Dibenzo[ b, e ][1,4]diazepin-1-ones and their Ring-Opened Derivatives: Revisited Synthesis, 2D NMR and Crystal Structure

Article abstract of DOI:10.1055/s-0036-1590306

The synthesis of 2,3,4,5,10,11-hexahydro-1 H -dibenzo[ b, e ][1,4]diazepin-1-ones was revisited and a catalyst-free method was established, by exploring the reactivity of 3-[(2-aminoaryl)amino]dimedones towards carbonylated electrophiles. 2D NMR and single-crystal X-ray diffraction studies were used to characterize the structures unequivocally and to review the mechanism leading to the formation of supposed positional isomers. The action of 3-[(2-aminoaryl)amino]dimedones on chromene-3-carboxylic acid, fumaryl, and oxalyl chloride has led to dibenzo[ b, e ][1,4]diazepin-1-one ring opening to produce novel Z -configured enaminone and linear diamides.

Full text of DOI:10.1055/s-0036-1590306

SYNLETT
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9
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6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
©
Georg Thieme Verlag Stuttgart · New York
2017, 28, A–F
letter
A
en
Synlett
B. Cherfaoui et al.
Letter
Dibenzo[b,e][1,4]diazepin-1-ones and their Ring-Opened Deriva-
tives: Revisited Synthesis, 2D NMR and Crystal Structure
Brahim Cherfaouia
Houria Lakhdaria,b
O
CHO
Me
Me
Me
Me
H
N
H
N
3
H
N
Me
R3
R2
Norah Bennamane*a
Rachid Ameraouib
Oualid Talhi*b,c
Filipe A. Almeida Pazd
Khaldoun Bacharib
Gilbert Kirsche
Me
O
CO2H
R1 = H
N
H
O
R1
NH2
R1
N
H
O
O
(37–87%) R2
2a–d
O
5
a
(47%)
1a–c
CHO
Me
R3
HO
O
oxalyl
Me
O
R1 = H chloride
Me
H
N
R1
O
CHO
Me
H
Kolli Nejar-Bellaraa
Me
Me
N
O
Me
Me
Cl
N
H
O
NH
O
O
NH
Artur M. S. Silva*c
0
0
0
0
0-
0
0
3
2-
8
6
1
8-
2
8
6
NH
HN
NH
O
R1
Me
N
H
O
4a
(55%)
HN
Me
HN
O
O
O
HN
O
O
a
Me
Me
Laboratoire de Chimie Organique Appliquée, Faculté de
Chimie, Université des Sciences et de la Technologie Houari
Boumediène, BP 32, El-Alia Bab-Ezzouar, 16111 Alger, Algeria
noraoussaid@yahoo.fr
Centre de Recherche Scientifique et Technique en Analyses
Physico-Chimiques CRAPC, BP 384, Bou-Ismail-RP, 42004
Tipaza, Algeria
3
a,b
free catalyst
11 examples
R1
6a,b
73–78%)
(57–66%)
(
7
a (81%)
b
c
QOPNA, Department of Chemistry, University of Aveiro,
3810-193 Aveiro, Portugal
artur.silva@ua.pt
oualid.talhi@ua.pt
d
e
CICECO – Aveiro Institute of Materials, Department of
Chemistry, University of Aveiro, 3810-193 Aveiro, Portugal
Laboratoire Structure et Réactivité des Systèmes Moléculaires
Complexes, UMR 7565, Université de Lorraine, Avenue du
Général Delestraint, Metz, France
3
Received: 02.05.2017
erties. This class of compounds is still the subject of in vivo
clinical trials associated with the treatment of several dis-
eases, such as insomnia, anxiety, seizures, agitation, alcohol
withdrawal, muscle spasms, and premedication for medical
Accepted after revision: 21.05.2017
Published online: 13.07.2017
DOI: 10.1055/s-0036-1590306; Art ID: st-2017-d0318-l
Abstract The synthesis of 2,3,4,5,10,11-hexahydro-1H-diben-
zo[b,e][1,4]diazepin-1-ones was revisited and a catalyst-free method
was established, by exploring the reactivity of 3-[(2-aminoaryl)ami-
no]dimedones towards carbonylated electrophiles. 2D NMR and single-
crystal X-ray diffraction studies were used to characterize the structures
unequivocally and to review the mechanism leading to the formation of
supposed positional isomers. The action of 3-[(2-aminoaryl)amino]di-
medones on chromene-3-carboxylic acid, fumaryl, and oxalyl chloride
has led to dibenzo[b,e][1,4]diazepin-1-one ring opening to produce
novel Z-configured enaminone and linear diamides.
4
or dental procedures. The main biological activity of ben-
zodiazepines is their action as stimulators of the central
nervous system. They usually reduce the activity of nerves
in the brain and the spinal cord, thus enhancing the effects
5
of the neurotransmitter γ-aminobutyric acid (GABA).
Researchers have paid much attention to novel benzodi-
6
azepines that are linked to other bioactive organic motifs.
A synthetic literature survey underlined the availability of
various procedures towards the synthesis of 1,4- and 1,5-
Key words 3-[(2-aminoaryl)amino]dimedones, carbonylated electro-
philes, dibenzo[b,e][1,4]diazepin-1-ones, reaction mechanism, 2D
NMR, single-crystal X-ray diffraction
7
benzodiazepines. For instance, one piece of work has dis-
closed the use of binucleophilic enaminones as key starting
materials in the reaction with diverse aromatic/heterocyclic
7f
aldehydes to generate novel benzodiazepine frameworks.
Nitrogen-containing heterocycles occupy an important
Most of the reported methods are, however, time-consum-
ing and multistep catalytic procedures.7
b–e,7g
Because of
position in synthetic organic chemistry due to their multi-
tude of applications in medicine, agriculture, and indus-
these drawbacks, it is pertinent to develop efficient and
simple processes for the preparation of benzodiazepine-
based drugs. Elaborating a molecular system containing di-
medone, benzodiazepine, phenolic, and chromone moieties
all in one scaffold is a promising strategy to create unprece-
dented new biologically active agents.
1,2
try. Several attractive chemotypes thereof have been re-
ported, such as benzodiazepine derivatives, which are a
common group of compounds in the area of psychoactive
drugs. Benzodiazepines are to date present in more than
forty approved medicines with a range of therapeutic prop-
©
Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–F

B
Synlett
B. Cherfaoui et al.
Letter
A study on the reactivity of 3-[(2-aminoaryl)amino]-
,5-dimethylcyclohex-2-en-1-ones 1 towards benzalde-
Me Me
H
N
5
H
Me
O
3
5
1
'
N
3
Me
1
'
hydes has already been disclosed, leading to the production
of useful dibenzo[b,e][1,4]diazepin-1-one structures.8
However, we decided to revisit the reaction in order to sim-
plify the experimental procedure, to prepare further novel
derivatives, and to establish the obtained structures un-
equivocally. Compounds 1a–c8 were used as enaminone
derivatives for the preparation of 11-substituted
5
1
4'
1
R1
NH2
O
2
CO H
N
H
O
O
3
"
5a
O
1
a–c
(47%)
fumaryl chloride
HO 2"'
d
R1
oxalyl chloride
2
,3,4,5,10,11-hexahydro-1H-dibenzo[b,e][1,4]diazepin-1-
Me
Me
3"
O
O
NH
ones 2a–d, 3a,b, and 4a through their reaction with benzal-
dehydes,
1
"
NH
O
8a–c,8e
cinnamaldehyde, and chromone-3-carbalde-
HN
1
2
Me
Me
8
a–
1'
hyde, respectively. Contrary to the reported procedures,
Me
Me
3"
O
HN
O
O
NH
c,8e
2'
our reaction proceeded in ethanol under catalyst-free
conditions at room temperature for 4–5 hours. The reaction
is worked up by simple filtration of the formed precipitate
showing a high purity of the products 2–4, isolated in mod-
erate-to-good yields (37–87%) after simple washing with
1
"
NH
HN
1
R1
6a–b
(73–78%)
Me
Me
1
'
HN
O
O
2
'
7a
81%)
a R1 = H, b R1 = Me
(
ethanol; thus avoiding any chromatographic purification
Scheme 2 Synthesis of enaminone 5a and diamides 6a,b and 7a. Reagents
and conditions: EtOH, r.t., 4–5 h.
9
(Scheme 1). Under similar conditions, we further investi-
gated the reaction of 1a–c with other electrophiles, such as
chromone-3-carboxylic acid, fumaryl chloride, and oxalyl
chloride, to afford new (Z)-3-[(2-{[3-(2-hydroxyphenyl)-3-
oxoprop-1-en-1-yl]amino}phenyl)amino]-5,5-dimethylcy-
clohex-2-en-1-one (5a) and linear diamides 6a,b and 7a, re-
Several mechanistic proposals have been described for
the formation of 11-aryl-3,3-dimethyl-2,3,4,5,10,11-hexa-
hydro-1H-dibenzo[b,e][1,4]diazepin-1-ones 2–4 (Scheme 3,
pathway A).8
a–c,8e
Maleki and Kamalzare described, howev-
9
spectively, in 47–81% yield (Scheme 2).
er, the unexpected formation of different isomers, 11-aryl-
,1-dimethyl-1,2,4,5,10,11-hexahydro-3H-diben-
1
Me
Me
zo[b,e][1,4]diazepin-3-ones (Scheme 3, pathway B), via a
one-pot catalytic three-component reaction of o-phenyl-
enediamines (OPDA), dimedone, and various benzalde-
H
N
3
Me
CHO
6
H
1'
N
3
5
Me
R3
R2
1
5
4'
10
N
1
R1
11
O
8e
8
hydes. The mechanistic difference between the pathways
R1
NH2
*
H
O
2a–d
37–87%)
A and B is the initial formation of the two key intermedi-
ates, namely: 3-[(2-aminoaryl)amino]-5,5-dimethyl-cyclo-
hex-2-en-1-ones 1 and 3-[(2-aminoaryl)amino]-5,5-di-
methylcyclohex-3-en-1-ones 8 (Scheme 3). These interme-
diates are formed by nucleophilic attack of the amino group
of OPDA onto one of the dimedone carbonyl groups. After
loss of water, it is most likely to form the cyclohex-2-en-1-
one 1 from deprotonation of the more acidic α-carbonyl
proton compared to that at the γ position, which generates
R2
(
O
O
1
a–c
R3
2a R , R = H, R2 = OH
1
3
CHO
CHO 2b R = Me, R2 = OH, R = H
1
3
2
2
c R1 = Cl, R2 = OH, R3 = H
d R = Cl, R2 = H, R3 = OMe
1
Me Me
Me
H
N
3
Me
6
H
N
5
3
6
5
1
10
11
O
Cl
8
N
*
R1
11
O
H
8
N
H
*
the cyclohex-3-en-1-one 8 (Scheme 3). Compounds 1, re-
2'
O
8a–c
3a,b
O
4'
ported as isolable products in this work and others,
can
4a
8
a'
3a R1 = H
3
(
57–66%)
4a'
8e
(
55%)
also be formed in situ during multicomponent processes.
Following the mechanistic pathways A and B that involve an
intramolecular diazepine ring closure of imine intermedi-
ates (9 or 10) and 1,3-proton shift (Scheme 3), two totally
different structures A and B are formed. We found, howev-
8
'
1
b R = Cl
6
'
Scheme 1 Synthesis of 11-substituted 2,3,4,5,10,11-hexahydro-1H-
dibenzo[b,e][1,4]diazepin-1-ones 2a–d and 4a, and of 3a,b. Reagents
and conditions: EtOH, r.t., 4–5 h.
8e
er, that the reported structure B has been compared to
8a–c
A
in terms of their physical characteristics, namely the
melting point. Although the resulting products structures
are distinct, there is a high probability to reach quasi simi-
lar values of melting points for the two isomers A and B
©
Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–F

C
Synlett
B. Cherfaoui et al.
Letter
(
Scheme 3). This fact requires a careful review of the spec-
protons, the latter appear as AB spin systems at δ = 2.02–
2.21 ppm for H-2 and δ = 2.57–2.75 ppm for H-4. The pro-
tons attributed to the 3,3-dimethyl groups are also affected
by the presence of the asymmetric center and appear at dif-
ferent chemical shifts around δ = 1.03–109 ppm. Carbon as-
signments were based on HSQC and HMBC correlations. For
instance in the case of compounds 2b and 3a: the four
diazepine quaternary carbons C-4a (δ = 155.1–155.7 ppm),
C-5a (δ = 125.0–130.2 ppm), C-9a (δ = 137.8–140.2 ppm),
and C-11a (δ = 106.5–110.7 ppm) have been assigned based
on the HMBC correlations C-4a/H-11, C-5a/10-NH, C-9a/H-
troscopic data relating to compounds featuring structure B
as reported in the literature.
8e
H
Me
H
N
OH Me
NH2
NH2
O
Me
Me
R
H
10
11
NH2
O
O
–
H2O
Pathway A
3-[(2-aminoaryl)amino]
dimedone intermediates
Pathway B
H
N
11/10-NH, and C-11a/H-4/5-NH, respectively (Figure 1).
H
N
Me
O
Me
The structure 2,3,4,5,10,11-hexahydro-1H-diben-
A
R
BH3
R
A
NH2
zo[b,e][1,4]-diazepin-1-one can be clearly distinguished
from its reported positional isomer 1,2,4,5,10,11-hexahy-
dro-3H-dibenzo[b,e][1,4]diazepin-3-one structure B: the
existing HMBC connectivity between the carbonyl carbon
C-1 and H-11 in the structure A will not be observed in the
structure B between C-3 and H-11 due to the distance be-
tween them (Figure 1). Furthermore, both carbonyls C-1
and C-4′ (δ = 192.1–192.2 and 176.1–176.4 ppm, respec-
tively) of the newly synthetized 11-chromone-
NH2
Me
Me
8
O
1
CHO
CHO
R
R
O
H
Me Me
H
N
N
imine
intermediate
R
Me
Me
R
N
N
O
10
R
2,3,4,5,10,11-hexahydro-1H-dibenzo[b,e][1,4]diazepin-1-
9
R
diazepine
ring closure
ones 3a and 3b have been assigned through HMBC connec-
tivities of C-4′/H-2′/H-11 and C-1/H-11, respectively (Figure
1
O
Me Me
N
, compound 3a).11
N
R
H
Me
Me
R
H
N
H
N
H
O
H
Me
Me
H
H
H
H
5
H
3
R
3
6
N
5
4a
11a
N
H
R
5a
4a
1
H11
10
*
5a
6
H
H
O
1a
1
1
,3-proton shift
1
3
1
H
O
5
9a
10
Me Me
H
4a
11
HN
N
*
O
H
9
a
OH
H
9
N
H
H
H
N
H
2'
N
H
11a
O
H
4'
1
HN
0
11
O
R
Me
Me
2b
O
*
3a
8a'
R
2'
non-observed 3-C=O/H-11
HMBC correlation in
structure B
4a'
N
H
N
H
O
R
clear 1-C=O/H-11 HMBC
correlation in structure A
H
5'
7'
R
Figure 1 Main HMBC correlations of 11-substituted-2,3,4,5,10,11-
hexahydro-1H-dibenzo[b,e][1,4]diazepin-1-ones 2b and 3a
1
1-aryl-3,3-dimethyl-
11-aryl-1,1-dimethyl-
2
,3,4,5,10,11-hexahydro-1H-
1,2,4,5,10,11-hexahydro-3H-
dibenzo[b,e][1,4]diazepin-3-ones
Structure B
dibenzo[b,e][1,4]diazepin-1-ones
Structure A
The reaction of 1a–c with chromone-3-carboxylic acid
resulted in the open-chain enaminone, (Z)-3-[(2-{[3-(2-hy-
droxyphenyl)-3-oxoprop-1-en-1-yl]amino}phenyl)amino]-
Scheme 3 Mechanism for the formation of 1,4-benzodiazepines 2–4
1
H NMR and 13C NMR spectroscopic analysis of com-
13
5,5-dimethylcyclohex-2-en-1-one (5a) through a decar-
10–12
pounds 2–4
clearly reveal the cyclic portions of the 11-
boxylative 1,4-conjugate addition and chromone ring open-
1
13
aryl-3,3-dimethyl-2,3,4,5,10,11-hexahydro-1H-diben-
zo[b,e][1,4]diazepin-1-one scaffold, including the benzodi-
ing (Scheme 4). H NMR, C NMR, HMBC, and NOESY spec-
troscopic analyses of 5a were used to confirm the Z config-
3
azepine ring featuring the asymmetric C-11 (δ = 5.64–5.90
uration ( J
= 8.0 Hz) of the enaminone olefin which
H
H–1′′H-2′′
ppm and δ = 49.2–55.1 ppm). The 1,4-diamino protons are
was unequivocally proved based on the strong NOE effects
C
easily assigned, the 10-NH proton appearing as a doublet
observed between the protons H-1′′ and H-2′′ (Figure 2).
(
1
J = 5.9–5.5 Hz) at δ = 5.28–5.85 ppm by coupling with H-
1, while the 5-NH proton can be assigned to a singlet ap-
The reaction of 1a–c with fumaryl chloride or oxalyl chlo-
ride afforded linear diamides 6 and 7,1
4,15
respectively, even
pearing at δ = 8.76–9.00 ppm. Due to the close proximity of
when using equimolar mixtures of the starting reagents.
the C-11 asymmetric center to the dimedone methylene
©
Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–F

D
Synlett
B. Cherfaoui et al.
Letter
H
N
H
N
O
chromone
ring
NH
O
HN
NH2
opening
– CO2
N
H
O
O
O
O
H
5a
O
1a
O
O
HO
HO
HOOC
Scheme 4 Reaction mechanism for the synthesis of 5a
H
H
Me
Me
Me
H
O
H
Me
H
O
H
5
1
5
1
3
3
1
'
N
N
1
'
H
H
H
H
2
'
2'
4'
H
4'
N
O
H
O
2"'
N
1"
O
OH
1"
3"
3"
2"'
H
H
H
H
H
4"'
H
4
"'
6"'
6"'
H
HMBC
NOESY
Figure 2 Main HMBC and NOESY correlations observed in 5a
Single-crystal X-ray diffraction studies were used to re-
veal the spatial arrangement of structure A of compounds
2b, 3a, and 5a, which is in good agreement with the afore-
mentioned 2D NMR studies. These studies show that the
polycyclic 2,3,4,5,10,11-hexahydro-1H-dibenzo[b,e][1,4]di-
azepin-1-one fragment approaches planarity (Figure 3)
with the maximum atomic deviation for the average plane
being of 0.537(2) and 0.673(1) Å for compounds 2b and 3a
(
both distances correspond to NH groups of the seven-
16,17
membered rings composing the molecules).
We also
note that it was not uncommon for the crystalline diben-
zo[b,e][1,4]diazepin-1-ones to contain crystallization sol-
vent. This is observed for compounds 2b·EtOH and
Figure 3 Schematic representation of the molecular units present in
crystal structures of compounds 2b·EtOH, 3a·5H O, and 5a·EtOH.
2
Asymmetric centers are depicted by an asterisk and intramolecular hy-
drogen-bonding interactions as dashed gold lines. Non-hydrogen at-
oms are represented as thermal ellipsoids drawn at the 50% probability
level and hydrogen atoms as small spheres with arbitrary radii. The sol-
vent molecules present in the crystal structures have been omitted for
clarity purposes.
3
a·5H O. This phenomenon affects the melting-point mea-
2
surement for 2a (170–172 °C determined in this work, see
Supporting Information), which is taken as an example
when compared to its reported non-crystalline amorphous
material which, supposedly, does not contain solvent mole-
18
cules (158–159 °C).
Single-crystal X-ray studies also provided additional
structural insights on compound 5a·EtOH. Crystals of this
material were isolated by slow evaporation at 6 °C of an
ethanol solution. The existence of two cooperative intramo-
lecular hydrogen bonds as depicted in Figure 3 promotes
considerable structural planarity. Indeed, the maximum
atomic deviation for the average plane being just of
teratomic distances being of 2.535(5) and 2.884(5) Å, re-
spectively (the latter even has an interaction angle of 171°
which approaches linearity).19 Noteworthy, the dimedone
moiety subtends an angle of 72.20(12)° with the average
plane of the remaining portion of the molecular unit.
In summary, the versatile reactivity of 3-[(2-amino-
aryl)amino]dimedones towards carbonylated electrophiles
is described. This constitutes an efficient, simple, and eco-
nomic method for the preparation of dibenzo[b,e][1,4]diaz-
epin-1-ones and their ring-opened derivatives. Clear advan-
0.132(3) Å, which is attributed to the hydroxyl group. As
shown in Figure 3, the two intramolecular O–H···O and N–
H···O hydrogen bonds are considerably strong with the in-
©
Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–F

E
Synlett
B. Cherfaoui et al.
Letter
tages are noticeable in our free-catalyst synthetic protocol,
such as mild reaction conditions, and simple workup proce-
dure to isolate pure 11-substituted-dibenzo[b,e][1,4]diaze-
pin-1-ones in optimal yields. 2D NMR spectroscopy and
single-crystal X-ray techniques were very helpful to differ-
entiate between the two possible isomers A and B de-
scribed in the literature (the latter should be carefully re-
viewed) and support the favorable formation of diben-
zo[b,e][1,4]diazepin-1-ones. We have further explored the
action of 3-[(2-aminoaryl)amino]dimedones on different
active carbonylated electrophiles to generate a novel Z-
enaminone and linear diamide molecules bearing chelating
groups which may find suitable application in coordination
chemistry.
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0, 1550. (c) Tonkikh, N. N.; Strakovs, A.; Rizhanova, K. V.;
Petrova, M. V. Chem. Heterocycl. Compd. 2004, 40, 949.
d) Bennamane, N.; Kaoua, K.; Hammal, L.; Nedjar-Kolli, B. Org.
Funding Information
4
Thanks are due to University of Aveiro and FCT/MEC for financial sup-
port to the QOPNA research project (FCT UID/QUI/00062/2013) and to
the CICECO-Aveiro Institute of Materials (POCI-01-0145-FEDER-
(
Commun. 2008, 1, 62. (e) Maleki, A.; Kamalzare, M. Tetrahedron
Lett. 2014, 55, 6931.
007679; FCT UID/CTM/50011/2013), financed by national funds and
when appropriate co-financed by FEDER under the PT2020 Partner-
ship Agreement, and to the Portuguese NMR Network. We would like
also to thank FCT/MEC and the General Directorate for Scientific Re-
search and Technological Development – DGRSDT of Algeria and
Agence Thématique de Recherche en Sciences et Technologie ATRST
for approving the co-financed bilateral project PT-DZ/0005. We fur-
ther wish to thank CICECO for funding the purchase of the single-
(
9) General Procedure for the Synthesis of Compounds 2–7
To a solution of 3-[(2-aminoaryl)amino]dimedone derivative
1a–c (0.001 mol) in EtOH (20 mL), the carbonylic derivative
(0.001 mol) was added, and the resulting reaction mixture was
stirred at r.t. for 4–5 h. In all the cases, a precipitate formed
which was filtered-off, dried, and recrystallized from EtOH to
give pure products 2–7.
Note: In the case of the synthesis of the diamides 6 and 7, 2
molar equiv of the 3-[(2-aminoaryl)amino]dimedones 1a–c
crystal X-ray diffractometers.
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0.002 mol) were used for 1 molar equiv of oxalyl chloride or
Supporting Information
fumaryl chloride. The reaction also works with an equimolar
mixture of the reagent but excess of 1a–c remain in the reaction
mixture.
Supporting information for this article is available online at
https://doi.org/10.1055/s-0036-1590306.
S
u
p
p
ortioIgnfrm oaitn
S
u
p
p
ortioIgnfrm oaitn
(
10) 11-(2-Hydroxyphenyl)-3,3,8-trimethyl-2,3,4,5,10,11-hexahy-
dro-1H-dibenzo[b,e][1,4]diazepin-1-one (2b)
1
C22H24N O (colorless crystals, 0.30 g, 87%, mp 175–177 °C). H
2
2
References and Notes
NMR (300 MHz, DMSO-d ): δ = 1.06 and 1.08 (2 s, 6 H, 3-CH ),
6
3
1
2
.99 (s, 3 H, 8-CH ), 2.04 and 2.19 (AB, J = 15.9 Hz, 2 H, H-2),
.60 (s, 2 H, H-4), 5.28 (d, J = 5.6 Hz, 1 H, 10-NH), 5.89 (d, J = 5.6
(
1) Garuti, L.; Roberti, M.; Pizzirani, D. Mini Rev. Med. Chem. 2007, 7,
3
481.
Hz, 1 H, H-11), 6.26 (d, J = 1.1 Hz, 1 H, H-9), 6.38 (dd, J = 8.0, 1.1
Hz, 1 H, H-7), 6.39–6.45 (m, 1 H, H-5′), 6.57 (dd, J = 7.5, 1.3 Hz, 1
H, H-6′), 6.71–6.74 (m, 1 H, H-3′), 6.82 (d, J = 8.0 Hz, 1 H, H-6)
(2) Suvarna, A. S. Int. J. Pharm. Tech. Res. 2015, 8, 170.
(3) (a) Karp, G. M.; Manfredi, M. C.; Guaciaro, M. A.; Ortlip, C. L.;
Marc, P.; Szamosi, I. T. J. Agric. Food Chem. 1997, 45, 493.
6.84–6.91 (m, 1 H, H-4′), 8.76 (s, 1 H, 5-NH), 9.70 (s, 1 H, 2′-OH)
(b) Joseph, C. G.; Wilson, K. R.; Wood, M. S.; Sorenson, N. B.;
13
ppm. C NMR (75 MHz, DMSO-d ): δ = 20.2 (8-CH ), 27.4 and
Phan, D. V.; Xiang, Z. M.; Witek, R. M.; Haskell-Luevano, C.
J. Med. Chem. 2008, 51, 1423. (c) Rabahi, A.; Hamdi, S. M.;
Rachedi, Y.; Hamdi, M.; Talhi, O.; Paz, F. A. A.; Silva, A. M. S.;
Balegroune, F.; Hamadène, M.; Taïbi, K. J. Mol. Struct. 2014,
6
3
2
1
1
8.6 (3-CH ), 31.8 (C-3), 44.2 (C-4), 49.6 (C-2), 52.1 (C-11),
08.9 (C-11a), 114.8 (C-3′), 118.0 (C-5′), 119.9 (C-6), 120.5 and
20.6 (C-7, C-9), 126.6 (C-6′), 127.4 (C-4′), 128.4 (C-5a), 129.9
3
(C-1′), 131.3 (C-8), 138.3 (C-9a), 155.1 and 155.3 (C-4a, C-2′),
1
061, 97.
4) Chouinard, G.; Lefko-Singh, K.; Teboul, E. Cell. Mol. Neurobiol.
997, 19, 533.
+
1
91.8 (C-1, C=O) ppm. HRMS (ESI ): m/z calcd for [C22H N O +
(
(
24
2
2
+
Na] : 371.1730; found: 371.1721.
1
(
11) 3,3-Dimethyl-11-(4-oxo-4H-chromen-3-yl)-2,3,4,5,10,11-
5) (a) Snjezana, L.; James, K. R.; Roger, D. S.; James, M. C.;
hexahydro-1H-dibenzo[b,e][1,4]diazepin-1-one (3a)
C24H22N O (colorless crystals, 0.22 g, 57%, mp 183–184 °C). H
NMR (300 MHz, DMSO-d ): δ = 1.06 and 1.08 (2 s, 6 H, 3-CH ),
Chunrong, M.; Xiaoyan, L.; Wenyuan, Y. Psychopharmacology
1
2002, 161, 180. (b) Mashayekh, S.; Rahmanipour, N.;
2
3
Mahmoodi, B.; Ahmadi, F.; Motaharian, D.; Shahhosseini, S.;
Shafaroodi, H.; Banafshe, H. R.; Shafiee, A.; Navidpour, L. Bioorg.
Med. Chem. 2014, 22, 1929.
6
3
2
1
.13 and 2.19 (AB, J = 16.2 Hz, 2 H, H-2), 2.52 and 2.75 (AB, J =
6.2 Hz, 2 H, H-4), 5.46 (d, J = 5.5 Hz, 1 H, 10-NH), 5.78 (d, J = 5.5
Hz, 1 H, H-11), 6.47 (dd, J = 7.6, 1.7 Hz, 1 H, H-9), 6.52–6.70 (m,
H, H-7, H-8), 7.01 (dd, J = 7.7, 1.6 Hz, 1 H, H-6), 7.41–7.55 (m, 3
H, H-6′, H-8′, H-2′), 7.74 (ddd, J = 8.6, 7.1, 1.7 Hz, 1 H, H-7′), 8.09
2
©
Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–F

F
Synlett
B. Cherfaoui et al.
Letter
(
(
(
dd, J = 8.0, 1.7 Hz, 1 H, H-5′), 8.95 (s, 1 H, 5-NH) ppm. 13C NMR
75 MHz, DMSO-d ): δ = 27.4 and 28.6 (3-CH ), 31.7 (C-3), 44.0
C-4), 49.3 (C-2), 49.8 (C-11), 106.5 (C-11a), 118.3 (C-8′), 120.4,
20.7 and 120.8 (C-6, C-7, C-9), 123.0 (C-8), 123.1 (C-4a′), 124.8
and 125.0 (C-5′, C-3′), 125.5 (C-6′), 131.0 (C-5a), 134.2 (C-7′),
(C-4′), 128.0 (C-5′), 129.5 (C-1′), 132.8 (C-2′), 134.0 (C-2), 162.3
(C-1), 170.6 (C-1′′), 191.2 (C-3′′) ppm. HRMS (ESI ): m/z calcd for
+
6
3
+
[C
H
N O + H] : 541.2815; found: 541.2776.
3
1
2
36
4
4
2
1
(15) N ,N -Bis{2-[(5,5-dimethyl-3-oxocyclohex-1-en-1-
yl)amino]phenyl}oxalamide (7a)
1
(
+
37.8 (C-9a), 152.5 (C-2′), 155.7 and 155.9 (C-4a, C-8a′), 176.4
C30H34N O (white solid, 0.42 g, 81%, mp 200–202 °C). 1H NMR
4
4
+
C-4′), 192.1 (C-1) ppm. HRMS (ESI ): m/z calcd for [C24H22N O
H] : 387.1703; found: 387.1729.
(300 MHz, DMSO-d ): δ = 1.03 (s, 12 H, 5′′-CH ), 2.02 (s, 4 H, H-
2
3
6
3
+
4′′), 2.39 (s, 4 H, H-6′′), 4.70 (s, 2 H, H-2′′), 7.27–7.40 (m, 6 H, H-
2
(
12) (E)-8-Chloro-3,3-dimethyl-11-styryl-2,3,4,5,10,11-hexahy-
3′, H-4′, H-5′), 7.96 (d, J = 7.9 Hz, 2 H, H-6′), 8.58 (s, 2 H, N H),
1
13
dro-1H-dibenzo[b,e][1,4]diazepin-1-one (4a)
C23H23ClN O (beige solid, 0.21 g, 55%, mp 160–161 °C). H NMR
9.96 (s, 2 H, N H) ppm. C NMR (75 MHz, DMSO-d ): δ = 28.0
6
1
(5-CH ), 32.5 (C-5′′), 41.6 (C-6′′), 50.1 (C-4′′), 96.8 (C-2′′), 123.2
2
3
(
300 MHz, DMSO-d ): δ = 1.00 and 1.05 (2 s, 6 H, 3-CH ), 2.08
(C-6′), 126.3 (C-3′) 127.2 (C-4′), 127.6 (C-5′), 130.5 (C-1′), 131.9
6
3
+
and 2.20 (AB, J = 15.9 Hz, 2 H, H-2), 2.51 (s, 2 H, H-4), 5.25 (dd,
J = 6.0, 5.9 Hz, 1 H, H-11), 6.03 (dd, J = 15.8, 6.0 Hz, 1 H, H-1′),
(C-2′), 157.6 (C-1′′), 162.3 (C-1), 195.2 (C-3′′) ppm. HRMS (ESI ):
+
m/z calcd for [C30H34N O + Na] : 537.2472; found: 537.2449.
4
4
6
6
7
.20 (d, J = 15.8 Hz, 1 H, H-2′), 6.26 (d, J = 5.9 Hz, 1 H, 10-NH),
.70 (dd, J = 8.6, 2.4 Hz, 1 H, H-7), 6.83 (d, J = 2.4 Hz, 1 H, H-9),
.01 (d, J = 8.6 Hz, 1 H, H-6), 7.11–7.29 (m, 5 H, H-2′′,6′′, H-3′′,5′′
(16) Crystal Data for Compound 2b·EtOH
C24H30N O , M = 394.50, monoclinic, space group P2 /c, Z = 4, a =
2
3
1
9.5603(7) Å, b = 18.5619(12) Å, c = 12.7403(11) Å, β =
13
3
–1
H-4′′), 8.86 (s, 1 H, 5-NH) ppm. C NMR (75 MHz, DMSO-d ): δ
=
111.863(3), V = 2098.3(3) Å , μ(MoKα) = 0.082 mm , D = 1.249
6
c
–3
3
27.3 and 28.5 (3-CH ), 31.9 (C-3), 44.0 (C-4), 49.5 (C-2), 53.2
g cm , colorless needle, crystal size of 0.13 × 0.05 × 0.04 mm .
Of a total of 20015 reflections collected, 3827 were indepen-
dent (Rint = 0.0548). Final R1 = 0.0455 [I > 2σ(I)] and wR2 =
0.1092 (all data). Data completeness to θ = 25.24°, 99.6%. CCDC
1531504 contains the supplementary crystallographic data for
this paper. The data can be obtained free of charge from The
3
(C-11), 110.3 (C-11a), 119.0 and 119.1 (C-7, C-9), 121.6 (C-6),
126.0 and 126.2 (C-2′′,6′′, C-8), 127.3 (C-4′′), 128.73 and 128.74
(C-3′′,5′′, C-2′), 129.6 (C-5a), 131.8 (C-1′), 136.6 (C-1′′), 140.0 (C-
+
9a), 154.0 (C-4a), 192.2 (C-1) ppm. HRMS (ESI ): m/z calcd for
+
[
C23H23ClN O + H] : 379.1572; found: 379.1586.
2
(13) (Z)-3-[(2-{[3-(2-Hydroxyphenyl)-3-oxoprop-1-en-1-
Cambridge
Crystallographic
Data
Centre
via
yl]amino}phenyl)amino]-5,5-dimethylcyclohex-2-en-1-one
www.ccdc.cam.ac.uk/getstructures..
(5a)
(17) Crystal Data for Compound 3a·5H O
2
C23H24N O (yellow crystals, 0.18 g, 47%, mp 234–235 °C). 1
H
C24H32N O , M = 476.51, triclinic, space group Pī, Z = 2, a =
2
3
2 8
NMR (300 MHz, DMSO-d ): δ = 1.09 (2 s, 6 H, 5-CH ), 2.03 (s, 2
H, H-6), 2.53 (s, 2 H, H-4), 4.46 (s, 1 H, H-2), 6.28 (d, J = 8.0 Hz, 1
H, H-2′′), 6.86–6.94 (m, 2 H, H-5′′′, H-3′′′), 7.14–7.26 (m, 2 H, H-
9.3720(6) Å, b = 11.4969(8) Å, c = 13.0910(9) Å, α = 113.510(2),
6
3
3
β = 90.028(2), γ = 92.865(2), V = 1291.51(15) Å , μ(Mo Kα) =
–
1
–3
0.092 mm , Dc = 1.225 g cm , colorless plate, crystal size of
3
5
′, H-6′), 7.36–7.49 (m, 2 H, H-4′′′, H-4′), 7.71 (d, J = 8.0 Hz, 1 H,
H-3′), 7.90–7.93 (m, 1 H, H-6′′′), 8.10 (dd, J = 12.8, 8.0 Hz, 1 H, H-
′′), 8.74 (s, 1 H, 3-NH), 11.82 (d, J = 12.8 Hz, 1 H, 1′′-NH), 13.12
0.12 × 0.12 × 0.04 mm . Of a total of 26256 reflections collected,
6884 were independent (Rint = 0.0266). Final R1 = 0.0501 [I >
2σ(I)] and wR2 = 0.1459 (all data). Data completeness to θ =
25.24°, 99.7%. CCDC 1531506 contains the supplementary crys-
tallographic data for this paper. The data can be obtained free of
charge from The Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/getstructures.
1
13
(
s, 1 H, 2′′′-OH) ppm. C NMR (75 MHz, DMSO-d ): δ = 28.1 (5-
6
CH ), 32.3 (C-5), 41.6 (C-4), 50.2 (C-6), 93.2 (C-2′′), 96.6 (C-2),
3
1
5
14.9 (C-3′), 117.8 (C-3′′′), 118.9 (C-5′′′), 119.8 (C-1′′′), 124.3 (C-
′), 126.9 (C-1′), 128.6 and 128.8 (C-4′, C-6′), 129.0 (C-6′′′), 134.9
(
1
C-4′′′), 136.1 (C-2′), 146.5 (C-1′′), 161.6 (C-2′′′), 162.3 (C-3),
(18) Maleki, A.; Kamalzare, M. Tetrahedron Lett. 2014, 55, 6931.
(19) Crystal Data for Compound 5a·EtOH
+
93.1 (C-3′′), 195.0 (C-1) ppm. HRMS (ESI ): m/z calcd for
+
[
C
H
N O + H] : 377.1860; found: 377.1871.
C25H30N O , M = 422.51, monoclinic, space group P2 /c, Z = 4, a =
2
1
3
24
2
3
2
4
1
4
(
14) N ,N -Bis{2-[(5,5-dimethyl-3-oxocyclohex-1-en-1-
13.8692(12) Å, b = 15.4961(10) Å, c = 11.3368(12) Å, β =
3
–1
yl)amino]phenyl}fumaramide (6a)
C32H36N O (brown solid, 0.40 g, 73%, mp 219–221 °C). H NMR
113.249(6), V = 2238.6(4) Å , μ(MoKα) = 0.085 mm , D = 1.254
c
1
–3
3
g cm , yellow plate, crystal size of 0.17 × 0.15 × 0.13 mm . Of a
total of 12149 reflections collected, 4011 were independent
(Rint = 0.1114). Final R1 = 0.0764 [I > 2σ(I)] and wR2 = 0.2393 (all
data). Data completeness to θ = 25.24°, 98.3%. CCDC 1531505
contains the supplementary crystallographic data for this
paper. The data can be obtained free of charge from The
4
4
(300 MHz, DMSO-d ): δ = 1.04 (s, 12 H, 5′′-CH ), 2.28 (s, 4 H, H-
6
3
4
7
′′), 2.56 (s, 4 H, H-6′′), 5.36 (s, 2 H, H-2′′), 7.30 (s, 2 H, H-2),
.31–7.35 (m, 4 H, H-3′, H-4′), 7.36–7.49 (m, 2 H, H-5′), 7.84 (d,
1
4
J = 8.0 Hz, 2H, H-6′), 10.41 (s, 2 H, N H), 10.70 (s, 2 H, N H) ppm.
1
3
C NMR (75 MHz, DMSO-d ): δ = 27.7 (5-CH ), 32.6 (C-5′′), 41.3
6
3
(C-6′′), 46.1 (C-4′′), 95.6 (C-2′′), 125.0 (C-6′), 125.9 (C-3′) 127.1
Cambridge
Crystallographic
Data
Centre
via
www.ccdc.cam.ac.uk/getstructures.
©
Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–F