Dibenzo[ b, e ]azepin-6-ones and Seven-Membered Sultam Derivatives: Convenient Synthesis via Palladium-Catalyzed Regioselective Intramolecular Heck Reaction and Application towards Drug-Like Small Molecules

Article abstract of DOI:10.1055/s-0037-1611548

A new, convenient synthesis of dibenzo[ b, e ]azepin-6-ones and seven-membered sultam derivatives have been envisaged via Pd-catalyzed regioselective intramolecular Heck reaction of the corresponding easily accessible precursors. This protocol has been successfully implemented to synthesize N -methyldarenzepine in four steps and in good yield. Moreover, one of the intermediates has been utilized for the synthesis of a new analogue of darenzepine. Preliminary modeling studies were performed to investigate the binding potential to muscarinic acetylcholine receptor (M4).

Full text of DOI:10.1055/s-0037-1611548

SYNTHESIS
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© Georg Thieme Verlag Stuttgart · New York
2019, 51, A–J
paper
A
en
A. Das et al.
Paper
Synthesis
Dibenzo[b,e]azepin-6-ones and Seven-Membered Sultam
Derivatives: Convenient Synthesis via Palladium-Catalyzed
Regioselective Intramolecular Heck Reaction and Application
towards Drug-Like Small Molecules
Arijit Dasa
Arup Maitib
Mrinalkanti Kundu*b
Kuldeep K. Royc
Inul Ansary*a
R1
X
N
X
Pd(OAc)2 (5 mol%), PPh3 (10 mol%)
N
Br
R1
TMEDA (2.0 equiv), DMF, 110 °C, 5 h
R2OC
COR2
a Department of Chemistry, The University of Burdwan, Burdwan-713104,
West Bengal, India
iansary@chem.buruniv.ac.in
b TCG Lifesciences Pvt. Ltd., BN-7, Salt Lake, Kolkata-700091, West Bengal, In-
dia
13 examples
51–75% yield
R1 = Me, Et, nPr, CH2CH2NMe2
R2 = OMe, OtBu, NMe2, N-methylpiperazine
X = CO, SO2
mrinal.kundu@tcgls.com
c National Institute of Pharmaceutical Education and Research, 168 Maniktala
Main Road, Kolkata- 700054, West Bengal, India
Received: 11.04.2019
Accepted after revision: 24.04.2019
Published online: 14.05.2019
zoazepinone scaffold has also been successfully employed
in the synthesis of new integrin v3 antagonists.4 More-
over, dibenzo[b,e]azepine systems are known to exhibit po-
tent central nervous system (CNS) activity such as neuro-
leptic and anticholinergic activities.7
DOI: 10.1055/s-0037-1611548; Art ID: ss-2019-t0077-op
Abstract A new, convenient synthesis of dibenzo[b,e]azepin-6-ones
and seven-membered sultam derivatives have been envisaged via Pd-
catalyzed regioselective intramolecular Heck reaction of the corre-
sponding easily accessible precursors. This protocol has been success-
fully implemented to synthesize N-methyldarenzepine in four steps and
in good yield. Moreover, one of the intermediates has been utilized for
the synthesis of a new analogue of darenzepine. Preliminary modeling
studies were performed to investigate the binding potential to musca-
rinic acetylcholine receptor (M4).
O
H2N
O
H
O
N
N
O
N
HO
F3C
CF3
O
D
O
B
N
Key words intramolecular Heck reaction, regioselectivity, diben-
zo[b,e]azepin-6-ones, seven-membered sultams, docking, M4 receptor
N
CO2H
N
A
N
H
N
N
N
H
darenzepine
H
O
Dibenzoazepinones are tricyclic lactams possessing a
seven-membered amide ring fused with benzene ring on
both sides. Being the privileged core and identified in many
alkaloids and pharmaceutically relevant organic molecules,
dibenzoazepinones have attracted much significance in or-
ganic synthesis.1 Amongst this class of compounds, diben-
zo[b,e]azepin-6-one ring systems in particular, has been the
subject of considerable research mainly due to their wide
range of pharmacological properties such as antiulcer agent
darenzepine (A),2 anticonvulsant drug (B),3 v3 antagonist
(C),4 and liver X receptor (LXR)-mediated transrepressional
and transactivational activities (D),5 etc. (Figure 1). Very re-
cent reports also showed that darenzepine, mediated
C
Figure 1 Some bioactive dibenzoazepinones
Despite the widespread importance, methods to pre-
pare the dibenzo[b,e]azepin-6-one skeletons such as diben-
zo[b,e]azepin-11-ylidene]acetic acid scaffolds per se, are
scarce though. For example, dibenzoazepinone derivatives
were synthesized via Schmidt rearrangement followed by
Wittig–Horner olefination reactions,4 tandem reduction-
lactamization sequence,8 and regio- and chemoselective di-
rect benzylation reaction.9 Recently, Mehta and co-work-
ers10 have reported the synthesis of darenzepine (A), an an-
tiulcer agent and a scaffold of dibenzo[b,e]azepin-6-one se-
ries via temperature controlled aryne insertion cascade
reaction on substituted oxindole (Scheme 1). Besides, syn-
theses of benzazepines are also reported.11
through
co-activation
of
the
M1
and
M4 muscarinic acetylcholine receptors, may be therapeuti-
cally beneficial for the treatment of schizophrenia and Alz-
heimer’s diseases.6 As stated above, N-substituted diben-
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2019, 51, A–J

B
A. Das et al.
Paper
Synthesis
The search for a new and more convenient strategy to
construct dibenzo[b,e]azepin-6-ones and seven-membered
sultam analogues thus remains to be attractive. Palladium-
catalyzed reactions are very powerful and useful tools for
the construction of carbon–carbon and carbon–heteroatom
bonds20 due to their efficient catalytic activities on the re-
action and having no interference properties towards a
wide range of functional groups present in the substrate
molecules. Moreover, most of the palladium-catalyzed reac-
tions, particularly the Heck reaction, proceeds via a stereo-
and regioselective pathway. These advantages have led to
significant growth on the Heck methodologies for the syn-
theses of heterocyclic compounds of various ring sizes.21–26
Thus, dibenzoazepinones and biaryls fused to a seven-
membered sultam have been synthesized by means of pal-
ladium-catalyzed intramolecular Heck/reductive Heck
strategies where either tributylvinyltin or 2,4,6-trivinylcy-
clotriboroxane or tosyl chloride or phenylacetylene were
used as alkene/alkyne substrates in the initial step.5,27–29
These observations prompted further investigation towards
identification of general methodology employing intramo-
lecular Heck reaction as the key step for the synthesis of
dibenzo[b,e]azepin-6-one derivatives as well as seven-
membered sultam analogues.
Boc
O
N
Boc
TMS
N
CsF, MeCN
O
+
90 °C, 12 h
OTf
O
O
F
E
G
OEt
O
EtO
DDQ, benzene
80 °C, 24 h
H
N
Boc
N
O
(i) 6M NaOH, THF
0 °C, 2 h
O
(ii) N-methylpiperazine,CDI
CH2Cl2, 12 h
N
O
EtO
H
N
A
Scheme 1 Recent report on the synthesis of darenzepine
Moreover, sultams, in particular fused biaryl sultams,
have also emerged as privileged structures in drug discov-
ery because of their diverse enzyme inhibitory activity and
active role in selective serotonin reuptake inhibition.12–14
Several methods for the synthesis of sultam derivatives
were reported.15 But, biaryls that are fused to a seven-
membered sultam have been synthesized with limited suc-
cess. These include Friedel–Crafts reactions,16 intramolecu-
lar direct C–H arylations,17 intramolecular oxidative cou-
pling reactions18 and carbometalation.19
In our strategy, we used a common intermediate of type
4 as Heck precursors. Thus, bromo N-alkyl-substituted N-
styrenyl benzamides 4a–k and/or sulfonamides 4l,m were
prepared in 60–74% and 57–68% yields, respectively, via a
chemoselective intermolecular Heck reaction30 of disubsti-
tuted amides 3a–e and/or sulfonamides 3f,g with readily
available acrylic acid derivatives. Intermediate precursors
Br
Br
COCl
O
O
O
COR2
Br
R1-Br
NH2
I
N
Br
R1
N
I
NH
I
(1.2 equiv)
(1.4 equiv)
(1.0 equiv)
(iii)
R1
(ii)
(i)
4a–k
(60–74%)
1
COR2
2a (75%)
3a–e (66–78%)
Br
O
Br
SO2Cl
O
O
O
S
COR2
S
S
O
O
R1-Br
N
Br
Br
NH2
I
R1
N
NH
(1.4 equiv)
R1
(1.2 equiv)
(1.0 equiv)
(iii)
(iv)
(ii)
I
I
4l,m
(57–68%)
1
COR2
2b (82%)
3f,g (53–65%)
4a: R1 = Me, R2 = OMe
4b: R1 = Et, R2 = OMe
3a: R1 = Me
3b: R1 = Et
4i: R1 = Me, R2 = NMe2
4j: R1 nPr, R2 = NMe2
4k: R1 = Me, R2
4l: R1 = Me, R2 = OtBu
4m: R1 nPr, R2 = OtBu
4c: R1
=
nPr, R2 = OMe
=
3c: R1
=
nPr
4d: R1 = iPr, R2 = OMe
3d: R1 = iPr
4e: R1 = (CH2)2NMe2, R2 = OMe
4f: R1 = (CH2)2NMe2, R2 = OtBu
4g: R1 = Me, R2 = OtBu
=
N
NMe
3e: R1 = (CH2)2NMe2
3f: R1 = Me
3g: R1
=
nPr
4h: R1 nPr, R2 = OtBu
=
=
Scheme 2 Synthesis of bromo N-alkyl-substituted N-styrenyl benzamide/sulfonamide derivatives 4a–m. Reagents and conditions: (i) Et3N (3.0 equiv),
DCM, r.t., 6 h; (ii) NaH (1.5 equiv), DMF, r.t., 16 h; (iii) Pd(OAc)2 (10 mol%), P(o-tol)3 (20 mol%), Et3N (3.0 equiv), MeCN, 80 °C, 16 h; (iv) pyridine (5 mL),
60 °C, 12 h.
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A. Das et al.
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3a–g were in turn synthesized in 53–78% yields by two-
step reactions of 2-iodoaniline (1) with commercially avail-
able 2-bromobenzoyl chloride or 2-bromobenzenesulfonyl
chloride followed by N-alkylation of the resulting mono-
substituted amide 2a/sulfonamide 2b (Scheme 2).29,31
For the construction of dibenzoazepinone core, we initi-
ated our investigation with the bromo N-alkyl-substituted
N-styrenyl benzamide 4a as a model precursor. Initially,
when the substrate 4a was reacted under the literature re-
ported Heck conditions,5 phenanthridinone framework 6a
was obtained as a major product (62%) instead of diben-
zo[b,e]azepin-6-one derivative 5a (Scheme 3). This could be
easily explained by a more favorable 6-exo-trig process ver-
sus a 7-exo-trig mode of cyclization according to the Bald-
win’s rules.
Me
O
O
O
N
N
Br
(i)
N
Me
Me
4a
MeO2C
5a
6a
CO2Me
CO2Me
(expected but
not found)
(62%)
Scheme 3 Reaction of precursor 4a under Heck conditions. Reagents
and conditions: (i) Pd(OAc)2 (25 mol%), PPh3 (50 mol%), NaOAc (1.3
equiv), DMF, 100 °C, 8 h.
Therefore, in order to determine the optimum reaction
conditions for the formation of our desired product 5a, a se-
ries of experiments were carried out with the Heck precur-
sor 4a. The results are summarized in Table 1. When the re-
action was performed with 5 mol% of Pd(OAc)2 and 10 mol%
of PPh3 under heating in DMF at 110 °C for 10 hours in the
Table 1 Optimization of Heck Conditions
R1
O
N
O
O
Pd catalyst
N
Br
R1
+
N
R1
ligand, base
solvent
MeO2C
6a (R1 = Me)
6a′ (R1 = H)
5a (R1 = Me)
5a′ (R1 = H)
CO2Me
4a (R1 = Me); 4a′ (R1 = H)
CO2Me
Entry
Catalyst (mol%)
Ligand (mol%)
Base (equiv)
Solvent
Temp ( °C)
Time (h)
Yield (%)a
5
6
1b
2b
Pd(OAc)2 (5)
Pd(OAc)2 (5)
Pd(OAc)2 (5)
Pd(OAc)2 (5)
Pd(OAc)2 (5)
Pd(OAc)2 (5)
Pd(OAc)2 (5)
Pd(OAc)2 (10)
Pd(OAc)2 (5)
Pd(OAc)2 (5)
Pd(OAc)2 (5)
Pd(OAc)2 (5)
Pd(OAc)2 (5)
Pd(PPh3)4 (5)
Pd(PPh3)2Cl2 (5)
Pd(OAc)2 (5)
PPh3 (10)
PPh3 (10)
PPh3 (10)
PPh3 (10)
P(o-tol)3 (10)
PPh3 (10)
PPh3 (10)
PPh3 (20)
PPh3 (10)
PPh3 (10)
PPh3 (10)
PPh3 (10)
PPh3 (10)
PPh3 (10)
PPh3 (10)
PPh3 (10)
NaOAc (1.5)
Et3N (1.5)
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
MeCN
DME
THF
110
110
110
110
110
110
110
110
140
80
10
10
10
5
5a (0)
6a (65)
6a (57)
6a (27)
6a (0)
6a (0)
6a (0)
6a (0)
6a (0)
6a (0)
6a (0)
6a (0)
6a (0)
6a (0)
6a (48)
6a (17)
6a′ (0)
5a (0)
3b
DIPEA (1.5)
TMEDA (1.5)
TMEDA (1.5)
TMEDA (2.0)
TMEDA (2.5)
TMEDA (2.0)
TMEDA (2.0)
TMEDA (2.0)
TMEDA (2.0)
TMEDA (2.0)
TMEDA (2.0)
TMEDA (2.0)
TMEDA (2.0)
TMEDA (2.0)
5a (15)
5a (63)
5a (0)
4b
5b
10
5
6b,c
7b
5a (75)
5a (75)
5a (75)
5a (74)
5a (46)
5a (30)
5a (41)
5a (23)
5a (5)
5
8b
5
9b
5
10b
11b
12b
13b
14b
15b
16d,e
16
16
8
80
110
80
10
10
10
5
DMF
DMF
DMF
110
110
110
5a (32)
5a′ (0)
a Isolated yield.
b Reaction was carried out with precursor 4a (0.27 mmol) in 5 mL of aforementioned solvent under sealed conditions.
c Optimized conditions.
d Reaction was carried out with precursor 4a′ (0.35 mmol) in 5 mL of DMF under sealed conditions.
e Debrominated product 4a′′ (Figure 2) was isolated in 45% yield.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2019, 51, A–J

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Synthesis
presence of 1.5 equivalents of NaOAc and Et3N, respectively,
the phenanthridinone derivative 6a was obtained in 65%
and 57% yield, respectively, as the sole product (Table 1, en-
tries 1 and 2). Interestingly, while conducting the reaction
in the presence of DIPEA (diisopropylethylamine) as base
under the same conditions, the desired product 5a was ob-
tained in 15% yield only along with 27% yield of unwanted
compound 6a (entry 3).
and/or piperazine moiety in the acrylate motif 4f–h, and 4k
resulted in relatively lower yields of the products 5f–h, and
5k compared to that of CO2Me group 5a–e, probably owing
to the steric factors. We then applied this methodology to
the substrates 4i–k containing acrylic acid amide moiety as
electron-withdrawing group affording the corresponding
dibenzoazepinone derivatives 5i–k. Among these, com-
pound 5k is the N-methyl derivative of darenzepine. Fur-
thermore, this optimized Heck protocol was successfully
implemented to other types of precursors, bromo N-alkyl-
substituted N-styrenyl sulfonamide derivatives 4l and 4m
to afford biaryl fused seven-membered sultams 5l and 5m,
respectively, in good yields (Scheme 4).
For further improvement of the yield of 5a the reaction
was repeated again with tetramethylethylenediamine
(TMEDA) base, and to our delight, the reaction was complet-
ed in 5 hours and the product 5a was isolated in 63% yield
(Table 1, entry 4). Next, when substrate 4a was subjected
with 5 mol% of Pd(OAc)2 and 10 mol% of P(o-tolyl)3 in the
presence of TMEDA in DMF under heating at 110 °C for 10
hours, the starting material 4a was recovered unchanged
(entry 5). The yield of dibenzoazepinone 5a increased to
75% by increasing the amount of TMEDA (entry 6); howev-
er, additional 0.5 equivalent did not afford further improve-
ment on the yield (entry 7). Increasing the amount of both
the catalyst Pd(OAc)2 and ligand PPh3 did not improve the
yield of product 5a either (entry 8). When the reaction tem-
perature was raised from 110 °C to 140 °C the yield of 5a
was found to be unaltered (entry 9). Decrease in tempera-
ture (80 °C) resulted in lower yield, though the reaction
time was extended up to 16 hours (entry 10). The effect of
other solvents on the yield of dibenzoazepinone 5a was
also investigated. It was observed that the use of either
MeCN, dimethoxyethane (DME) or THF as solvents, howev-
er, were detrimental (entries 11–13). Other palladium cata-
lysts such as Pd(PPh3)4 and Pd(PPh3)2Cl2 were also used, but
unfortunately a mixture of products 5a and 6a was ob-
tained in both the cases (entries 14 and 15). From the above
observations, we thus chose entry 6 as the optimized con-
ditions for all of our future reactions. It is also to note that
when the amide 4a′ was subjected to the optimized Heck
conditions (entry 6), neither product 5a′ nor 6a′ was
formed, instead the debrominated compound 4a′′ was iso-
lated in 45% yield (entry 16, Figure 2).
R1
X
N
N
X
Br Pd(OAc)2 (5 mol%)
PPh3 (10 mol%)
R1
TMEDA (2.0 equiv)
DMF, 110 °C, 5 h
R2OC
5a–m
4a–m
COR2
X: C=O, SO2
5a: X = CO, R1 = Me, R2 = OMe, 75%
5b: X = CO,R1 = Et, R2 = OMe, 71%
5c: X = CO, R1
=
nPr, R2 = OMe, 70% (X-ray)
5d: X = CO, R1 = iPr, R2 = OMe, 73%
5e: X = CO, R1 = (CH2)2NMe2, R2 = OMe, 68%
5f: X = CO, R1 = (CH2)2NMe2, R2 = OtBu, 51%
5g: X = CO, R1 = Me, R2 = OtBu, 55%
5h: X = CO, R1
5i: X = CO, R1 = Me, R2 = NMe2, 65%
5j: X = CO, R1 nPr, R2 = NMe2, 61%
=
nPr, R2 = OtBu, 57%
=
5k: X = CO, R1 = Me, R2 = N-methylpiperazine, 53%
5l: X = SO2, R1 = Me, R2 = OtBu, 57% (X-ray)
5m: X = SO2, R1
=
nPr, R2 = OtBu, 55%
Scheme 4 Substrate scope of regioselective intramolecular Heck reac-
tion. Reagents and conditions: 4 (100 mg), Pd(OAc)2 (5 mol%), PPh3 (10
mol%), TMEADA (2.0 equiv), DMF (2 mL), sealed tube, 110 °C, 5 h.
The structures of all the dibenzo[b,e]azepin-6-ones 5a–
k and sultam derivatives 5l,m were established by their
spectroscopic data. As representative examples, structures
of 5c and 5l were also confirmed by single crystal X-ray dif-
fraction study of which ORTEP diagrams are shown in Fig-
ure 3.32 It is seen from the X-ray structures that the diben-
zoazepinone and sultam derivatives possess Z- and E-con-
figuration, respectively.
H
N
In our laboratory, we have also been engaged in identi-
fying drug-like small molecular entities of medicinal im-
portance.33 Towards that goal and as an extension of this
new methodology, we synthesized a novel compound 8
from dibenzoazepinone 5g in a two-step reaction. Initially
the ester hydrolysis of compound 5g was performed using
trifluoroacetic acid (TFA) to afford the corresponding acid
derivative 7, which was converted into the target amide 8
by amidation with N,N-dimethylethylenediamine under
mild conditions (Scheme 5).
O
4a′′
CO2Me
Figure 2 Structure of the debrominated product 4a′′
The substrate scope of this methodology was investigat-
ed either using other acrylates or with different N-alkylated
amides. Accordingly, substrates 4a–h were treated under
the optimized reaction conditions (Table 1, entry 6) to af-
ford 6-oxo-5,6-dihydrodibenzo[b,e]azepin-11-ylidene ace-
tic acid esters 5a–h in 55–75% yields (Scheme 4). It was ob-
served that the substrates having bulky groups like CO2t-Bu
In conclusion, we have developed a new, convenient
synthesis of dibenzo[b,e]azepin-6-ones and seven-mem-
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2019, 51, A–J

E
A. Das et al.
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Synthesis
200 mesh) was used for chromatographic separation. All the 1H NMR
and 13C NMR spectra were recorded using a model DPX400 spectrom-
eter (TOP Spin 2.1 Ultra shieldTM) in CDCl3/DMSO-d6 solvents and
chemical shifts are reported in  (ppm) units relative to the internal
standard TMS. LCMS spectra were recorded on QTRAP Applied Bio-
system/Shimadzu Autosampler, Agilent 6890 series with 5973 Mass
selective detector. HRMS were recorded on XEVO G2-XS QTOF, and
Waters QTOF Micro YA263 spectrometer, respectively. IR spectra were
recorded on a PerkinElmer FTIR spectrophotometer by preparing a
KBr pellet containing the title compound and are reported in wave-
length numbers (cm–1). Single crystal X-ray diffraction study was per-
formed using Bruker Smart Apex-II diffractometer.
2-Bromo-N-(2-iodophenyl)benzamide (2a)31
To a stirred solution of 2-iodoaniline (1; 1.0 g, 4.56 mmol) in DCM (60
mL) was added Et3N (1.9 mL, 13.68 mmol) followed by 2-bromoben-
zoyl chloride (1.2 g, 5.47 mmol) at 0 °C under N2 atmosphere and the
reaction mixture was stirred at r.t. for 6 h. Then the mixture was di-
luted with DCM (40 mL). The combined organic layers were washed
successively with sat. aq NaHCO3 (2 × 25 mL), H2O (25 mL) and brine
(25 mL), dried (anhyd Na2SO4), and concentrated. The crude material
was purified by triturating with Et2O/pentane to afford 2a (1.4 g, 75%)
as a white solid; mp 155–156 °C.
1H NMR (400 MHz, DMSO-d6):  = 10.14 (s, 1 H, NH), 7.93 (d, J = 7.8
Hz, 1 H, ArH), 7.73 (d, J = 7.9 Hz, 1 H, ArH), 7.64 (d, J = 6.8 Hz, 1 H,
ArH), 7.53 (t, J = 7.4 Hz, 1 H, ArH), 7.49–7.42 (m, 3 H, ArH), 7.0–7.05
(m, 1 H, ArH).
Figure 3 X-ray crystal structures of compounds 5c and 5l
LCMS: m/z [M + H]+ = 401.8.
Me
Me
Me
NH2
O
O
O
Me2N
(1.5 equiv)
N
N
N
2-Bromo-N-(2-iodophenyl)benzenesulfonamide (2b)29
(i)
To a stirred solution of 2-iodoaniline (1; 1.0 g, 4.56 mmol) in pyridine
(5 mL) was added 2-bromobenzenesulfonyl chloride (1.4 g, 5.47
mmol) under N2 atmosphere. Then the reaction mixture was heated
at 60 °C for 12 h. Excess solvent was removed under reduced pressure
and the crude mass was dissolved in DCM (100 mL). The organic layer
was washed with H2O (3 × 25 mL) and brine (25 mL), dried (anhyd
Na2SO4), and concentrated. The crude mass was purified by triturat-
ing with Et2O/pentane to afford 2b as a white solid (1.6 g, 82%); mp
105–107 °C.
(ii)
HO
O
tBu
H
N
Me
5g
7 (95%)
8 (61%)
N
O
O
O
Me
Scheme 5 Hydrolysis followed by amidation of ester 5g. Reagents and
conditions: (i) TFA (1.5 equiv), DCM, r.t., 2 h; (ii) EDC·HCl (1.5 equiv),
HOBt (1.5 equiv), DIPEA (3.0 equiv), THF, r.t., 16 h.
1H NMR (400 MHz, DMSO-d6):  = 9.93 (s, 1 H, NH), 7.88–7.84 (m, 3 H,
ArH), 7.57–7.52 (m, 2 H, ArH), 7.29 (t, J = 7.6 Hz, 1 H, ArH), 7.01–6.96
(m, 2 H, ArH).
bered sultam derivatives in moderate to good yields (51–
75%) via a Pd-catalyzed regioselective intramolecular Heck
reaction of the corresponding easily accessible precursors,
bromo N-alkyl-substituted N-styrenyl benzamide/sulfon-
amide derivatives. The protocol is simple and by employing
this strategy we have achieved the N-methyl derivative of
darenzepine in four steps in good yield. Further, we have
synthesized a novel, non-cytotoxic (Supporting Informa-
tion) small molecule 8 via implementation of this protocol.
Preliminary docking studies were performed on com-
pounds 5k and 8 to understand their binding potential to
muscarinic acetylcholine receptor subtype 4 (M4) (Sup-
porting Information).
LCMS: m/z [M + H]+ = 437.6.
Disubstituted Amides 3a–e and Sulfonamides 3f,g;31 2-Bromo-N-
(2-iodophenyl)-N-methylbenzamide 3a; Typical Procedure
To a stirred solution of 2-bromo-N-(2-iodophenyl)benzamide (2a; 1.4
g, 3.48 mmol) in DMF (10 mL) was added NaH (60% in oil, 209 mg,
5.22 mmol) portionwise at 0 °C under N2 atmosphere and the stirring
was continued for 30 min at 0 °C followed by dropwise addition of
MeI (0.3 mL, 4.87 mmol). Then the reaction mixture was stirred at r.t.
for 16 h and poured into ice-water (100 mL). The precipitate was col-
lected by filtration and then washed with ice cold water and
Et2O/pentane, and dried in vacuo to afford 3a (1.13 g, 78%) as an off-
white solid; mp 123 °C.
Accordingly, other compounds 3b–e were synthesized. However, the
precursors 3f,g were obtained following the above mentioned proce-
dure starting from 2-bromo-N-(2-iodophenyl)benzenesulfonamide
(2b) as starting material.
All chemicals and reagents used in current study were commercially
available. Melting points were determined in open capillaries and are
uncorrected. All the reactions were monitored by analytical TLC using
0.25 mm E-Merk precoated silica gel plates (60F254). Silica gel (100–
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A. Das et al.
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Synthesis
Bromo N-Alkyl-Substituted N-Styrenyl Benzamides 4a–k and Sul-
fonamides 4l,m;30 Methyl (E)-3-[2-(2-Bromo-N-methylbenzami-
do)phenyl]acrylate (4a); Typical Procedure
Methyl (Z)-3-(2-Benzamidophenyl)acrylate (4a′′) (Table 1, entry
16)
The product was obtained by reacting the N-unsubstituted amide 4a′
following the typical procedure and isolated by column chromatogra-
phy (eluent: hexanes/EtOAc 2:1) as a colorless sticky solid (35 mg,
45%).
To a degassed stirred mixture of 2-bromo-N-(2-iodophenyl)-N-meth-
ylbenzamide (3a; 500 mg, 1.20 mmol), methyl acrylate (0.1 mL, 1.20
mmol), Et3N (0.5 mL, 3.60 mmol) in anhyd MeCN (10 mL) was added
P(o-tol)3 (73 mg, 0.24 mmol) and Pd(OAc)2 (27 mg, 0.12 mmol). Then
the reaction mixture was heated at 80 °C for 16 h. The mixture was
cooled to r.t. and diluted with H2O (20 mL). The organic parts were
extracted with EtOAc (3 × 30 mL), and the combined organic extracts
were washed with sat. aq NaHCO3 (30 mL) and brine (30 mL), dried
(anhyd Na2SO4), and concentrated under reduced pressure. The crude
mass was purified by column chromatography (silica gel 100–200
mesh, 25–35% EtOAc/hexane) to afford 4a (315.0 mg, 70%) as a
brownish sticky solid.
IR (KBr): 3353, 3042, 2939, 2845, 1720, 1651 cm–1
.
1H NMR (400 MHz, DMSO-d6):  = 10.31 (s, 1 H, NH), 8.00 (d, J = 7.2
Hz, 2 H, ArH), 7.90 (d, J = 7.3 Hz, 1 H, ArH), 7.75 (d, J = 15.9 Hz, 1 H,
CH=CHCO2Me), 7.62 (d, J = 7.2 Hz, 1 H, ArH), 7.58–7.54 (m, 2 H, ArH),
7.50–7.46 (m, 1 H, ArH), 7.39 (d, J = 7.6 Hz, 1 H, ArH), 7.34 (t, J = 7.6
Hz, 1 H, ArH), 6.62 (d, J = 15.9 Hz, 1 H, CH=CHCO2Me), 3.72 (s, 3 H,
OCH3).
LCMS: m/z [M + H]+ = 282.1.
IR (KBr): 3066, 2950, 2924, 2851, 1716, 1652, 1597, 1488 cm–1
.
Methyl (Z)-2-(5-Ethyl-6-oxo-5H-dibenzo[b,e]azepin-11(6H)-
ylidene)acetate (5b)
1H NMR (400 MHz, DMSO-d6):  = 8.00 (d, J = 7.8 Hz, 1 H, ArH), 7.80
(d, J = 7.8 Hz, 1 H, ArH), 7.75 (d, J = 15.8 Hz, 1 H, CH=CHCO2Me), 7.58
(t, J = 6.8 Hz, 1 H, ArH), 7.44 (d, J = 7.4 Hz, 1 H, ArH), 7.34 (t, J = 7.4 Hz,
1 H, ArH), 7.26 (t, J = 7.2 Hz, 1 H, ArH), 7.15–7.10 (m, 2 H, ArH), 6.65
(d, J = 15.9 Hz, 1 H, CH=CHCO2Me), 3.77 (s, 3 H, OCH3), 3.29 (s, 3 H,
NCH3).
The product was isolated by column chromatography (eluent: hex-
anes/EtOAc 1:1) as a colorless sticky solid (56 mg, 71%).
IR (KBr): 2955, 2927, 2867, 1728, 1634 cm–1
.
1H NMR (400 MHz, DMSO-d6):  = 7.72 (d, J = 7.4 Hz, 1 H, ArH), 7.55–
7.50 (m, 2 H, ArH), 7.45 (t, J = 7.4 Hz, 1 H, ArH), 7.38–7.31 (m, 2 H,
ArH), 7.19 (d, J = 3.8 Hz, 2 H, ArH), 6.28 (s, 1 H, C=CHCO2Me), 4.49 (q,
J = 6.9 Hz, 1 H, NCHaHbCH3), 3.69 (q, J = 6.9 Hz, 1 H, NCHaHbCH3), 1.06
(t, J = 6.9 Hz, 3 H, NCH2CH3).
13C NMR (100 MHz, CDCl3):  = 166.9, 165.4, 154.1, 143.0, 137.9,
137.2, 131.7, 131.6, 130.9, 128.9, 128.8, 127.9, 125.6, 124.4, 123.9,
119.3, 51.4, 44.6, 13.3.
LCMS: m/z [M + H]+ = 374.0; [M + H + 2]+ = 376.2.
Other compounds 4b–k were synthesized accordingly. Similarly, sul-
fonamide derivatives 4l,m were synthesized starting from the corre-
sponding precursors 3f,g.
Dibenzo[b,e]azepin-6-ones 5a–k and Sultam Derivatives 5l,m;
Methyl (Z)-2-(5-Methyl-6-oxo-5H-dibenzo[b,e]azepin-11(6H)-
ylidene)acetate (5a); Typical Procedure
LCMS: m/z [M + H]+ = 308.2.
HRMS (ESI): m/z [M + H]+ calcd for C19H18NO3: 308.1287; found:
308.1282.
To a degassed stirred mixture of methyl (E)-3-[2-(2-bromo-N-meth-
ylbenzamido)phenyl]acrylate (4a; 100 mg, 0.27 mmol) and TMEDA (8
L, 0.54 mmol) in anhyd DMF (2 mL) was added PPh3 (7 mg, 0.027
mmol) and Pd(OAc)2 (3 mg, 0.01 mmol). Then the reaction mixture
was heated at 110 °C for 5 h in a sealed tube. The mixture was cooled
to r.t. and diluted with ice cold H2O (10 mL). The organic phase was
extracted with EtOAc (3 × 30 mL), and the combined organic layers
were washed with H2O (3 × 20 mL) and brine (15 mL), and dried (an-
hyd Na2SO4). The solvent was evaporated under reduced pressure and
the crude mass obtained was purified by column chromatography
(silica gel 100–200 mesh) eluting with 40–45% EtOAc/hexane to af-
ford 5a (59 mg, 75%) as a white solid; mp 131–132 °C.
Methyl (Z)-2-(6-Oxo-5-propyl-5H-dibenzo[b,e]azepin-11(6H)-
ylidene)acetate (5c)
The product was isolated by column chromatography (eluent: hex-
anes/EtOAc 1:1) as a white solid (56 mg, 70%); mp 117–118 °C.
IR (KBr): 2957, 2926, 2871, 1727, 1634 cm–1
.
1H NMR (400 MHz, CDCl3):  = 7.89 (d, J = 7.2 Hz, 1 H, ArH), 7.44–7.36
(m, 2 H, ArH), 7.29–7.28 (m, 2 H, ArH), 7.20 (d, J = 7.0 Hz, 2 H, ArH),
7.14 (t, J = 7.0 Hz, 1 H, ArH), 6.16 (s, 1 H, C=CHCO2Me), 4.67–4.59 (m, 1 H,
NCHaHbCH2CH3), 3.64 (s, 3 H, OCH3), 3.62–3.57 (m, 1 H, NCHaHbCH2CH3),
1.67–1.62 (m, 1 H, NCH2CHaHbCH3), 1.59–1.52 (m, 1 H, NCH2CHaHbCH3),
0.84 (t, J = 7.2 Hz, 3 H, NCH2CH2CH3).
13C NMR (100 MHz, CDCl3):  = 167.1, 165.3, 154.4, 143.0, 137.7,
137.3, 131.7, 131.6, 131.0, 128.9, 128.7, 128.1, 125.5, 124.5, 123.9,
119.2, 51.4, 50.8, 21.0, 11.1.
IR (KBr): 2950, 2924, 2852, 1726, 1637 cm–1
.
1H NMR (400 MHz, CDCl3):  = 7.94 (d, J = 7.4 Hz, 1 H, ArH), 7.46 (t, J =
7.2 Hz, 1 H, ArH), 7.40 (t, J = 7.2 Hz, 1 H, ArH), 7.33–7.27 (m, 2 H, ArH),
7.23 (d, J = 7.4 Hz, 2 H, ArH), 7.14 (t, J = 7.2 Hz, 1 H, ArH), 6.15 (s, 1 H,
C=CHCO2Me), 3.66 (s, 3 H, OCH3), 3.58 (s, 3 H, NCH3).
13C NMR (100 MHz, CDCl3):  = 167.3, 165.3, 154.3, 142.8, 138.9,
135.2, 131.9, 131.2, 130.93, 128.9, 128.9, 128.3, 125.2, 124.8, 122.6,
119.5, 51.5, 37.8.
LCMS: m/z [M + H]+ = 321.9.
HRMS (ESI): m/z [M + H]+ calcd for C20H20NO3: 322.1443; found:
LCMS: m/z [M + H]+ = 294.1.
322.1445.
HRMS (ESI): m/z [M + Na]+ calcd for C18H15NO3Na: 316.0950; found:
316.0940.
Methyl (Z)-2-(5-Isopropyl-6-oxo-5H-dibenzo[b,e]azepin-11(6H)-
ylidene)acetate (5d)
The product was isolated by column chromatography (eluent: hex-
anes/EtOAc 1:1) as a white solid (58 mg, 73%); mp 125–127 °C.
IR (KBr): 2959, 2925, 2874, 1725, 1632 cm–1
.
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A. Das et al.
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Synthesis
1H NMR (400 MHz, DMSO-d6):  = 7.71 (d, J = 7.2 Hz, 1 H, ArH), 7.50
(td, J = 7.4, 0.8 Hz, 1 H, ArH), 7.45–7.42 (m, 2 H, ArH), 7.34–7.29 (m, 2
H, ArH), 7.23–7.17 (m, 2 H, ArH), 6.29 (s, 1 H, C=CHCO2Me), 4.63–4.56
(m, 1 H, NCHMe2), 3.59 (s, 3 H, OCH3), 1.51 [d, J = 6.8 Hz, 3 H,
NCH(CH3)a(CH3)b], 1.15 [d, J = 6.8 Hz, 3 H, NCH(CH3)a(CH3)b].
13C NMR (100 MHz, CDCl3):  = 167.5, 165.4, 154.5, 143.2, 139.5,
135.9, 132.2, 131.3, 131.0, 128.9, 128.0, 127.7, 126.2, 125.3, 124.3,
118.8, 52.2, 51.4, 22.8, 20.6.
13C NMR (100 MHz, CDCl3):  = 167.5, 164.6, 151.5, 142.9, 138.9,
136.2, 131.8, 131.1, 130.9, 128.6, 128.5, 128.1, 125.2, 124.7, 122.5,
122.4, 80.8, 37.7, 27.7.
LCMS: m/z [M + H]+ = 336.2.
HRMS (ESI): m/z [M + H]+ calcd for C21H22NO3: 336.1600; found:
336.1604.
tert-Butyl (Z)-2-(6-Oxo-5-propyl-5H-dibenzo[b,e]azepin-11(6H)-
ylidene)acetate (5h)
LCMS: m/z [M + H]+ = 322.4.
HRMS (ESI): m/z [M + H]+ calcd for C20H20NO3: 322.1443; found:
The product was isolated by column chromatography (eluent: hex-
anes/EtOAc 1:1) as a white solid (46 mg, 57%); mp 111–112 °C.
322.1436.
IR (KBr): 2963, 2926, 2873, 1704, 1638 cm–1
.
Methyl (Z)-2-{5-[2-(Dimethylamino)ethyl]-6-oxo-5H-diben-
zo[b,e]azepin-11(6H)-ylidene}acetate (5e)
1H NMR (400 MHz, CDCl3):  = 7.87 (d, J = 7.4 Hz, 1 H, ArH), 7.41 (t, J =
7.2 Hz, 1 H, ArH), 7.36 (t, J = 7.2 Hz, 1 H, ArH), 7.29 (t, J = 8.0 Hz, 2 H,
ArH), 7.20 (d, J = 8.0 Hz, 2 H, ArH), 7.13 (t, J = 7.4 Hz, 1 H, ArH), 6.06 (s,
1 H, C=CHCO2t-Bu), 4.70–4.63 (m, 1 H, NCHaHbCH2CH3), 3.63–3.56 (m,
1 H, NCHaHbCH2CH3), 1.69–1.54 (m, 2 H, NCH2CH2CH3), 1.31 [s, 9 H,
C(CH3)3], 0.86 (t, J = 7.4 Hz, 3 H, NCH2CH2CH3).
13C NMR (100 MHz, CDCl3):  = 167.3, 164.5, 152.0, 143.2, 138.2,
137.3, 131.6, 131.6, 131.0, 128.7, 128.5, 128.4, 125.4, 124.6, 123.8,
121.9, 80.9, 50.7, 27.8, 21.0, 11.2.
The product was isolated by column chromatography (eluent: hex-
anes/EtOAc 1:4) as a brown sticky solid (55 mg, 68%).
IR (KBr): 2957, 2922, 2857, 1727, 1631 cm–1
.
1H NMR (400 MHz, CDCl3):  = 7.87 (d, J = 6.7 Hz, 1 H, ArH), 7.43–7.36
(m, 3 H, ArH), 7.31–7.29 (m, 1 H, ArH), 7.21–7.14 (m, 3 H, ArH), 6.15
(s, 1 H, C=CHCO2Me), 4.75–4.72 (m, 1 H, NCHaHbCH2NMe2), 3.77–3.73
(m, 1 H, NCHaHbCH2NMe2), 3.65 (s, 3 H, OCH3), 2.51 (t, J = 7.0 Hz, 2 H,
NCH2CH2NMe2), 2.20 [s, 6 H, N(CH3)2].
13C NMR (100 MHz, CDCl3):  = 166.7, 163.7, 151.9, 142.6, 137.5,
136.8, 131.3, 130.7, 130.4, 128.4, 128.3, 127.7, 125.3, 124.1, 123.2,
121.4, 55.6, 51.4, 46.7, 44.4.
LCMS: m/z [M + H]+ = 364.1.
HRMS (ESI): m/z [M + H]+ calcd for C23H26NO3: 364.1913; found:
364.1920.
LCMS: m/z [M + H]+ = 350.9.
HRMS (ESI): m/z [M + H]+ calcd for C21H23N2O3: 351.1709; found:
(Z)-N,N-Dimethyl-2-(5-methyl-6-oxo-5H- dibenzo[b,e]azepin-
11(6H)-ylidene)acetamide (5i)
351.1711.
The product was isolated by column chromatography (eluent: hex-
anes/EtOAc 2:3) as a white solid (51 mg, 65%); mp 173–174 °C.
IR (KBr): 3066, 2921, 1632, 1614 cm–1
.
tert-Butyl (Z)-2-{5-[2-(Dimethylamino)ethyl]-6-oxo-5H-diben-
zo[b,e]azepin-11(6H)-ylidene}acetate (5f)
1H NMR (400 MHz, DMSO-d6):  = 7.78 (d, J = 7.6 Hz, 1 H, ArH), 7.56 (t,
J = 7.4 Hz, 1 H, ArH), 7.46–7.43 (m, 2 H, ArH), 7.37–7.34 (m, 2 H, ArH),
7.16 (t, J = 7.4 Hz, 1 H, ArH), 7.10 (d, J = 7.6 Hz, ArH), 6.48 (s, 1 H,
C=CHCONMe2), 3.46 (s, 3 H, NCH3), 2.88 [s, 3 H, N(CH3)a(CH3)b], 2.73
[s, 3 H, N(CH3)a(CH3)b].
13C NMR (100 MHz, CDCl3):  = 167.5, 166.6, 143.3, 142.3, 139.1,
135.1, 131.7, 130.8, 130.6, 128.5, 128.1, 127.8, 125.4, 125.3, 123.1,
122.0, 37.7, 37.0, 34.1.
The product was isolated by column chromatography (eluent: hex-
anes/EtOAc 1:4) as a brown sticky solid (42 mg, 51%).
IR (KBr): 3050, 2962, 2927, 2872, 1706, 1633 cm–1
.
1H NMR (400 MHz, CDCl3):  = 7.84 (d, J = 7.2 Hz, 1 H, ArH), 7.43–7.27
(m, 4 H, ArH), 7.20–7.14 (m, 3 H, ArH), 6.05 (s, 1 H, C=CHCO2t-Bu),
4.80–4.73 (m, 1 H, NCHaHbCH2NMe2), 3.92–3.85 (m, 1 H, NCHaHbCH2NMe2),
2.70 (s, 2 H, NCH2CH2NMe2), 2.34 [s, 6 H, N(CH3)2], 1.32 [s, 9 H,
C(CH3)3].
13C NMR (100 MHz, CDCl3):  = 166.9, 164.0, 151.2, 142.6, 137.4,
136.8, 131.3, 130.7, 130.4, 128.4, 128.3, 127.7, 125.3, 124.1, 123.2,
121.6, 80.6, 55.9, 46.7, 44.4, 27.4.
LCMS: m/z [M + H]+ = 307.2.
HRMS (ESI): m/z [M + H]+ calcd for C19H19N2O2: 307.1447; found:
307.1442 and m/z [M + K]+ calcd for C19H18N2O2K: 345.1005; found:
345.1006.
LCMS: m/z [M + H]+ = 393.2.
HRMS (ESI): m/z [M + H]+ calcd for C24H29N2O3: 393.2178; found:
393.2172.
(Z)-N,N-Dimethyl-2-(6-oxo-5-propyl-5H-dibenzo[b,e]azepin-
11(6H)-ylidene)acetamide (5j)
The product was isolated by column chromatography (eluent: hex-
anes/EtOAc 2:3) as a white solid (49 mg, 61%); mp 137–140 °C.
tert-Butyl (Z)-2-(5-Methyl-6-oxo-5H-dibenzo[b,e]azepin-11(6H)-
IR (KBr): 3029, 2964, 2920, 2850, 1636, 1607 cm–1
.
ylidene)acetate (5g)
The product was isolated by column chromatography (eluent: hex-
anes/EtOAc 1:1) as a white solid (44 mg, 55%); mp 123–127 °C.
1H NMR (400 MHz, CDCl3):  = 7.88 (d, J = 7.3 Hz, 1 H, ArH), 7.43 (t, J =
7.2 Hz, 1 H, ArH), 7.37 (t, J = 7.2 Hz, 1 H, ArH), 7.32–7.28 (m, 3 H, ArH),
7.12 (t, J = 7.3 Hz, 1 H, ArH), 6.32 (s, 1 H, C=CHCONMe2), 4.22–4.14 (m,
1 H, NCHaHbCH2CH3), 3.83–3.76 (m, 1 H, NCHaHbCH2CH3), 2.94 [s, 3 H,
N(CH3)a(CH3)b], 2.88 [s, 3 H, N(CH3)a(CH3)b], 1.89–1.84 (m, 1 H,
NCH2CHaHbCH3), 1.80–1.69 (m, 1 H, NCH2CHaHbCH3), 0.94 (t, J = 7.4
Hz, 3 H, NCH2CH2CH3).
IR (KBr): 3035, 2961, 2924, 2875, 1708, 1637 cm–1
.
1H NMR (400 MHz, CDCl3):  = 7.92 (d, J = 7.4 Hz, 1 H, ArH), 7.45 (t, J =
7.4 Hz, 1 H, ArH), 7.38 (t, J = 7.4 Hz, 1 H, ArH), 7.29–7.25 (m, 3 H, ArH),
7.17–7.13 (m, 2 H, ArH), 6.06 (s, 1 H, C=CHCO2t-Bu), 3.58 (s, 3 H,
NCH3), 1.29 [s, 9 H, C(CH3)3].
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Synthesis
13C NMR (100 MHz, CDCl3):  = 167.6, 166.4, 145.3, 143.0, 138.6,
136.6, 131.9, 131.6, 130.9, 128.7, 128.5, 128.4, 125.6, 125.4, 122.9,
52.5, 37.7, 34.6, 21.6, 11.5.
Methyl (E)-3-(5-Methyl-6-oxo-5,6-dihydrophenanthridin-4-yl)ac-
rylate (6a) (Scheme 3)
This compound was prepared by following the literature reported
Heck conditions5 and was isolated by column chromatography (elu-
ent: hexanes/EtOAc 3:2) as a white solid (62%); mp 102–105 °C.
LCMS: m/z [M + H]+ = 335.0.
HRMS (ESI): m/z [M + H]+ calcd for C21H23N2O2: 335.1760; found:
335.1447 and m/z [M + Na]+ calcd for C21H22N2O2Na: 357.1579; found:
357.1723.
IR (KBr): 3036, 2975, 2924, 2851, 1717, 1639 cm–1
.
1H NMR (400 MHz, DMSO-d6):  = 8.54 (d, J = 8.0 Hz, 2 H, ArH), 8.34
(d, J = 8.0 Hz, 1 H, ArH), 8.14 (d, J = 15.9 Hz, 1 H, CH=CHCO2Me), 7.87
(t, J = 7.4 Hz, 1 H, ArH), 7.74 (d, J = 7.3 Hz, 1 H, ArH), 7.67 (t, J = 7.4 Hz,
1 H, ArH), 7.39 (t, J = 7.7 Hz, 1 H, ArH), 6.47 (d, J = 15.8 Hz, 1 H,
CH=CHCO2Me), 3.76 (s, 3 H, OCH3), 3.64 (s, 3 H, NCH3).
(Z)-5-Methyl-11-[2-(4-methylpiperazin-1-yl)-2-oxoethylidene]-
5H-dibenzo[b,e]azepin-6(11H)-one (5k)
The product was isolated by column chromatography (eluent: hex-
anes/EtOAc 1:3) as a white solid (43 mg, 53%); mp 165–168 °C.
LCMS: m/z [M + H]+ = 294. 0.
IR (KBr): 3063, 2981, 2925, 1631, 1615 cm–1
.
HRMS (ESI): m/z [M + H]+ calcd for C18H16NO3: 294.1130; found:
294.1119 and m/z [M + Na]+ calcd for C18H15NO3Na: 316.0950; found:
316.0936.
1H NMR (400 MHz, DMSO-d6):  = 7.79 (d, J = 7.6 Hz, 1 H, ArH), 7.57 (t,
J = 7.4 Hz, 1 H, ArH), 7.47–7.43 (m, 2 H, ArH), 7.41–7.34 (m, 2 H, ArH),
7.19 (t, J = 7.4 Hz, 1 H, ArH), 7.11 (d, J = 7.6 Hz, 1 H, ArH), 6.41 (s, 1 H,
C=CHCON), 3.46 (s, 3 H, NCH3), 3.25–3.23 (m, 1 Hpiperazine), 2.54 (s, 3 H,
piperazine NCH3), 2.27–2.23 (m, 2 Hpiperazine), 2.04 (s, 3 Hpiperazine),
1.86–1.83 (m, 1 Hpiperazine), 1.46–1.44 (m, 1 Hpiperazine).
13C NMR (100 MHz, CDCl3):  = 168.0, 165.7, 143.2, 142.4, 139.6,
135.2, 132.2, 131.2, 130.9, 129.1, 128.6, 128.3, 126.0, 125.8, 123.0,
122.5, 54.9, 54.1, 46.0, 45.8, 41.0, 38.1.
2-(5-Methyl-6-oxo-5H-dibenzo[b,e]azepin-11(6H)-ylidene)acetic
Acid (7)
To a stirred solution of compound 5g (250.0 mg, 0.75 mmol) in DCM
(10 mL) was added TFA (8.0 L, 1.12 mmol) at 0 °C under N2 atmo-
sphere and the reaction mixture was stirred at r.t. for 2 h. Then the
mixture was concentrated under reduced pressure and the crude ma-
terial was purified by triturating with Et2O/pentane to afford 7 (198.0
mg, 95%) as white solid; mp 195 °C.
LCMS: m/z [M + H]+ = 362.2.
HRMS (ESI): m/z [M + H]+ calcd for C22H24N3O2: 362.1869; found:
IR (KBr): 3405, 2930, 2851, 1719, 1633 cm–1
.
362.1861.
1H NMR (400 MHz, DMSO-d6):  = 12.52 (s, 1 H, CO2H), 7.77 (d, J = 7.4
Hz, 1 H, ArH), 7.54 (t, J = 7.0 Hz, 1 H, ArH), 7.48–7.43 (m, 2 H, ArH),
7.35–7.33 (m, 2 H, ArH), 7.23–7.17 (m, 2 H, ArH), 6.18 (s, 1 H, C=CH-
CO2H), 3.47 (s, 3 H, NCH3).
LCMS: m/z [M + H]+ = 280.2.
HRMS (ESI): m/z [M + H]+ calcd for C17H14NO3: 280.0974; found:
Sultam Derivative 5l
The product was isolated by column chromatography (eluent: hex-
anes/EtOAc 1:3) as a white solid (47 mg, 57%); mp 166–168 °C.
IR (KBr): 3078, 2981, 2875, 1710, 1333, 1156 cm–1
1H NMR (400 MHz, DMSO-d6):  = 7.83 (d, J = 7.4 Hz, 1 H, ArH), 7.69–
7.61 (m, 3 H, ArH), 7.54–7.48 (m, 2 H, ArH), 7.43 (t, J = 7.0 Hz, 1 H,
ArH), 7.25 (d, J = 7.4 Hz, 1 H, ArH), 6.49 (s, 1 H, C=CHCO2t-Bu), 3.47 (s,
3 H, NCH3), 1.16 [s, 9 H, C(CH3)3].
13C NMR (100 MHz, CDCl3):  = 164.6, 149.6, 140.5, 140.0, 136.0,
135.7, 132.2, 130.2, 130.0, 129.9, 129.2, 128.9, 128.6, 128.2, 127.5,
81.6, 38.6, 27.6.
.
280.0975.
N-[2-(Dimethylamino)ethyl]-2-(5-methyl-6-oxo-5H-diben-
zo[b,e]azepin-11(6H)-ylidene)acetamide (8)
To a stirred solution of 7 (150.0 mg, 0.54 mmol) in THF (10 mL) were
added EDC·HCl (154.5 mg, 0.81 mmol), HOBt (108.8 mg, 0.81 mmol)
and DIPEA (0.3 mL, 1.62 mmol). The reaction mixture was stirred for
10 min under ice cooling and N,N-dimethylethylenediamine (8 L,
0.81 mmol) was added to the mixture. The mixture and stirred at r.t.
for 16 h and diluted with ice-water (10 mL). The organic phase was
extracted with EtOAc (2 × 25 mL) and the combined organic layers
were washed successively with water (2 × 15 mL) followed by brine
(20 mL) and dried (anhyd Na2SO4), and concentrated under reduced
pressure. The residue was purified by column chromatography (silica
gel 100–200 mesh, 60% EtOAc in hexane) to afford 8 (124.0 mg, 61%)
as an off-white solid; mp 136–138 °C.
LCMS: m/z [M + Na]+ = 394.0.
HRMS (ESI): m/z [M + Na]+ calcd for C20H21NO4SNa: 394.1089; found:
394.1088.
Sultam Derivative 5m
The product was isolated by column chromatography (eluent: hex-
anes/EtOAc, 1:3) as a white solid (46 mg, 55%); mp 147–149 °C.
IR (KBr): 2986, 2958, 2876, 1710, 1331, 1142 cm–1
.
1H NMR (400 MHz, DMSO-d6):  = 7.82 (d, J = 7.0 Hz, 1 H, ArH), 7.68–
7.60 (m, 3 H, ArH), 7.51–7.42 (m, 3 H, ArH), 7.28 (d, J = 7.0 Hz, 1 H,
ArH), 6.48 (s, 1 H, C=CHCO2t-Bu), 3.72 (br s, 1 H, NCHaHbCH2CH3), 3.51
(br s, 1 H, NCHaHbCH2CH3), 1.61–1.56 (m, 2 H, NCH2CH2CH3), 1.16 [s, 9
H, C(CH3)3], 0.92 (t, J = 7.3 Hz, 3 H, NCH2CH2CH3).
13C NMR (100 MHz, CDCl3):  = 164.5, 149.9, 140.8, 140.5, 135.9,
134.5, 132.0, 131.4, 130.1, 129.7, 129.4, 128.8, 128.7, 128.3, 127.2,
81.5, 53.0, 27.7, 22.7, 10.9.
IR (KBr): 2981, 2925, 2873, 1636, 1615 cm–1
.
1H NMR (400 MHz, DMSO-d6):  = 7.95 (br s, 1 H, NH), 7.75 (d, J = 7.2
Hz, 1 H, ArH), 7.55 (t, J = 7.2 Hz, 1 H, ArH), 7.45–7.40 (m, 2 H, ArH),
7.32–7.30 (m, 2 H, ArH), 7.19–7.11 (m, 2 H, ArH), 6.29 (s, 1 H, C=CH-
CONH), 3.46 (s, 3 H, NCH3), 3.15–3.12 (m, 2 H, NHCH2CH2NMe2), 2.25–
2.20 (m, 2 H, NHCH2CH2NMe2), 2.10 [s, 6 H, (NCH3)2].
13C NMR (100 MHz, CDCl3):  = 167.7, 165.4, 146.7, 142.9, 139.5,
135.2, 132.0, 131.1, 130.9, 128.9, 128.5, 128.3, 125.7, 125.0, 124.9,
122.6, 56.8, 44.7, 37.6, 36.2.
LCMS: m/z [M + H]+ = 400.1.
HRMS (ESI): m/z [M + H]+ calcd for C22H26NO4S: 400.1583; found:
LCMS: m/z [M + H]+ = 350.0.
400.1587.
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A. Das et al.
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Synthesis
HRMS (ESI): m/z [M + H]+ calcd for C21H24N3O2: 350.1869; found:
350.1855 and m/z [M + Na]+ calcd for C21H23N3O2Na: 372.1688; found:
372.1673.
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Acknowledgment
We sincerely thank Arpita Mandal for her assistance in the project ini-
tially. IA thanks UGC (New Delhi) for providing Shimadzu FTIR and
GCMS spectrometers. DST (New Delhi) is also gratefully acknowl-
edged for providing Bruker single crystal XRD and Thermo Scientific
HRMS instruments under the PURSE Phase-1 and FIST program, re-
spectively. IA and AD also thank DSTBT-West Bengal for funding sup-
port.
Notes
The authors declare no competing financial interest.
Supporting Information
Supporting information for this article is available online at
https://doi.org/10.1055/s-0037-1611548.
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