An approach to dihydroisoindolobenzodiazepinones - Three-dimensional molecular frameworks

Article abstract of DOI:10.1016/j.tetlet.2012.12.065

A concise two-step procedure is developed for the preparation of dihydroisoindolobenzodiazepinones, which represent derivatives of three-dimensional molecular frameworks derived from classical privileged structures of medicinal chemistry. The method commences from the readily available starting materials (i.e., 2-formylbenzoic acid, o-phenylenediamine, and various ketones) and enables the synthesis of the title compounds in 58-82% overall yields.

Full text of DOI:10.1016/j.tetlet.2012.12.065

Accepted Manuscript
An approach to dihydroisoindolobenzodiazepinones – three-dimensional mo‐
lecular frameworks
Anatoliy G. Yaremenko, Vyacheslav V. Shelyakin, Dmitriy M. Volochnyuk,
Eduard B. Rusanov, Oleksandr O. Grygorenko
PII:
S0040-4039(12)02218-6
DOI:
http://dx.doi.org/10.1016/j.tetlet.2012.12.065
TETL 42313
Reference:
To appear in:
Tetrahedron Letters
Received Date:
Revised Date:
Accepted Date:
7 October 2012
3 December 2012
13 December 2012
Please cite this article as: Yaremenko, A.G., Shelyakin, V.V., Volochnyuk, D.M., Rusanov, E.B., Grygorenko, O.O.,
An approach to dihydroisoindolobenzodiazepinones – three-dimensional molecular frameworks, Tetrahedron
Letters (2012), doi: http://dx.doi.org/10.1016/j.tetlet.2012.12.065
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An approach to dihydroisoindolobenzodiazepinones –
three-dimensional molecular frameworks
Anatoliy G. Yaremenko, Vyacheslav V. Shelyakin,* Dmitriy M. Volochnyuk, Eduard B. Rusanov,
Oleksandr O. Grygorenko*

Tetrahedron Letters
1
TETRAHEDRON
LETTERS
Pergamon
An approach to dihydroisoindolobenzodiazepinones –
three-dimensional molecular frameworks
Anatoliy G. Yaremenko,a Vyacheslav V. Shelyakin,a,* Dmitriy M. Volochnyuk,a
Eduard B. Rusanov,a Oleksandr O. Grygorenkob,c,*
aInstitute of Organic Chemistry, National Academy of Sciences of Ukraine, Murmanska Street 5, Kyiv 02660, Ukraine
bEnamine Ltd., Alexandra Matrosova Street 23, Kyiv 01103, Ukraine
cKyiv National Taras Shevchenko University, Volodymyrska Street 60, Kyiv 01601, Ukraine
Abstract— A concise two-step procedure is developed for the preparation of dihydroisoindolobenzodiazepinones, which represent
derivatives of three-dimensional molecular frameworks derived from classical privileged structures of medicinal chemistry. The method
commences from the readily available starting materials (i.e. 2-formylbenzoic acid, o-phenylenediamine and various ketones) and enables
the synthesis of the title compounds in 58–82% overall yields. © 2012 Elsevier Science. All rights reserved
O
S
In medicinal chemistry, aromatic heterocyclic compounds
have remained a major source of chemotypes used in drug
discovery. As aromatic heterocyclic systems are widely
recognized for their ability to serve as useful ligands for
more than one type of biological target, many of them were
named ―privileged structures‖.1 Originally Evans et al.
introduced this term for 1,4-benzodiazepines, which are
found in several types of CNS agents and ligands of ion
channel and G-protein coupled receptors (GPCR).2 Recent
trends in drug discovery, however, show an attempt to
move away from flattened aromatic structures to their
saturated counterparts. Increasing saturation seems to
improve the success rate of the compounds transition from
discovery, through clinical testing, to drugs.3
Implementation of this idea to 1,4- and 1,5-benzodiazepine
scaffolds, as well as to their fused analogues gives rise to
three-dimensional molecular frameworks which potentially
might preserve the ―privileged‖ status of their aromatic
precursors. Some of the resulting structures have already
proven their utility in medicinal chemistry, e.g. the
selective 5-HT2C receptor agonist vabicaserin (1), the
reverse transcriptase inhibitor tivirapine (2), the anxiolytics
clobazam (3) and bretazenil (4) and the cholecystokinin B
receptor antagonist 5 (Figure 1).4
N
H
HN
N
N
H
N
O
N
Cl
NH
Cl
vabicaserin (1)
tivirapine (2)
clobazam (3)
O
N
N
H
O
H
N
N
H
N
O
N
O
O
N
OH
O
O
Br
bretazenil (4)
5
Figure 1. Biologically active saturated analogues of benzodiazepines
In our retrosynthetic approach to the target compounds 6,
we split the molecule into three readily available building
blocks: 2-formylbenzoic acid (7), o-phenylenediamine and
ketone 8 (Scheme 1). Recently, an analogous approach was
described involving 1,3-cyclohexanediones or tetronic acid
as the ketone component.6, 7 However, the method was
limited to -dicarbonyl compounds and used microwave
irradiation to activate the reaction components, which
required special laboratory equipment.
Herein, we report an approach to the synthesis of 7,7a-
dihydro-12H-isoindolo[2,1-a][1,5]benzodiazepin-12-one
derivatives 6. To the best of our knowledge, only the fused
benzo-analogue of 6 was reported in the literature prior to
2011;5 it was prepared from 2-(2-anilinophenyl)-3-
hydroxyisoindolin-1-one.
———
Keywords: Condensation; Isoindoles; Benzodiazepines; Three-dimensional heterocycles.
*Corresponding authors. Tel.: +38-044-239-33-15; fax: +38-044-502-48-32; e-mail: gregor@univ.kiev.ua (O. O. G.), shelyakin@ioch.kiev.ua (V. V. S.)

2
Tetrahedron Letters
planar arrangements within each group, namely, C8, C9,
O
C10, C16 (off-the-plane root-mean-square deviation
(RMSD) 0.1054 Å), N2, C10, C15, C16 (off-the-plane
RMSD 0.0120 Å), and N1, C8, C9. The angle between the
first and the second planes is 52.74(22)º, the first and the
third – 42.95(18)º, the second and the third –84.32(24)º.
O
HO
NH2
NH2
O
N
7
N
O
R
R
6
8
In the crystals of 10, the seven-membered ring has a
butterfly-like conformation. Two groups of atoms N1, N2,
C8, C15, C16 and N1, N2, C9, C10 have an almost planar
arrangement with off-the-plane RMSD 0.0315 Å and
0.0385 Å, respectively. The dihedral angle between the
planes formed by above mentioned groups of atoms is
45.24(13). The cyclohexane ring formed by C15 – C20
atoms is also non-planar: whereas C15 – C18 atoms lay in
plane with RMSD 0.0144 Å, C19 and C20 atoms deviate
from this plane by –0.7822(97) Å and –0.2267(98) Å,
respectively. The C15–C16 double bond is slightly twisted
(the twist angle12 is 13.03).
Scheme 1
We used a two-step reaction sequence for the preparation
of 7,7a-dihydro-12H-isoindolo[2,1-a][1,5]benzodiazepin-
12-ones 6. In the first step, acid 7 reacted with ketones 8 to
give isobenzofuran-1(3H)-ones
9 in 75–93% yields
(Scheme 2).8 Cyclization of 9 with o-phenylenediamine led
to the formation of target compounds 6 (76–88%).
NH2
O
O
O
COOH
CHO
R
N
NH2
8
O
O
N
R
7
9
6
R
Yield, %
Ketone
R
7  9
9  6
76
8a
8b
8c
8d
8e
8f
C6H5
90
93
84
75
76
82
4-ClC6H4
88
4-CH3C6H4
73
3-CH3OC6H4
77
3,4,5-(CH3O)3C6H2
4-BrC6H4
81
Figure 2 X-ray crystal structure of the compound 6b (ball-and-stick
representation)
86
Scheme 29, 10
O
NH2
NH2
O
O
O
N
O
O
7
93%
81%
O
N
H
O
10
Scheme 3
Figure 3 X-ray crystal structure of the compound 10 (ball-and-stick
representation)
When dimedone was introduced into the reaction sequence
described above as the ketone compound, the product 10
was obtained in 75% overall yield (Scheme 3). This result
was consistent with the recent report of Li et al.7
A plausible mechanism for the formation of the compounds
6 is given in Scheme 4. First, imine 11 is formed by
nucleophilic attack of the nitrogen atom of o-
phenylenediamine on the ketone moiety of 9.
Intramolecular lactone ring-opening of 11 accompanied by
the simultaneous formation of the seven-membered ring
gives acid 12, which undergoes spontaneous lactamization
to give 6 due to the spatial proximity of the carboxyl group
and nitrogen atom of the benzodiazepine system.
The structures of products 6b and 10 were confirmed
unambiguously by X-ray diffraction studies (Figures 2 and
3),11 as well as by other standard physical methods. In the
crystals of 6b, the seven-membered ring adopts a twisted
boat conformation. The three groups of atoms adopt almost

Tetrahedron Letters
3
NH2
NH2
4. MDL Drug Data Report, Elsevier MDL, version 2011.02 /
32.11, accessed on July 2011.
5. Cul, A.; Daich, A.; Decroix, B.; Sanz, G.; Hijfte, L. Van
Tetrahedron 2004, 60, 11029–11040.
O
O
H2N
O
O
O
N
6. Ukhin, L. Yu.; Belousova, L. V.; Orlova, Zh. I.; Borodkina,
G. S.; Suponitskii, K. Yu.; Shepelenko, E. N. Russ. Chem.
Bull. 2011, 60, 1729–1733.
R
9
R
11
7. (a) Wang, S.-L.; Cheng, C.; Wu, F.-Y.; Jiang, B.; Shi, F.; Tu,
S.-J.; Rajale, T.; Li, G. Tetrahedron 2011, 67, 4485–4493.
(b) Wang, S.-L.; Cheng, C.; Wu, F.-Y.; Li, J.; Jiang, B.; Tu,
S.-J. Chem. Lett. 2011, 40, 834–836.
O
H
N
COOH
N
8. (a) Mali, R. S.; Massey, A. P. Synth. Commun. 1997, 27,
1049–1058. (b) Paradkar, M. V.; Gadre, S. Y.; Pujari, T. A.;
Khandekar, P. P.; Kumbhar, V. B. Synth. Commun. 2005,
35, 471–474. (c) Landge, S. M.; Berryman, M.; Toeroek, B.
Tetrahedron Lett. 2008, 49, 4505–4508. (d) Heravi, M. M.;
Rasmi, V.; Sadjadi, S.; Fotouhi, L.; Sadjadi, S.;
Bamoharram, F. F.; Bakavoli, M. Synth. Commun. 2009,
39, 4109–4116. (e) Gutsche, C. D.; Jason , E. F.; Coffey, R.
S.; Johnson, H. E. J. Am. Chem. Soc. 1958, 80, 5756–5767.
9. General procedure for the synthesis of 9: To a solution of
ketone 8 (0.1 mol) in MeOH (80 mL), KOH (0.2 mol) was
added with stirring. To the clear solution formed,
compound 7 (0.1 mol) was added slowly also with stirring.
The resulting mixture was refluxed for 1 h, then cooled to rt
and acidified with 12 M aq HCl to pH = 3. The resulting
precipitate was filtered, washed with MeOH, dried, and
recrystallized from AcOH to give 9. 3-(2-Oxo-2-
phenylethyl)-isobenzofuran-1(3H)-one (9a): yield 90%.
White crystals. Mp 143–144 C (AcOH). 1H NMR (DMSO-
d6, 400 MHz)  3.73 (dd, J = 18.0 Hz and 7.9 Hz, 1H), 3.87
(dd, J = 18.0 Hz and 3.9 Hz, 1H), 6.14 (dd, J = 7.9 Hz and
3.9 Hz, 1H), 7.55 (t, J = 7.4 Hz, 2H), 7.63 (t, J = 7.4 Hz,
1H), 7.68 (t, J = 7.4 Hz, 1H), 7.76 (d, J = 7.4 Hz, 1H), 7.80
(t, J = 7.4 Hz, 1H), 7.87 (d, J = 7.4 Hz, 1H), 8.02 (d,
J = 7.4 Hz, 2H). 13C NMR (DMSO-d6, 125.74 MHz)  43.3,
77.6, 123.4, 125.4, 126.0, 128.6, 129.2, 129.7, 134.0, 134.7,
136.7, 150.4, 170.2, 196.8. MS (APCI) m/z 251 (M–H+).
Anal. Calcd for C16H12O3 C 76.18; H 4.79. Found C 76.30;
H 4.82.
10. General procedure for the synthesis of 6: To a suspension
of 9 (10 mmol) and o-phenylenediamine (1.08 g, 10 mmol)
in toluene (50 mL), p-toluenesulfonic acid (0.30 g,
1.7 mmol) was added. The resulting mixture was refluxed
using a Dean – Stark apparatus for 8 – 10 h, then cooled,
and evaporated in vacuo. The residue was recrystallized
from MeCN to give 6. 6-Phenyl-7,7a-dihydro-12H-
isoindolo[2,1-a][1,5]benzodiazepin-12-one (6a): yield 76%.
Yellowish crystals. Mp 232–234 °C (MeCN). 1H NMR
(CDCl3, 500 MHz)  3.27 (dd, J = 14.5 Hz and 7.3 Hz, 1H),
3.85 (d, J = 14.5 Hz, 1H), 6.76 (d, J = 7.3 Hz, 1H), 7.28–
7.41 (m, 5H), 7.45–7.55 (m, 3H), 7.64 (d, J = 7.6 Hz, 1H),
7.67 (t, J = 7.6 Hz, 1H), 7.76 (d, J = 7.6 Hz, 2H), 7.97 (d,
J = 7.6 Hz, 1H). 13C NMR (DMSO-d6, 125.74 MHz)  32.5,
70.7, 123.5, 123.9, 126.0, 126.3, 127.61, 127.64, 128.6,
128.7, 128.8, 129.3, 129.6, 130.1, 132.8, 138.1, 144.7,
147.0, 167.5, 168.1. MS (APCI) m/z 323 (M–H+). Anal.
Calcd. for C22H16N2O C 81.47; H 4.97; N 8.64. Found: C
81.3; H 4.75; N 8.53.
N
N
R
R
6
12
Scheme 4
In conclusion, a two-step reaction of 2-formylbenzoic acid
with various ketones and then with o-phenylenediamine
gives derivatives of dihydroisoindolobenzodiazepinones in
58–82% overall yields. The molecules of the target
compounds show three-dimensional and non-flattened
structures in crystals, mainly due to pronounced non-
planarity of the partially saturated seven-membered rings.
Acknowledgements
The authors thank Professor Andrey A. Tolmachev for
great encouragement and support.
Supplementary data
General experimental details, description of X-Ray
diffraction studies, and characterization data for the
compounds 9b–f and 6b–f.
References
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11. The crystals of 6b and 10 were obtained by slow
evaporation from acetonitrile. Crystal data for 6b:
C22H15ClN2O, M = 358.81, yellowish crystals, monoclinic,
а= 9.570(3), b = 14.650(3), c = 13.202(3) Å,  = 107.25(2),
V = 1767.6(8) Å3, Z = 4, dcalc = 1.348 g·cm-3, space group
P 21/n,  = 0.229 mm-1, F(000) = 744, crystal size ca. 0.12
 0.45  0.45 mm. Crystal data for 10: C22H20N2O2,
MW = 344.4, colourless crystals, monoclinic, а= 6.837(3),

4
Tetrahedron Letters
b = 11.682(4), c = 11.604(2) Å,  = 105.98(3)V = 890.9(5)
Å3, Z = 2, dcalc = 1.284 g·cm-3, space group P n,  = 0.083
mm-1, F(000) = 364, crystal size ca. 0.15  0.23  0.47 mm.
The structures were solved by direct methods and refined
by full-matrix least-squares technique in the anisotropic
approximation for non-hydrogen atoms using SHELXS97
and SHELXL97 programs.13 Full crystallographic
parameters have been deposited at Cambridge
Crystallographic Data Centre (CCDC).14 Any request to the
CCDC for these materials should quote the full literature
citation and reference number CCDC 901483 (6b) and
901482 (10).
12. Kirby, A. J.; Komarov, I. V.; Feeder, N. J. Chem. Soc.,
Perkin Trans. 2, 2001, 522–529.
13. Sheldrick, G. M. Acta Cryst. 2008, A64, 112–122.
14. Cambridge Crystallographic Data Centre, 11 Union Road,
Cambridge,
CB2
1EZ,
UK
(E-mail:
deposit@ccdc.cam.ac.uk; fax: +44 1223 336033).