hz, 1
H, H6B), 6.40 (d, J = 8.5 Hz, 1 H, H4), 6.91 (dd, J = 8.5, 2.3 Hz, 1
H, H3), 7.10 (d, J = 2.3 Hz, 1 H, H1), 7.13 (dd, J = 8.0, 2.0 Hz, 1 H,
H7), 7.17 (dd, J = 8.0, 2.0 Hz, 1 H, H10), 7.21 (td, J = 8.0, 2.0 Hz,
1 H, H8), 7.23 (td, J = 8.0, 2.0 Hz, 1 H, H9).
13C NMR (100 MHz, CDCl3): d = 13.0 (13-CH3), 31.6 (12-CH2),
51.1 (C6), 54.8 (C11), 117.9 (C4), 118.2 (C2), 126.8 (C10), 127.2
(C3), 127.4 (C9), 128.3 (C8), 129.0 (C7), 130.2 (C11a), 130.8 (C1),
136.5 (C6a), 142.1 (C10a), 146.2 (C4a).
11-Ethyl-6,11-dihydrodibenz[b,e]azepines 3; General Proce-
dure
Method A: A suspension of 2-allyl-N-benzylaniline 2 (1.0 g) in 95%
H2SO4 (2 mL) was stirred at 60–90 °C for 5–60 min (TLC control).
The mixture was cooled to r.t. and then it was poured into ice H2O
(50 mL), treated with 25% NH4OH soln to pH 8, and extracted with
CH2Cl2 (3 × 50 mL). The combined organic extracts were dried (an-
hyd Na2SO4), filtered, and evaporated to dryness in vacuo. The
crude material was purified by column chromatography (silica gel,
heptane–EtOAc, 20:1, 15:1, and 10:1). Compounds 3a–c,e–i were
obtained as viscous maroon oils, and compound 3d as white crys-
tals.
MS (EI, 70 eV): m/z (%) = 257 (35Cl, 19) [M+], 228 (100), 193 (46),
Method B: A suspension of 2-allyl-N-benzylaniline 2 (1.0 g) in 70%
HClO4 (4 mL) was stirred at 85–120 °C for 30–60 min (TLC con-
trol). The mixture was cooled to r.t. and then it was poured into ice
H2O (50 mL), treated with sat. Na2CO3 soln to pH 8, and extracted
165 (17), 115 (6), 89 (5).
Anal. Calcd for C16H16ClN: C, 74.55; H, 6.26; N, 5.43. Found: C,
74.38; H, 6.49; N, 5.35.
Synthesis 2010, No. 8, 1291–1302 © Thieme Stuttgart · New York

PAPER
Synthesis of Dibenzo[c,f]thiazolo[3,2-a]azepines
1297
11-Ethyl-2-methyl-6,11-dihydro-5H-dibenz[b,e]azepine (3d)
White crystals; mp 69–70 °C (heptane).
IR (KBr): 3399 (N–H), 3016 (C–H Ar), 1615 (N–H), 1509 cm–1
(C=C Ar).
1H NMR (400 MHz, CDCl3): d = 0.97 (t, J = 7.4 Hz, 3 H, 13-CH3),
2.19–2.29 (m, 2 H, 12-CH2), 2.31 (s, 3 H, 2-CH3), 3.80 (t, J = 6.9
Hz, 1 H, H11), 3.95 (br s, 1 H, NH), 4.16 (d, J = 14.2 Hz, 1 H, H6A),
4.83 (d, J = 14.2 Hz, 1 H, H6B), 6.52 (d, J = 8.0 Hz, 1 H, H4), 6.88
(dd, J = 8.0, 1.6 Hz, 1 H, H3), 6.97 (d, J = 1.6 Hz, 1 H, H1), 7.16
(dd, J = 7.2, 2.0 Hz, 1 H, H7), 7.21–7.26 (m, 3 H, H8, H9, H10).
13C NMR (100 MHz, CDCl3): d = 13.1 (13-CH3), 20.5 (2-CH3),
31.7 (12-CH2), 49.7 (C6), 54.5 (C11), 118.5 (C4), 126.7 (C8), 127.3
(C9), 127.9 (C11a), 128.0 (C3), 128.2 (C2), 128.3 (C10), 129.5
(C7), 131.8 (C1), 136.9 (C6a), 142.1 (C10a), 143.9 (C4a).
1H NMR (400 MHz, CDCl3): d = 0.94 (t, J = 7.4 Hz, 3 H, 13-CH3),
2.11–2.19 (m, 2 H, 12-CH2), 2.34 (s, 3 H, 8-CH3), 3.42 (br s, 1 H,
NH), 3.74 (t, J = 7.6 Hz, 1 H, H11), 3.91 (d, J = 14.8 Hz, 1 H, H6A),
5.03 (d, J = 14.8 Hz, 1 H, H6B), 6.41 (dd, J = 8.4, 1.3 Hz, 1 H, H4),
6.93 (d, J = 8.4 Hz, 1 H, H3), 6.97 (s, 1 H, H7), 7.06–7.12 (m, 3 H,
H1, H9, H10).
13C NMR (100 MHz, CDCl3): d = 13.0 (13-CH3), 21.0 (8-CH3),
32.7 (12-CH2), 49.1 (C6), 53.1 (C11), 119.2 (C4), 122.5 (C2), 127.0
(C3, C7), 128.3 (C9), 129.1 (C11a), 129.2 (C10), 130.5 (C1), 136.0
(C8), 136.6 (C6a), 138.6 (C10a), 144.8 (C4a).
MS (EI, 70 eV): m/z (%) = 271 (35Cl, 23) [M+], 242 (100), 240 (4),
213 (1), 181 (1), 179 (2).
Anal. Calcd for C17H18ClN: C, 75.13; H, 6.68; N, 5.15. Found: C,
75.23; H, 6.80; N, 5.09.
MS (EI, 70 eV): m/z (%) = 237 (23) [M+], 208 (100), 193 (22), 178
(4), 165 (6), 96 (5).
11-Ethyl-2,9-dimethyl-6,11-dihydro-5H-dibenz[b,e]azepine
(3h)
IR (KBr): 3406 (N–H), 3005 (C–H Ar), 1614 (N–H), 1508 cm–1
(C=C Ar).
Anal. Calcd for C17H19N: C, 86.03; H, 8.07; N, 5.90. Found: C,
86.14; H, 8.00; N, 5.85.
1H NMR (400 MHz, CDCl3): d = 0.98 (t, J = 7.4 Hz, 3 H, 13-CH3),
2.17–2.27 (m, 2 H, 12-CH2), 2.29 (s, 3 H, 2-CH3), 2.38 (s, 3 H, 9-
CH3), 3.75 (t, J = 7.4 Hz, 1 H, H11), 3.95 (br s, 1 H, NH), 4.14 (d,
J = 14.0 Hz, 1 H, H6A), 4.80 (d, J = 14.0 Hz, 1 H, H6B), 6.50 (d,
J = 8.0 Hz, 1 H, H4), 6.86 (dd, J = 8.0, 1.6 Hz, 1 H, H3), 6.94 (d,
J = 1.6 Hz, 1 H, H1), 7.05 (br s, 3 H, H7, H8, H10).
13C NMR (100 MHz, CDCl3): d = 13.2 (13-CH3), 20.5 (2-CH3),
21.2 (9-CH3), 31.5 (12-CH2), 49.3 (C6), 54.3 (C11), 118.5 (C4),
127.3 (C8), 127.7 (C11a), 128.0 (C3), 128.2 (C2), 128.3 (C10),
130.1 (C7), 131.7 (C1), 133.8 (C6a), 136.8 (C9), 142.1 (C10a),
143.8 (C4a).
11-Ethyl-2-methoxy-6,11-dihydro-5H-dibenz[b,e]azepine (3e)
IR (KBr): 3373 (N–H), 3023 (C–H Ar), 1614 (N–H), 1504 cm–1
(C=C Ar).
1H NMR (400 MHz, CDCl3): d = 0.92 (t, J = 7.4 Hz, 3 H, 13-CH3),
2.10–2.33 (m, 2 H, 12-CH2), 3.78 (s, 3 H, 2-OCH3), 3.83 (t, J = 6.5
Hz, 1 H, H11), 3.95 (br s, 1 H, NH), 4.19 (d, J = 14.7 Hz, 1 H, H6A),
4.71 (d, J = 14.7 Hz, 1 H, H6B), 6.58 (d, J = 8.5 Hz, 1 H, H4), 6.65
(dd, J = 8.5, 2.8 Hz, 1 H, H3), 6.72 (d, J = 2.8 Hz, 1 H, H1), 7.11
(dd, J = 7.4, 2.0 Hz, 1 H, H7), 7.17–7.24 (m, 3 H, H8, H9, H10).
13C NMR (100 MHz, CDCl3): d = 13.2 (13-CH3), 31.2 (12-CH2),
50.4 (C6), 55.7 (C11), 55.7 (2-OCH3), 112.9 (C3), 116.5 (C1),
119.9 (C4), 126.7 (C9), 127.1 (C8), 128.4 (C7, C10), 131.1 (C11a),
137.0 (C6a), 140.4 (C4a), 141.6 (C10a), 153.2 (C2).
MS (EI, 70 eV): m/z (%) = 251 (21) [M+], 222 (100), 207 (23), 191
(4), 178 (4), 165 (3), 103 (7).
Anal. Calcd for C18H21N: C, 86.01; H, 8.42; N, 5.57. Found: C,
86.13; H, 8.38; N, 5.49.
MS (EI, 70 eV): m/z (%): 253 (32) [M+], 224 (100), 209 (7), 193 (9),
180 (25), 152 (7).
Anal. Calcd for C17H19NO: C, 80.60; H, 7.56; N, 5.53. Found: C,
80.48; H, 7.44; N, 5.60.
11-Ethyl-2,8-dimethyl-6,11-dihydro-5H-dibenz[b,e]azepine (3i)
IR (KBr): 3405 (N–H), 3007 (C–H Ar), 1613 (N–H), 1508 cm–1
(C=C Ar).
1H NMR (400 MHz, CDCl3): d = 0.94 (t, J = 7.3 Hz, 3 H, 13-CH3),
2.11–2.25 (m, 2 H, 12-CH2), 2.27 (s, 3 H, 2-CH3), 2.35 (s, 3 H, 8-
CH3), 3.84 (t, J = 6.8 Hz, 1 H, H11), 3.85 (br s, 1 H, NH), 4.10 (d,
J = 14.4 Hz, 1 H, H6A), 4.79 (d, J = 14.4 Hz, 1 H, H6B), 6.49 (d,
J = 8.0 Hz, 1 H, H4), 6.84 (dd, J = 8.0, 1.7 Hz, 1 H, H3), 6.92 (d,
J = 1.7 Hz, 1 H, H1), 6.93 (s, 1 H, H7), 7.04 (dd, J = 7.6, 1.1 Hz, 1
H, H9), 7.10 (d, J = 7.6 Hz, 1 H, H10).
13C NMR (100 MHz, CDCl3): d = 13.2 (13-CH3), 20.5 (2-CH3),
21.0 (8-CH3), 32.0 (12-CH2), 49.7 (C6), 54.0 (C11), 118.5 (C4),
127.8 (C2), 127.9 (C3), 128.5 (C11a), 129.5 (C7), 129.6 (C9, C10),
131.7 (C1), 136.2 (C8), 136.7 (C6a), 139.1 (C10a), 143.9 (C4a).
11-Ethyl-9-methyl-6,11-dihydro-5H-dibenz[b,e]azepine (3f)
IR (KBr): 3408 (N–H), 3011 (C–H Ar), 1601 (N–H), 1492 cm–1
(C=C Ar).
1H NMR (400 MHz, CDCl3): d = 0.95 (t, J = 7.4 Hz, 3 H, 13-CH3),
2.14–2.23 (m, 2 H, 12-CH2), 2.34 (s, 3 H, 9-CH3), 3.75 (t, J = 7.1
Hz, 1 H, H11), 3.95 (br s, 1 H, NH), 4.13 (d, J = 14.0 Hz, 1 H, H6A),
4.81 (d, J = 14.0 Hz, 1 H, H6B), 6.51 (dd, J = 8.0, 1.0 Hz, 1 H, H4),
6.70 (td, J = 8.0, 1.0 Hz, 1 H, H2), 6.99 (td, J = 8.0, 1.0 Hz, 1 H,
H3), 7.01–7.06 (m, 3 H, H7, H8, H10), 7.08 (dd, J = 8.0, 1.0 Hz, 1
H, H1).
13C NMR (100 MHz, CDCl3): d = 13.1 (13-CH3), 21.2 (9-CH3),
29.8 (12-CH2), 49.0 (C6), 54.3 (C11), 118.1 (C4), 118.3 (C2), 127.4
(C3, C10), 127.5 (C11a), 128.3 (C7), 130.0 (C8), 131.3 (C1), 133.7
(C6a), 137.1 (C9), 142.2 (C10a), 146.3 (C4a).
MS (EI, 70 eV): m/z (%) = 251 (20) [M+], 222 (100), 207 (29), 191
(5), 178 (4), 165 (4), 103 (6).
Anal. Calcd for C18H21N: C, 86.01; H, 8.42; N, 5.57. Found: C,
85.88; H, 8.53; N, 5.50.
MS (EI, 70 eV): m/z (%): 237 (18) [M+], 208 (100), 193 (24), 178
(4), 165 (6), 96 (7).
Anal. Calcd for C17H19N: C, 86.03; H, 8.07; N, 5.90. Found: C,
86.14; H, 8.00; N, 5.85.
11-Ethyldibenz[b,e]azepines 4; General Procedure
PCC (1 mmol) was added portionwise within 10 min to a stirred and
cooled (ice bath) soln of dihydrodibenz[b,e]azepine 3 (1 mmol) in
CH2Cl2 (10 mL). Upon complete addition, the suspension was
stirred at 0 °C for an additional 20–30 min (TLC control). The re-
sulting orange precipitate was removed by filtration and the filtrate
was concentrated in vacuo. The crude material was purified by col-
umn chromatography (silica gel, heptane–EtOAc, 10:1, 5:1). Com-
pounds 4a–i were obtained as high-viscosity yellow oils.
2-Chloro-11-ethyl-8-methyl-6,11-dihydro-5H-
dibenz[b,e]azepine (3g)
IR (KBr): 3415 (N–H), 2965 (C–H Ar), 1603 (N–H), 1501 cm–1
(C=C Ar).
Synthesis 2010, No. 8, 1291–1302 © Thieme Stuttgart · New York

1298
A. Palma et al.
PAPER
11-Ethyl-11H-dibenz[b,e]azepine (4a)
Time: 35 min; yield: 95%.
IR (KBr): 3018 (C–H Ar), 1617 (C=N), 1482 (C=C Ar), 1299 cm–1
(C–N).
IR (KBr): 2962 (C–H Ar), 1616 (C=N), 1478 (C=C Ar), 1214 cm–1
(C–N).
1H NMR (400 MHz, CDCl3): d = 0.70 (t, J = 7.4 Hz, 3 H, 13-CH3),
1.62–1.72 (m, 2 H, 12-CH2), 2.36 (s, 3 H, 2-CH3), 3.64 (t, J = 8.0
Hz, 1 H, H11), 7.03 (s, 1 H, H1), 7.11 (dd, J = 8.0, 1.2 Hz, 1 H, H3),
7.27 (d, J = 8.4 Hz, 1 H, H10), 7.31 (td, J = 7.6, 1.0 Hz, 1 H, H8),
7.39 (d, J = 8.0 Hz, 1 H, H4), 7.44 (td, J = 7.6, 1.2 Hz, 1 H, H9),
7.51 (d, J = 7.6 Hz, 1 H, H7), 8.74 (s, 1 H, H6).
13C NMR (100 MHz, CDCl3): d = 12.6 (13-CH3), 21.0 (2-CH3),
24.4 (12-CH2), 54.9 (C11), 126.6 (C8), 128.1 (C3), 128.9 (C4),
129.0 (C10), 130.1 (C7), 130.5 (C1), 131.3 (C6a), 131.7 (C9), 135.9
(C11a), 137.9 (C2), 142.1 (C4a), 145.2 (C10a), 159.4 (C6).
1H NMR (400 MHz, CDCl3): d = 0.70 (t, J = 7.4 Hz, 3 H, 13-CH3),
1.61–1.75 (m, 2 H, 12-CH2), 3.69 (t, J = 8.0 Hz, 1 H, H11), 7.20 (dd,
J = 7.6, 1.5 Hz, 1 H, H10), 7.21 (td, J = 8.0, 1.8 Hz, 1 H, H3), 7.26
(dd, J = 8.0, 1.2 Hz, 1 H, H4), 7.29 (dd, J = 8.0, 1.8 Hz, 1 H, H1),
7.34 (td, J = 7.6, 1.0 Hz, 1 H, H8), 7.46 (td, J = 7.6, 1.2 Hz, 1 H,
H9), 7.47 (td, J = 8.0, 1.2 Hz, 1 H, H2), 7.53 (d, J = 7.6 Hz, 1 H,
H7), 8.79 (s, 1 H, H6).
13C NMR (100 MHz, CDCl3): d = 12.1 (13-CH3), 23.7 (12-CH2),
54.3 (C11), 126.7 (C3), 127.2 (C4), 128.3 (C8), 128.4 (C2), 129.0
(C1), 129.6 (C10), 129.9 (C7), 130.1 (C6a), 131.2 (C9), 135.5
(C11a), 143.9 (C4a), 144.9 (C10a), 159.6 (C6).
MS (EI, 70 eV): m/z (%) = 235 (14) [M+], 206 (100), 191 (10), 190
(13), 178 (8).
Anal. Calcd for C17H17N: C, 86.77; H, 7.28; N, 5.95. Found: C,
86.80; H, 7.25; N, 5.92.
MS (EI, 70 eV): m/z (%) = 221 (12) [M+], 192 (100), 165 (19), 139
(3), 89 (2), 63 (5), 51 (3).
11-Ethyl-2-methoxy-11H-dibenz[b,e]azepine (4e)
Time: 30 min; yield: 85%.
IR (KBr): 3015 (C–H Ar), 1615 (C=N), 1487 (C=C Ar), 1315 cm–1
(C–N).
Anal. Calcd for C16H15N: C, 86.84; H, 6.83; N, 6.33. Found: C,
86.70; H, 6.98; N, 6.29.
11-Ethyl-2-fluoro-11H-dibenz[b,e]azepine (4b)
Time: 40 min; yield: 89%.
IR (KBr): 2964 (C–H Ar), 1618 (C=N), 1481 (C=C Ar), 1243 cm–1
(C–N).
1H NMR (400 MHz, CDCl3): d = 0.70 (t, J = 7.4 Hz, 3 H, 13-CH3),
1.59–1.74 (m, 2 H, 12-CH2), 3.61 (t, J = 8.0 Hz, 1 H, H11), 6.90 (dd,
J = 9.2, 3.0 Hz, 1 H, H1), 6.98 (td, J = 8.0, 3.0 Hz, 1 H, H3), 7.25
(d, J = 7.2 Hz, 1 H, H10), 7.36 (td, J = 7.6, 1.2 Hz, 1 H, H8), 7.43
(t, J = 9.2 Hz, 1 H, H4), 7.46 (td, J = 7.6, 1.2 Hz, 1 H, H9), 7.52 (d,
J = 7.6 Hz, 1 H, H7), 8.73 (s, 1 H, H6).
1H NMR (400 MHz, CDCl3): d = 0.69 (t, J = 7.4 Hz, 3 H, 13-CH3),
1.61–1.71 (m, 2 H, 12-CH2), 3.62 (t, J = 8.0 Hz, 1 H, H11), 3.81 (s,
3 H, 2-OCH3), 6.74 (d, J = 2.8 Hz, 1 H, H1), 6.85 (dd, J = 8.7, 2.8
Hz, 1 H, H3), 7.25 (d, J = 7.6 Hz, 1 H, H10), 7.33 (td, J = 7.4, 1.0
Hz, 1 H, H8), 7.44 (d, J = 8.7 Hz, 1 H, H4), 7.44 (td, J = 7.4, 1.2 Hz,
1 H, H9), 7.51 (d, J = 7.6 Hz, 1 H, H7), 8.67 (s, 1 H, H6).
13C NMR (100 MHz, CDCl3): d = 12.5 (13-CH3), 24.4 (12-CH2),
55.1 (C11), 55.5 (2-OCH3), 112.4 (C3), 114.6 (C1), 126.7 (C8),
128.9 (C10), 130.5 (C4), 130.6 (C7), 130.7 (C6a), 131.6 (C9), 137.3
(C11a), 138.4 (C4a), 144.4 (C10a), 158.1 (C6), 159.6 (C2).
13C NMR (100 MHz, CDCl3): d = 12.5 (13-CH3), 24.2 (12-CH2),
54.7 (C11), 114.1 (d, 2JC,F = 20.0 Hz, C3), 115.8 (d, 2JC,F = 20.0 Hz,
C1), 127.0 (C8), 128.9 (C10), 130.5 (C7), 130.6 (C6a), 130.9 (d,
MS (EI, 70 eV): m/z (%) = 251 (21) [M+], 222 (100), 207 (3), 190
(4), 179 (20), 178 (10).
3JC,F = 10.0 Hz, C4), 131.9 (C9), 137.0 (d, JC,F = 10.0 Hz, C11a),
3
Anal. Calcd for C17H17NO: C, 81.24; H, 6.82; N, 5.57. Found: C,
81.07; H, 6.95; N, 5.48.
141.1 (d, 4JC,F = 10.0 Hz, C4a), 144.4 (C10a), 159.6 (C6), 162.5 (d,
1JC,F = 250.0 Hz, C2).
MS (EI, 70 eV): m/z (%) = 239 (12) [M+], 210 (100), 190 (12), 183
11-Ethyl-9-methyl-11H-dibenz[b,e]azepine (4f)
(16), 157 (3), 133 (2), 63 (8), 51 (2).
Time: 35 min; yield: 88%.
Anal. Calcd for C16H14FN: C, 80.31; H, 5.90; N, 5.85. Found: C,
8.14; H, 6.03; N, 5.79.
IR (KBr): 3016 (C–H Ar), 1610 (C=N), 1476 (C=C Ar), 1306 cm–1
(C–N).
1H NMR (400 MHz, CDCl3): d = 0.71 (t, J = 7.4 Hz, 3 H, 13-CH3),
1.60–1.74 (m, 2 H, 12-CH2), 2.39 (s, 3 H, 9-CH3), 3.65 (t, J = 8.0
Hz, 1 H, H11), 7.11 (s, 1 H, H10), 7.14 (d, J = 7.7 Hz, 1 H, H8), 7.20
(dd, J = 7.7, 1.7 Hz, 1 H, H1), 7.24 (td, J = 7.7, 1.4 Hz, 1 H, H2),
7.30 (td, J = 7.7, 1.7 Hz, 1 H, H3), 7.41 (d, J = 7.7 Hz, 1 H, H7),
7.51 (d, J = 7.7 Hz, 1 H, H4), 8.76 (s, 1 H, H6).
13C NMR (100 MHz, CDCl3): d = 12.6 (13-CH3), 21.5 (9-CH3),
24.4 (12-CH2), 54.9 (C11), 127.2 (C2), 127.4 (C3), 127.6 (C8),
128.2 (C6a), 128.9 (C4), 129.4 (C10), 129.5 (C1), 130.1 (C7), 136.0
(C11a), 142.5 (C9), 144.5 (C4a), 145.4 (C10a), 160.0 (C6).
2-Chloro-11-ethyl-11H-dibenz[b,e]azepine (4c)
Time: 35 min; yield: 93%.
IR (KBr): 2963 (C–H Ar), 1616 (C=N), 1472 (C=C Ar), 1210 cm–1
(C–N).
1H NMR (400 MHz, CDCl3): d = 0.69 (t, J = 7.2 Hz, 3 H, 13-CH3),
1.59–1.73 (m, 2 H, 12-CH2), 3.61 (t, J = 8.0 Hz, 1 H, H11), 7.20 (d,
J = 2.4 Hz, 1 H, H1), 7.24 (dd, J = 8.4, 2.4 Hz, 1 H, H3), 7.26 (d,
J = 7.6 Hz, 1 H, H10), 7.35 (td, J = 7.6, 1.0 Hz, 1 H, H8), 7.39 (d,
J = 8.4 Hz, 1 H, H4), 7.46 (td, J = 7.6, 1.2 Hz, 1 H, H9), 7.52 (d,
J = 7.6 Hz, 1 H, H7), 8.75 (s, 1 H, H6).
13C NMR (100 MHz, CDCl3): d = 12.6 (13-CH3), 24.2 (12-CH2),
54.6 (C11), 127.0 (C8), 127.3 (C3), 128.9 (C10), 129.2 (C1), 130.3
(C4), 130.6 (C6a, C7), 132.0 (C9), 133.3 (C2), 137.5 (C11a), 143.2
(C4a), 144.7 (C10a), 160.5 (C6).
MS (EI, 70 eV): m/z (%) = 235 (11) [M+], 206 (100), 191 (10), 190
(13), 178 (6).
Anal. Calcd for C17H17N: C, 86.77; H, 7.28; N, 5.95. Found: C,
86.70; H, 7.38; N, 5.89.
MS (EI, 70 eV): m/z (%) = 255 (35Cl, 12) [M+], 226 (100), 199 (4),
2-Chloro-11-ethyl-8-methyl-11H-dibenz[b,e]azepine (4g)
190 (34), 163 (11), 63 (5), 51 (2).
Time: 35 min; yield: 87%.
Anal. Calcd for C16H14ClN: C, 75.14; H, 5.52; N, 5.48. Found: C,
74.98; H, 5.45; N, 5.54.
IR (KBr): 2963 (C–H Ar), 1615 (C=N), 1467 (C=C Ar), 1248 cm–1
(C–N).
1H NMR (400 MHz, CDCl3): d = 0.69 (t, J = 7.2 Hz, 3 H, 13-CH3),
1.57–1.72 (m, 2 H, 12-CH2), 2.36 (s, 3 H, 8-CH3), 3.58 (t, J = 8.0
11-Ethyl-2-methyl-11H-dibenz[b,e]azepine (4d)
Time: 30 min; yield: 90%.
Synthesis 2010, No. 8, 1291–1302 © Thieme Stuttgart · New York

PAPER
Synthesis of Dibenzo[c,f]thiazolo[3,2-a]azepines
1299
Hz, 1 H, H11), 7.14 (d, J = 8.0 Hz, 1 H, H10), 7.19 (d, J = 2.0 Hz,
1 H, H1), 7.24 (dd, J = 8.4, 2.0 Hz, 1 H, H3), 7.27 (d, J = 8.0 Hz, 1
H, H9), 7.32 (br s, 1 H, H7), 7.38 (d, J = 8.4 Hz, 1 H, H4), 8.71 (s,
1 H, H6).
material was purified by column chromatography (silica gel, hep-
tane–EtOAc, 10:1, 5:1, and 2:1).
9-Ethyl-9,13b-dihydrodibenzo[c,f]thiazolo[3,2-a]azepin-3(2H)-
one (5a)
13C NMR (100 MHz, CDCl3): d = 12.6 (13-CH3), 20.9 (8-CH3),
24.3 (12-CH2), 54.1 (C11), 127.2 (C3), 128.9 (C1), 129.1 (C10),
130.3 (C7), 130.4 (C6a), 131.1 (C4), 132.9 (C9), 133.2 (C2), 136.7
(C8), 137.7 (C11a), 142.0 (C10a), 143.2 (C4a), 160.6 (C6).
Time: 24 h; pale-yellow crystals; yield: 55%; mp 128–129 °C (hep-
tane).
IR (KBr): 2962 (C–H Ar), 1695 (C=O), 1478 (C=C Ar), 1360 cm–1
(C–N).
MS (EI, 70 eV): m/z (%) = 269 (35Cl, 15) [M+], 240 (100), 204 (10),
190 (15), 178 (5), 77 (3), 65 (2).
1H NMR (400 MHz, CDCl3): d = 1.13 (t, J = 7.2 Hz, 3 H, 15-CH3),
2.24–2.40 (m, 2 H, 14-CH2), 3.64 (d, J = 15.2 Hz, 1 H, H2A), 3.99
(dd, J = 15.2, 2.0 Hz, 1 H, H2B), 4.40 (t, J = 7.6 Hz, 1 H, H9), 6.23
(d, J = 0.8 Hz, 1 H, H13b), 7.08 (dd, J = 8.0, 1.0 Hz, 1 H, H5), 7.14
(td, J = 8.0, 1.0 Hz, 1 H, H7), 7.23 (dd, J = 8.0, 1.0 Hz, 1 H, H8),
7.24–7.30 (m, 3 H, H6, H12, H13), 7.32–7.36 (m, 2 H, H10, H11).
13C NMR (100 MHz, CDCl3): d = 12.5 (15-CH3), 20.9 (14-CH2),
33.6 (C2), 42.1 (C9), 64.6 (C13b), 124.5 (C5), 124.8 (C6, C10),
126.8 (C12), 127.1 (C7), 128.1 (C8), 128.5 (C13), 128.6 (C8a),
128.8 (C11), 135.4 (C13a), 141.3 (C9a), 143.5 (C4a), 171.7 (C3).
Anal. Calcd for C17H16ClN: C, 75.69; H, 5.98; N, 5.19. Found: C,
75.60; H, 6.04; N, 5.09.
11-Ethyl-2,9-dimethyl-11H-dibenz[b,e]azepine (4h)
Time: 30 min; yield: 86%.
IR (KBr): 3014 (C–H Ar), 1609 (C=N), 1485 (C=C Ar), 1307 cm–1
(C–N).
1H NMR (400 MHz, CDCl3): d = 0.70 (t, J = 7.4 Hz, 3 H, 13-CH3),
1.61–1.71 (m, 2 H, 12-CH2), 2.36 (s, 3 H, 2-CH3), 2.39 (s, 3 H, 9-
CH3), 3.59 (t, J = 8.0 Hz, 1 H, H11), 7.02 (s, 1 H, H1), 7.06 (s, 1 H,
H10), 7.11 (dd, J = 8.0, 1.2 Hz, 1 H, H3), 7.13 (d, J = 8.0 Hz, 1 H,
H8), 7.39 (d, J = 8.0 Hz, 1 H, H4), 7.41 (d, J = 8.0 Hz, 1 H, H7),
8.71 (s, 1 H, H6).
MS (EI, 70 eV): m/z (%) = 295 (57) [M+], 266 (72), 248 (12), 221
(14), 220 (26), 206 (21), 192 (100).
Anal. Calcd for C18H17NOS: C, 73.19; H, 5.80; N, 4.74. Found: C,
73.00; H, 5.95; N, 4.84.
13C NMR (100 MHz, CDCl3): d = 12.6 (13-CH3), 21.0 (2-CH3),
21.5 (9-CH3), 24.4 (12-CH2), 55.0 (C11), 127.4 (C8), 128.0 (C3),
128.3 (C6a), 128.9 (C10), 129.4 (C4), 130.1 (C1), 130.6 (C7), 135.8
(C11a), 137.6 (C2), 142.3 (C4a, C9), 145.2 (C10a), 159.3 (C6).
MS (EI, 70 eV): m/z (%) = 249 (12) [M+], 220 (100), 205 (4), 204
(8), 190 (14), 178 (5).
9-Ethyl-7-fluoro-9,13b-dihydrodibenzo[c,f]thiazolo[3,2-
a]azepin-3(2H)-one (5b)
Time: 28 h; yellow crystals; yield: 60%; mp 131–132 °C (heptane).
IR (KBr): 2963 (C–H Ar), 1693 (C=O), 1492 (C=C Ar), 1362 cm–1
(C–N).
1H NMR (400 MHz, CDCl3): d = 1.12 (t, J = 7.2 Hz, 3 H, 15-CH3),
2.16–2.36 (m, 2 H, 14-CH2), 3.63 (d, J = 15.6 Hz, 1 H, H2A), 3.98
(dd, J = 15.6, 2.0 Hz, 1 H, H2B), 4.36 (t, J = 7.6 Hz, 1 H, H9), 6.19
(d, J = 1.2 Hz, 1 H, H13b), 6.94–6.98 (m, 2 H, H6, H8), 7.09 (dd,
J = 7.6, 1.2 Hz, 1 H, H13), 7.16 (td, J = 7.6, 1.2 Hz, 1 H, H12), 7.26
(td, J = 7.6, 1.2 Hz, 1 H, H11), 7.28–7.30 (m, 1 H, H5), 7.32 (d,
J = 7.6 Hz, 1 H, H10).
Anal. Calcd for C18H19N: C, 86.70; H, 7.68; N, 5.62. Found: C,
86.81; H, 7.59; N, 5.68.
11-Ethyl-2,8-dimethyl-11H-dibenz[b,e]azepine (4i)
Time: 30 min; yield: 87%.
IR (KBr): 3011 (C–H Ar), 1617 (C=N), 1487 (C=C Ar), 1310 cm–1
(C–N).
13C NMR (100 MHz, CDCl3): d = 12.4 (15-CH3), 20.8 (14-CH2),
1H NMR (400 MHz, CDCl3): d = 0.69 (t, J = 7.4 Hz, 3 H, 13-CH3),
1.61–1.70 (m, 2 H, 12-CH2), 2.35 (s, 3 H, 2-CH3), 2.36 (s, 3 H, 8-
CH3), 3.61 (t, J = 8.0 Hz, 1 H, H11), 7.01 (d, J = 1.3 Hz, 1 H, H1),
7.10 (dd, J = 8.0, 1.3 Hz, 1 H, H3), 7.16 (d, J = 7.7 Hz, 1 H, H10),
7.26 (dd, J = 7.7, 1.0 Hz, 1 H, H9), 7.32 (s, 1 H, H7), 7.38 (d, J = 8.0
Hz, 1 H, H4), 8.70 (s, 1 H, H6).
13C NMR (100 MHz, CDCl3): d = 12.6 (13-CH3), 20.9 (2-CH3),
21.0 (8-CH3), 24.6 (12-CH2), 54.5 (C11), 128.0 (C3), 128.9 (C4,
C10), 130.1 (C1), 130.5 (C6a), 131.0 (C7), 132.6 (C9), 136.1
(C11a), 136.3 (C8), 137.8 (C2), 142.1 (C4a), 142.5 (C10a), 159.6
(C6).
2
33.5 (C2), 42.2 (C9), 64.5 (C13b), 112.0 (d, JC,F = 30.0 Hz, C8),
2
114.0 (d, JC,F = 30.0 Hz, C6), 124.6 (C10), 127.1 (C12), 128.7
3
(C13), 128.9 (C11), 129.8 (d, JC,F = 10.0 Hz, C5), 131.0 (C8a),
134.3 (C13a), 140.6 (C9a), 146.1 (d, 4JC,F = 10.0 Hz, C4a), 162.4 (d,
1JC,F = 240.0 Hz, C7), 171.8 (C3).
MS (EI, 70 eV): m/z (%) = 313 (45) [M+], 284 (46), 266 (10), 239
(16), 238 (23), 224 (21), 210 (100).
Anal. Calcd for C18H16FNOS: C, 68.99; H, 5.15; N, 4.47. Found: C,
68.90; H, 5.03; N, 4.60.
7-Chloro-9-ethyl-9,13b-dihydrodibenzo[c,f]thiazolo[3,2-
a]azepin-3(2H)-one (5c)
Time: 26 h; yellow crystals; yield: 62%; mp 136–137 °C (heptane).
MS (EI, 70 eV): m/z (%) = 249 (12) [M+], 220 (100), 204 (8), 190
(14), 178 (5), 164 (1).
IR (KBr): 2962 (C–H Ar), 1697 (C=O), 1490 (C=C Ar), 1361 cm–1
(C–N).
Anal. Calcd for C18H19N: C, 86.70; H, 7.68; N, 5.62. Found: C,
86.90; H, 7.49; N, 5.53.
1H NMR (400 MHz, CDCl3): d = 1.12 (t, J = 7.2 Hz, 3 H, 15-CH3),
2.17–2.37 (m, 2 H, 14-CH2), 3.63 (d, J = 15.6 Hz, 1 H, H2A), 3.98
(dd, J = 15.6, 2.0 Hz, 1 H, H2B), 4.36 (t, J = 7.6 Hz, 1 H, H9), 6.20
(s, 1 H, H13b), 7.09 (d, J = 8.0 Hz, 1 H, H13), 7.16 (t, J = 8.0 Hz, 1
H, H12), 7.23–7.30 (m, 4 H, H5, H6, H8, H11), 7.32 (d, J = 8.0 Hz,
1 H, H10).
13C NMR (100 MHz, CDCl3): d = 12.4 (15-CH3), 20.9 (14-CH2),
33.6 (C2), 42.2 (C9), 64.5 (C13b), 125.0 (C5), 125.1 (C10), 127.1
(C6), 127.3 (C12), 128.7 (C8), 129.0 (C13), 129.4 (C11), 133.8
Dihydrodibenzo[c,f]thiazolo[3,2-a]azepin-3(2H)-ones 5; Gener-
al Procedure
A mixture of morphanthridine 4 (1 mmol), mercaptoacetic acid (3
mmol) and a catalytic amount of BF3·OEt2 (1 drop) in anhyd toluene
(50 mL) was refluxed for 24–40 h using a Dean–Stark trap. The
mixture was cooled to r.t. and then it was poured into H2O (50 mL),
neutralized with sat. NaHCO3 soln, and extracted with CH2Cl2
(3 × 50 mL). The combined organic extracts were dried (anhyd
Na2SO4), filtered, and evaporated to dryness in vacuo. The crude
Synthesis 2010, No. 8, 1291–1302 © Thieme Stuttgart · New York

1300
A. Palma et al.
PAPER
(C8a), 134.1 (C13a), 134.4 (C7), 140.5 (C9a), 145.4 (C4a), 171.7
(C3).
6.98 (d, J = 7.8 Hz, 1 H, H13), 7.14 (s, 1 H, H10), 7.26–7.34 (m, 4
H, H5, H6, H7, H8).
MS (EI, 70 eV): m/z (%) = 329 (35Cl, 47) [M+], 300 (51), 282 (12),
255 (15), 254 (17), 240 (18), 226 (100).
13C NMR (100 MHz, CDCl3): d = 12.4 (15-CH3), 20.7 (14-CH2),
21.3 (11-CH3), 33.5 (C2), 41.9 (C9), 64.4 (C13b), 124.3 (C8), 125.4
(C10), 126.9 (C6), 127.2 (C12), 127.9 (C7), 128.3 (C5), 128.4
(C13), 131.1 (C13a), 135.2 (C8a), 138.5 (C11), 141.0 (C9a), 143.4
(C4a), 171.6 (C3).
Anal. Calcd for C18H16ClNOS: C, 65.54; H, 4.89; N, 4.25. Found:
C, 65.70; H, 4.73; N, 4.18.
9-Ethyl-7-methyl-9,13b-dihydrodibenzo[c,f]thiazolo[3,2-
a]azepin-3(2H)-one (5d)
MS (EI, 70 eV): m/z (%) = 309 (55) [M+], 280 (56), 262 (12), 235
(15), 234 (34), 220 (22), 206 (100).
Time: 24 h; yellow crystals; yield: 60%; mp 152–154 °C (heptane).
IR (KBr): 3030 (C–H Ar), 1701 (C=O), 1453 (C=C Ar), 1263 cm–1
(C–N).
Anal. Calcd for C19H19NOS: C, 73.75; H, 6.19; N, 4.53. Found: C,
73.82; H, 6.30; N, 4.44.
7-Chloro-9-ethyl-12-methyl-9,13b-dihydrodibenzo[c,f]thiazo-
lo[3,2-a]azepin-3(2H)-one (5g)
Time: 35 h; yellow viscous oil; yield: 50%.
IR (KBr): 2953 (C–H Ar), 1712 (C=O), 1484 (C=C Ar), 1345 cm–1
(C–N).
1H NMR (400 MHz, CDCl3): d = 1.11 (t, J = 7.3 Hz, 3 H, 15-CH3),
2.25 (s, 3 H, 12-CH3), 2.20–2.35 (m, 2 H, 14-CH2), 3.63 (d, J = 15.4
Hz, 1 H, H2A), 3.98 (dd, J = 15.4, 2.0 Hz, 1 H, H2B), 4.30 (t, J = 7.6
Hz, 1 H, H9), 6.15 (s, 1 H, H13b), 6.90 (s, 1 H, H13), 7.07 (d, J = 8.0
Hz, 1 H, H11), 7.20 (d, J = 8.0 Hz, 1 H, H10), 7.23–7.31 (m, 3 H,
H5, H6, H8).
13C NMR (100 MHz, CDCl3): d = 12.4 (15-CH3), 20.9 (14-CH2),
22.8 (12-CH3), 33.6 (C2), 41.8 (C9), 64.5 (C13b), 124.9 (C10),
125.0 (C5), 127.2 (C6), 128.8 (C8), 129.4 (C11), 129.7 (C13), 133.9
(C8a), 134.1 (C13a), 134.4 (C7), 136.8 (C12), 137.4 (C9a), 145.7
(C4a), 171.8 (C3).
1H NMR (400 MHz, CDCl3): d = 1.13 (t, J = 7.3 Hz, 3 H, 15-CH3),
2.28 (s, 3 H, 7-CH3), 2.22–2.38 (m, 2 H, 14-CH2), 3.63 (dd,
J = 15.4, 0.7 Hz, 1 H, H2A), 3.98 (dd, J = 15.4, 1.9 Hz, 1 H, H2B),
4.36 (t, J = 7.6 Hz, 1 H, H9), 6.21 (s, 1 H, H13b), 7.07 (br s, 1 H,
H8), 7.08 (d, J = 7.8 Hz, 2 H, H5, H13), 7.14 (td, J = 7.6, 1.0 Hz, 1
H, H12), 7.22 (d, J = 7.8 Hz, 1 H, H6), 7.25 (td, J = 7.3, 1.7 Hz, 1
H, H11), 7.33 (d, J = 7.8 Hz, 1 H, H10).
13C NMR (100 MHz, CDCl3): d = 12.5 (15-CH3), 20.9 (14-CH2),
21.6 (7-CH3), 33.6 (C2), 42.0 (C9), 64.6 (C13b), 124.8 (C10), 125.2
(C8), 126.7 (C12), 127.7 (C11), 127.8 (C6), 128.1 (C5), 128.7
(C13), 132.7 (C8a), 134.6 (C13a), 138.5 (C7), 141.4 (C9a), 143.2
(C4a), 171.7 (C3).
MS (EI, 70 eV): m/z (%) = 309 (43) [M+], 280 (61), 262 (7), 235
(11), 234 (17), 220 (10), 206 (100).
Anal. Calcd for C19H19NOS: C, 73.75; H, 6.19; N, 4.53. Found: C,
73.87; H, 6.12; N, 4.61.
MS (EI, 70 eV): m/z (%) = 343 (35Cl, 39) [M+], 314 (69), 296 (9),
9-Ethyl-7-methoxy-9,13b-dihydrodibenzo[c,f]thiazolo[3,2-
a]azepin-3(2H)-one (5e)
Time: 40 h; yellow crystals; yield: 65%; mp 52–53 °C (heptane).
IR (KBr): 3061 (C–H Ar), 1690 (C=O), 1462 (C=C Ar), 1277 cm–1
(C–N).
269 (10), 268 (17), 254 (18), 240 (100).
Anal. Calcd for C19H18ClNOS: C, 66.36; H, 5.28; N, 4.07. Found:
C, 66.50; H, 5.13; N, 3.98.
9-Ethyl-7,11-dimethyl-9,13b-dihydrodibenzo[c,f]thiazolo[3,2-
a]azepin-3(2H)-one (5h)
Time: 35 h; yellow crystals; yield: 65%; mp 144–145 °C (heptane).
IR (KBr): 3024 (C–H Ar), 1694 (C=O), 1455 (C=C Ar), 1263 cm–1
(C–N).
1H NMR (400 MHz, CDCl3): d = 1.13 (t, J = 7.2 Hz, 3 H, 15-CH3),
2.30 (s, 6 H, 7-CH3, 11-CH3), 2.20–2.38 (m, 2 H, 14-CH2), 3.62 (dd,
J = 15.5, 0.7 Hz, 1 H, H2A), 3.97 (dd, J = 15.5, 2.0 Hz, 1 H, H2B),
4.33 (t, J = 7.6 Hz, 1 H, H9), 6.19 (s, 1 H, H13b), 6.94 (d, J = 7.8
Hz, 1 H, H12), 6.97 (d, J = 7.8 Hz, 1 H, H13), 7.07 (s, 1 H, H8), 7.08
(d, J = 6.6 Hz, 1 H, H5), 7.13 (s, 1 H, H10), 7.21 (dd, J = 6.6, 2.0
Hz, 1 H, H6).
13C NMR (100 MHz, CDCl3): d = 12.8 (15-CH3), 21.1 (14-CH2),
21.8 (7-CH3), 21.9 (11-CH3), 33.9 (C2), 42.2 (C9), 64.8 (C13b),
125.4 (C8), 125.8 (C10), 127.6 (C12), 128.0 (C5, C6), 128.9 (C13),
131.7 (C13a), 133.0 (C8a), 138.7 (C7), 138.9 (C11), 141.6 (C9a),
143.6 (C4a), 172.1 (C3).
1H NMR (400 MHz, CDCl3): d = 1.12 (t, J = 7.2 Hz, 3 H, 15-CH3),
2.20–2.33 (m, 2 H, 14-CH2), 3.63 (d, J = 15.5 Hz, 1 H, H2A), 3.77
(s, 3 H, 7-OCH3), 3.97 (dd, J = 15.5, 2.0 Hz, 1 H, H2B), 4.33 (t,
J = 7.6 Hz, 1 H, H9), 6.18 (d, J = 0.7 Hz, 1 H, H13b), 6.77 (dd,
J = 8.7, 2.8 Hz, 1 H, H6), 6.79 (d, J = 2.8 Hz, 1 H, H8), 7.07 (dd,
J = 7.6, 1.0 Hz, 1 H, H13), 7.13 (td, J = 7.6, 1.0 Hz, 1 H, H12), 7.28
(d, J = 8.7 Hz, 1 H, H5), 7.28 (td, J = 7.6, 1.0 Hz, 1 H, H11), 7.32
(d, J = 7.6 Hz, 1 H, H10).
13C NMR (100 MHz, CDCl3): d = 12.5 (15-CH3), 20.8 (14-CH2),
33.6 (C2), 42.2 (C9), 55.5 (7-OCH3), 64.7 (C13b), 111.1 (C6),
111.4 (C8), 124.9 (C10), 126.8 (C12), 128.0 (C8a), 128.6 (C5),
128.8 (C13), 128.9 (C11), 134.6 (C13a), 141.2 (C9a), 145.0 (C4a),
159.6 (C7), 171.9 (C3).
MS (EI, 70 eV): m/z (%) = 325 (37) [M+], 296 (13), 278 (8), 251
(11), 250 (12), 236 (14), 222 (100).
Anal. Calcd for C19H19NO2S: C, 70.12; H, 5.88; N, 4.30. Found: C,
70.21; H, 5.80; N, 4.25.
MS (EI, 70 eV): m/z (%) = 323 (36) [M+], 294 (43), 276 (10), 249
(11), 248 (24), 234 (19), 220 (100).
9-Ethyl-11-methyl-9,13b-dihydrodibenzo[c,f]thiazolo[3,2-
a]azepin-3(2H)-one (5f)
Time: 26 h; yellow crystals; yield: 60%; mp 155–156 °C (heptane).
Anal. Calcd for C20H21NOS: C, 74.27; H, 6.54; N, 4.33. Found: C,
74.11; H, 6.70; N, 4.26.
IR (KBr): 3038 (C–H Ar), 1693 (C=O), 1457 (C=C Ar), 1288 cm–1
(C–N).
9-Ethyl-7,12-dimethyl-9,13b-dihydrodibenzo[c,f]thiazolo[3,2-
a]azepin-3(2H)-one (5i)
Time: 38 h; yellow crystals; yield: 65%; mp 54–55 °C (heptane).
IR (KBr): 3029 (C–H Ar), 1693 (C=O), 1455 (C=C Ar), 1265 cm–1
(C–N).
1H NMR (400 MHz, CDCl3): d = 1.11 (t, J = 7.2 Hz, 3 H, 15-CH3),
2.24 (s, 3 H, 12-CH3), 2.21–2.35 (m, 2 H, 14-CH2), 2.31 (s, 3 H, 7-
1H NMR (400 MHz, CDCl3): d = 1.13 (t, J = 7.2 Hz, 3 H, 15-CH3),
2.22–2.38 (m, 2 H, 14-CH2), 2.32 (s, 3 H, 11-CH3), 3.63 (d, J = 15.5
Hz, 1 H, H2A), 3.98 (dd, J = 15.5, 1.8 Hz, 1 H, H2B), 4.37 (t, J = 7.6
Hz, 1 H, H9), 6.21 (s, 1 H, H13b), 6.94 (d, J = 7.8 Hz, 1 H, H12),
Synthesis 2010, No. 8, 1291–1302 © Thieme Stuttgart · New York

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Synthesis of Dibenzo[c,f]thiazolo[3,2-a]azepines
1301
CH3), 3.63 (dd, J = 15.5, 0.7 Hz, 1 H, H2A), 3.98 (dd, J = 15.5, 2.0
Hz, 1 H, H2B), 4.29 (t, J = 7.6 Hz, 1 H, H9), 6.15 (s, 1 H, H13b),
6.88 (s, 1 H, H13), 7.04 (dd, J = 7.8, 1.0 Hz, 1 H, H6), 7.05 (br s, 1
H, H8), 7.06 (d, J = 8.0 Hz, 1 H, H11), 7.19 (d, J = 7.8 Hz, 1 H, H5),
7.21 (d, J = 8.0 Hz, 1 H, H10).
13C NMR (100 MHz, CDCl3): d = 12.6 (15-CH3), 20.8 (12-CH3),
20.9 (14-CH2), 21.6 (7-CH3), 33.6 (C2), 41.7 (C9), 64.6 (C13b),
124.8 (C10), 125.1 (C8), 127.7 (C5, C6), 129.3 (C13), 129.4 (C11),
132.7 (C7), 134.4 (C13a), 136.4 (C12), 138.4 (C9a), 138.6 (C8a),
143.5 (C4a), 171.8 (C3).
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MS (EI, 70 eV): m/z (%) = 323 (45) [M+], 294 (92), 276 (10), 249
(10), 248 (20), 234 (16), 220 (100).
Anal. Calcd for C20H21NOS: C, 74.27; H, 6.54; N, 4.33. Found: C,
74.20; H, 6.49; N, 4.30.
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Acknowledgment
The authors would like to acknowledge for the financial support due
by the Colombian Institute for Science and Research (COLCIEN-
CIAS, Grant No 1102-408-20563). A.P. also thanks Dr. E. Stashen-
ko (Laboratory of Chromatography, School of Chemistry,
Industrial University of Santander) for providing GC-MS spectra.
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