Synthesis, structure, and properties of new spirooxindolodibenzodiazepine derivatives

Article abstract of DOI:10.1007/s11172-013-0203-1

An acid-catalyzed reaction of 3-(2-aminophenylamino)-5,5- dimethylcyclohexen-1-one with isatines leads to the formation of the earlier undescribed 3,3-dimethyl-2,3,4,5,10,11- hexahydrospiro[1H-dibenzo[b,e][1,4] diazepine-11,3-2H-indole]-1,2-dione derivati

Full text of DOI:10.1007/s11172-013-0203-1

Russian Chemical Bulletin, International Edition, Vol. 62, No. 6, pp. 1409—1416, June, 2013
1409
Synthesis, structure, and properties
of new spirooxindolodibenzodiazepine derivatives
Zh. I. Orlova,a† L. Yu. Ukhin,a K. Yu. Suponitskii,b E. N. Shepelenko,c
L. V. Belousova,a G. S. Borodkin,a and O. S. Popovaa
aResearch Institute of Physical and Organic Chemistry, Southern Federal University,
194/2 prosp. Stachki, 344090 Rostov on Don, Russian Federation.
Fax: +7 (863) 243 4700. Eꢀmail: may@ipoc.sfedu.ru
bA. N. Nesmeyanov Institute of Organoelement Compounds, Russian Academy of Sciences,
28 ul. Vavilova, 119991 Moscow, Russian Federation.
Fax: +7 (499) 135 5085. Eꢀmail: kira@xrlab.ineos.ac.ru
cSouthern Research Center, Russian Academy of Sciences,
41 ul. Chekhova, 344006 Rostov on Don, Russian Federation.
Eꢀmail: dubon@ipoc.sfedu.ru
An acidꢀcatalyzed reaction of 3ꢀ(2ꢀaminophenylamino)ꢀ5,5ꢀdimethylcyclohexenꢀ1ꢀone
with isatines leads to the formation of the earlier undescribed 3,3ꢀdimethylꢀ2,3,4,5,10,11ꢀ
hexahydrospiro[1Hꢀdibenzo[b,e][1,4]diazepineꢀ11,3´ꢀ2Hꢀindole]ꢀ1,2´ꢀdione derivatives (6).
Spiranes 6 upon heating undergo autoꢀredox rearrangement with disintegration to 3,3ꢀdimethꢀ
ylꢀ1,2,3,4ꢀtetrahydrophenazine and the corresponding oxindole. Crystals of four derivatives of
compound 6 were studied by Xꢀray diffraction method.
Key words: 3ꢀ(2ꢀaminophenylamino)ꢀ5,5ꢀdimethylcyclohexenꢀ1ꢀone, isatines, acid catalꢀ
ysis, spiroꢀoxindolodibenzodiazepine derivatives, Xꢀray diffraction analysis.
An ability to the formation of spiro compounds at poꢀ
sition C(3) in the reactions with nucleophiles and diꢀ
polarophiles is a characteristic feature of isatines, which is
reflected in the reviews.1—3 The constantly growing interꢀ
est of chemists to isatines is explained by their synthetic
versatility and biological activity frequently exhibited by
compounds derived from them. In the majority of deꢀ
scribed spirooxindoles, the isatine fragment is spirocoupled
with the fiveꢀ or sixꢀmembered rings.1—3
Only several examples of the oxindole fragment spiroꢀ
coupled with the sevenꢀmembered heterocycles are known.
The compounds structurally the closest to those described
by us below, viz., spirooxindolobenzodiazepines 1, were
obtained by the reaction of the products of condensaꢀ
tion of isatine and 3ꢀacetylcoumarins with oꢀphenyleneꢀ
diamine.4 Compounds 1 were tested in mice as potential
tranquilizing agents, as well as in vitro on the antibacterial
activity.4
The work5 described a stereocontrolled synthesis of
cisꢀ and transꢀspirooxindolooxepenes 2 by the [5+2]ꢀcycloꢀ
addition of chiral crotylsilanes bearing primary alcohol
group and isatine dimethyl ketal. A oneꢀpot threeꢀcompoꢀ
nent synthesis leading to spiroindolineꢀ3,4´ꢀpyrazoloꢀ
[3,4ꢀe][1,4]thiazepinediones 3 was reported recently.6
†
Deceased.
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 6, pp. 1409—1416, June, 2013.
1066ꢀ5285/13/6206ꢀ1409 © 2013 Springer Science+Business Media, Inc.

1410
Russ.Chem.Bull., Int.Ed., Vol. 62, No. 6, June, 2013
Orlova et al.
In the present work, we suggest a oneꢀpot synthesis of
the earlier unknown spirooxindolodibenzodiazepine deꢀ
rivatives. In continuation of our studies on the reactions
of 3ꢀ(2ꢀaminophenylamino)ꢀ5,5ꢀdimethylcyclohexenꢀ1ꢀ
one (4),7—9 we found that its heating in EtOH with the
equivalent amounts of isatines 5a—h in the presence of
a catalytic amount of CF3COOH led to the condensation
to spirooxindolobenzodiazepines 6a—h (Scheme 1).
is poorly soluble in nitromethane on reflux and does not
form stable solvate with it. Most of spiranes 6 form with
alcohols strong solvates with a definite stoichiometry. In
1
the work, we report the H NMR spectroscopic and eleꢀ
mental analysis data for such solvates of compounds 6f
and 6h. At the same time, compound 6g recrystallized
from propanol does not contain the solvent molecule.
Compounds 6 are stable in acidic media. Thus, the
unchanged starting compound was isolated with water
from the solution of 6a in CF3COOH standing for 1 day at
room temperature. Compound 6a remained unchanged
after reflux for several hours in EtOH in the presence of
a catalytic amount of CF3COOH.
Scheme 1
The stoichiometry of compounds 6a,c—f was conꢀ
firmed by their mass spectra. Compound 6g does not form
molecular ion, however, the fragmentation confirms the
suggested structure (a Finnigan MATINCOS 50 inꢀ
strument, direct injection of the sample). Attempted reꢀ
cording of the mass spectrum of 6g on a Shimadzu
GCMSꢀQP2010 SE GLCꢀMS spectrometer with the inꢀ
jection of the sample through the chromatograph with
a Supelco SLBꢀ5ms column with the injector temperaꢀ
tures of 250—280 C led to the unexpected result. The
compound decomposed in the injector to give two comꢀ
pounds with the molecular weights of 226 and 282, that
corresponded to the phenazine 7 and oxindole 8g derivaꢀ
tives, respectively (Scheme 2).
The fragmentation agrees with these structures. It reꢀ
sulted from the intramolecular oxidationꢀreduction proꢀ
cess with the transfer of two hydrogen atoms of the diꢀ
azepine fragment to the oxindole one, which was accomꢀ
panied by the rearrangement of the sevenꢀmembered diꢀ
azepine ring to the sixꢀmembered one and the disintegraꢀ
tion of spirane 6g (molecular weight 508) to 3,3ꢀdimethꢀ
ylꢀ1,2,3,4ꢀtetrahydrophenazinꢀ1ꢀone (7) and 5ꢀ(morꢀ
pholinosulfonyl)oxindole (8g).
It can be suggested that the enamine form B of comꢀ
pound 6g undergoes the rearrangement, in which both
hydrogen atoms to be transferred are in the close proximiꢀ
ty to the acceptor, i.e., the electrophilic spirane carbon
atom (see Scheme 2).
Reagents and conditions: EtOH, CF3COOH, , –H2O.
R = R´ = H (a); R = H, R´ = Me (b); MeO (c); F (d); Cl (e); Br (f);
(g); R = CH2OH, R´ = H (h)
The formation of spiranes 6 proceeded rapidly and in
high yields. The IR and 1H NMR spectroscopic data
showed that in the samples obtained by precipitation with
water after the reaction reached completion, the target
products are the major components. For the reaction to
reach completion, it was enough to shortly reflux the comꢀ
ponents in EtOH in the presence of a catalytic amount of
CF3COOH. However, the time of crystallization varied
within a wide range. It was accelerated by the addition of
seeds and the trituration with a glass rod after cooling the
reaction mixture. Compounds 6 have the tendency to form
solvates, and the rapid crystallization can indicate the preꢀ
cipitation of a solvate with the solvent. The behavior of
compounds 6 with solvents is so individual, that it is imꢀ
possible to formulate any general principles. For example,
compounds 6b and 6e fairly well crystallize from nitroꢀ
methane, to form solvates with one or two CH3NO2 molꢀ
ecules, respectively. In the solvate 6a with acetonitrile, the
ratio compound : solvent = 1 : 2.375, whereas in the solꢀ
vate 6h with nitromethane, it is 1 : 1.36. These ratios were
found in the process of the Xꢀray diffraction studies. In
contrast to the aforementioned substances, compound 6c
The reaction has proved to be of general character for
compounds 6. Other spiranes 6 also underwent similar
thermal autoꢀredox rearrangement with disintegration to
phenazine 7 and the corresponding oxindole 8 in the inꢀ
strument injector at t > 250 C.
R = H, R´ = H (a), Me (b); MeO (c); F (d); Cl (e); Br (f);
(g); R = CH2OH, R´ = H (h)

Derivatives of spirooxindolodibenzodiazepine
Russ.Chem.Bull., Int.Ed., Vol. 62, No. 6, June, 2013
1411
Scheme 2
Scheme 3
Taking spirane 6a as an example, the reaction was
carried out on a preparative scale. Phenazine 7 was isolatꢀ
ed in 63% yield, whereas the presence of oxindole 8a in the
residue was confirmed by mass spectrometry (Scheme 3).
The molecular weight of compound 6h is 389, howevꢀ
er, the peak of 371 units corresponds to the highest weight
in its mass spectrum. This can be explained by the comꢀ
plete decomposition with elimination of H2O molecule
caused by the electron impact. The structure of 6h was
unambiguously confirmed by Xꢀray diffraction analysis.
All four structurally characterized compounds
(6a,d,e,h) contain the solvent molecules of acetonitrile or
nitromethane, some of which are rather strongly disorꢀ
dered. The symmetrically independent part of the unit cell
in the structures 6a and 6d contains two molecules (A and
A´, respectively). All the molecules have very close strucꢀ
tures (Fig. 1).
The indolinone bicycle is bonded to the tricyclic diꢀ
benzodiazepine fragment through the spiroꢀatom C(7).
The central diazepine ring is characterized by the distortꢀ
ed and flattened boat conformation, the cyclohexenone
fragment has the conformation the intermediate between
sofa and chair. The major differences in the structures of
the molecules consist in the different degrees of distortion
of the conformations indicated. In all the molecules conꢀ
sidered, atom N(2) is pyramidal in shape, whereas atom
N(3), on the contrary, is planar (Table 1), apparently,
because of its involvement in the conjugation in the fragꢀ
ment N(3)—C(15)=C(16)—C(17)=O(2), which is charꢀ
acterized by the flattened structure (the torsional angles
deviate from 180 by no more than 12).
bicycle (R = H, Cl, F, respectively) and having different
composition of the symmetrically independent part of the
unit cell, form similar hydrogenꢀbonded layers in the crystal
structure (Fig. 2, Table 2). The molecules are bound to diꢀ
mers the strongest due to the interactions N(1)—H(1)...O(2),
which form layers due to the interactions N(3)—H(3)...O(1).
The dimers are bound between each other by the second
order axis. In the structure 6e, the molecules in the dimer
are bound by the center of symmetry, whereas in the strucꢀ
tures 6a and 6d, the dimer is formed by two symmetrically
independent molecules A and A´, which are pseudocenꢀ
trosymmetric. Note that the group N(2)—H(2) either is
Table 1. Geometry of nitrogenꢀcontaining
groups in compounds 6a, 6e, 6d, and 6h
a
b
Compound


N(3)
N(2)
deg
6a (A)
6a (A´)
6e
6d (A)
6d (A´)
6h
329
329
334
335
332
337
360
360
359
360
360
359
Analysis of crystal packing of compounds under conꢀ
sideration seems to be of the most interest. The experiꢀ
mental data obtained show that compounds 6a, 6e, and
6d, though differing in the substituent in the indolinone
a The sum of angles at atom N(2).
b The sum of angles at atom N(3).

1412
Russ.Chem.Bull., Int.Ed., Vol. 62, No. 6, June, 2013
a
Orlova et al.
b
c
C(21)
C(20)
C(13)
C(10)
C(13)
C(21)
C(19)
C(21´)
C(20)
C(13´)
C(14)
C(20´)
C(15)
C(14)
C(15)
N(3)
C(14´)
C(15´)
N(3´)
N(2´)
C(12)
C(19)
C(22)
N(3)
C(12)
C(11)
C(12´)
C(19´)
C(18´)
C(22)
C(18)
C(10´)
C(10)
N(2)
C(16)
N(2)
C(16)
C(7)
C(18)
C(11)
C(11´)
C(9)
C(7´)
C(16´)
C(9)
C(9´)
C(7)
O(1)
N(1)
C(17´)
O(2´)
C(17)
C(17)
O(2)
C(1´)
C(1)
Cl(1)
C(1)
C(2)
O(1´)
C(6´)
N(1´)
C(6)
O(1)
C(6)
O(2)
C(8)
C(2´)
C(5´)
N(1)
C(5)
C(4)
C(3´)
C(2)
C(3)
C(4´)
C(3)
C(5)
C(4)
6a (A´)
6a (A)
6e
d
e
f
C(21)
C(13)
C(20)
C(22´)
C(21´)
C(22)
C(20)
C(17)
C(21)
C(14)
C(13)
N(3´)
N(3)
C(13´)
C(12)
C(14´)
C(14)
N(3)
C(19)
C(16)
C(19´)
C(18´)
C(15)
C(22)
C(18)
C(20´)
C(12)
C(11)
C(19)
C(18)
C(12´)
C(15´)
N(2´)
C(10)
C(15)
N(2)
C(10´)
C(11´)
C(10)
N(2)
C(16´)
C(11)
C(9)
C(16)
C(9)
C(9´)
C(17)
O(2)
C(7)
O(1)
C(17´)
O(2´)
C(7´)
C(7)
C(8)
C(1)
O(2)
O(1´)
C(6´)
C(8´)
O(1)
C(6)
N(1)
C(1´)
C(2´)
C(1)
C(2)
C(6)
N(1)
C(23)
C(5)
C(2)
C(3)
N(1´)
F(1)
C(4)
C(5´)
C(4´)
C(5)
C(4)
C(3´)
C(3)
O(3)
6d (A)
6d (A´)
6h
Fig. 1. General view of molecules 6a (a, b), 6e (c), 6d (d, e), 6h (f) in representation of atoms by the ellipsoids of atomic displacements
with 50% probability. For compounds 6a and 6d, the structures of two independent molecules A (a, c) and A´ (b, d) are given.
not involved in the Hꢀbonding or forms a weak Hꢀbond
Table 2. Geometry of hydrogen bonds in the crystal structures of
with the solvent molecules. To sum up, in compounds 6a, 6e,
6d, the interactions of groups N(1)—H(1) and N(3)—H(3)
with the carbonyl oxygen atoms O(1) and O(2) lead to the
formation of the stable enough motif, despite the fact that
such a mutual arrangement of molecules leads to the forꢀ
mation of cavities, which, in turn, explains the presence of
solvent molecules in the structures.
The structure 6h differs from the molecules considered
above by the replacement of the group N(1)—H(1) with
N(1)—CH2—OH, that leads to a dramatic change in the
system of hydrogen bonds in the crystal structure, despite
the similarity of the molecular structures, as it was menꢀ
tioned above. In this case, the group N(2)—H(2) is not
practically involved in the Hꢀbonding of compounds 6a,
6e, and 6d. In the case of 6h, the group N(1)—CH2—OH
is simultaneously involved as both the proton donor and
the proton acceptor. The molecules are combined in the
centrosymmetric dimers by the bonds N(2)—H(2)...O(1)
and O(3)—H(1)...N(2), the dimers form chains due to the
bonds N(3)—H(3)...O(3), whereas O(2) atom of the carbꢀ
onyl group is not involved in the system of Hꢀbonds (Fig. 3).
To sum up, the stable enough motif of the crystal packꢀ
ing formed by the strongest protonꢀdonor and protonꢀ
6a, 6e, 6d, and 6h
Comꢀ
pound
Hꢀbond
d(H...O) d(N...O) N—H...O
/deg
Å
6a
N(1)—H(1)...O(2´)
N(2)—H(2)...N(1S)
N(3)—H(3)...O(1)a
N(1´)—H(1´)...O(2)
1.95
2.22
1.97
1.91
2.826(3)
3.109(4)
2.851(3)
2.799(3)
2.848(3)
2.860(2)
3.288(2)
2.971(2)
2.839(2)
2.864(2)
2.881(2)
2.843(2)
2.807(2)
2.985(2)
2.950(2)
165
173
167
170
166
175
170
158
170
168
171
161
163
168
172
N(3´)—H(3´)...O(1´)b 1.97
6e
6d
N(1)—H(1)...O(2´)c
N(2)—H(2)...O(2S)
N(3)—H(3)...O(1)d
N(1)—H(1)...O(2´)
N(3)—H(3)...O(1)e
N(1´)—H(1´)...O(2)
1.96
2.40
2.12
1.95
1.98
1.99
N(3´)—H(3´)...O(1´)f 1.98
6h
O(3)—H(1)...N(2)g
N(2)—H(2)...O(1)g
N(3)—H(3)...O(3)h
1.98
2.10
2.06
a 1.5 – x, y – 0.5, 0.5 – z. b 0.5 – x, y + 0.5, 0.5 – z.
c 1 – x, 2 – y, –z. d 1.5 – x, y – 0.5, 0.5 – z.
e 1.5 – x, y – 0.5, 0.5 – z. f 0.5 – x, y + 0.5, 0.5 – z.
g 2 – x, –y, 2 – z. h x – 1, y, z.

Derivatives of spirooxindolodibenzodiazepine
Russ.Chem.Bull., Int.Ed., Vol. 62, No. 6, June, 2013
1413
O(1B)
N(3)
O(1B)
N(3)
O(2)
O(2)
N(1´)
N(1)
O(1)
N(1D)
N(3A)
O(1)
N(3A)
N(3C)
N(2D)
O(1´)
N(1)
N(3´C)
O(2´)
O(2D)
6a
6e
O(1B)
N(3)
O(2)
N(3A)
O(1´)
N(1´)
N(1)
O(2´)
6d
Fig. 2. Fragments of Hꢀbonded layers in the crystal structures of compounds 6a, 6e, and 6d.
O(3A)
O(1A)
N(2A)
N(2)
O(1)
O(3)
O(3B)
Fig. 3. Fragment of the Hꢀbonded chain in the crystal structure of 6h.
acceptor groups in compounds 6a, 6e, and 6d completely
changes upon the replacement of the fragment NH with
the fragment N—CH2OH, and in this case, the strongest
donors of protons (the N(3)—H(3) group and the hydroxy
group) form hydrogen bonds with relatively weak accepꢀ
tors of protons (atoms N(2), O(3)), whereas one of the

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Russ.Chem.Bull., Int.Ed., Vol. 62, No. 6, June, 2013
Orlova et al.
3,3,5´ꢀTrimethylꢀ2,3,4,5,10,11ꢀhexahydrospiro[1Hꢀdibenzoꢀ
[b,e][1,4]diazepineꢀ11,3´ꢀ2Hꢀindole]ꢀ1,2´ꢀdione (6b). A mixꢀ
ture of 4 (0.23 g, 1 mmol) and 5b (0.16 g, 1 mmol) was refluxed
in EtOH (4 mL) until dissolution, 1 drop of CF3COOH was
added. The mixture was heated to the boiling point, allowed to
stand for 1 h, and poured into cold water (20 mL). A precipitate
formed was filtered off, washed with H2O, and dried. The yield
of crude product was 0.33 g (88%); m.p. 197—200 C (from
MeCN). The product was recrystallized from MeCN and dried
at 100 C. Found (%): C, 73.61; H, 6.49. C23H23N3O2. Calcuꢀ
lated (%): C, 73.97; H, 6.21. IR, /cm–1: 3305, 3234, 3148 (NH);
1686 (CO); 1609, 1583, 1535 (arom.). 1H NMR (DMSOꢀd6),
: 1.04, 1.15 (both s, 6 H, CH3); 1.88, 2.03 (both d, 2 H, CH2,
J = 16.2 Hz); 2.55, 2.62 (both d, 2 H, CH2, J = 16.5 Hz); 5.07
(s, 1 H, NH); 6.01 (s, 1 H, CHarom); 6.50—6.95 (m, 5 H, CHarom);
7.07 (d, 1 H, CHarom, J = 8.1 Hz); 8.87 (s, 1 H, NH); 9.96
(s, 1 H, NH). At 280 C, disintegrates to two compounds, viz.,
phenazine 7 and oxindole 8b, m/z 147 [M]+.
most efficient proton acceptors (atom O(2)) is not inꢀ
volved in the Hꢀbonding.
In conclusion, note that the circle of representatives of
this new heterocyclic spiro system can be considerably
extended by the involvement in the synthesis of analogs of
compound 4. The latter can be obtained from the Cꢀsubꢀ
stituted derivatives of oꢀphenylenediamine, as well as from
other aromatic and heteroaromatic diamines in the reacꢀ
tions with dimedone and other cyclic ꢀdiketones. The
use of such complex, functionally substituted spiranes 6 in
the thermal rearrangement described in the present work
with the purpose of preparative synthesis of its products
should not be excluded either.
Experimental
IR spectra were recorded on a Varian Excalibur 3100 FTꢀIR
spectrometer using FTIR method. 1H NMR spectra were recordꢀ
ed on a Varian UNITYꢀ300 spectrometer. Mass spectra were
obtained on a Finnigan MAT INCOS 50 instrument with direct
injection of the samples (EI, ionization energy 70 eV).
Experiments on the thermal rearrangement of compounds 6
were carried out on a Shimadzu GCMSꢀQP2010 SE GLCꢀMS
spectrometer with injection of the samples through a Supꢀ
elco SLBꢀ5 ms chromatographic column, injector temperaꢀ
ture 280 C.
5´ꢀMethoxyꢀ3,3ꢀdimethylꢀ2,3,4,5,10,11ꢀhexahydrospiroꢀ
[1Hꢀdibenzo[b,e][1,4]diazepineꢀ11,3´ꢀ2Hꢀindole]ꢀ1,2´ꢀdione
(6c) was obtained from 4 (0.23 g, 1 mmol) and 5c (0.18 g, 1 mmol)
in EtOH (4 mL) with one drop of CF3COOH. After 2 h,
a plentiful light precipitate was formed from a dark solution,
which was filtered off, washed with cold EtOH and light petroꢀ
leum, and dried at 100 C. The yield was 0.254 g (65%). Colorless
compound, poorly soluble in boiling MeNO2; m.p. 238—241 C
(from MeNO2). Found (%): C, 70.75; H, 6.23. C23H23N3O3.
Calculated (%): C, 70.93; H, 5.95. IR, /cm–1: 3298, 3249, 3200
(NH); 1713 (CO); 1604, 1583, 1536, 1491 (arom.). 1H NMR
(DMSOꢀd6), : 0.96, 1.08 (both s, 6 H, CH3); 1.88, 2.01 (both d,
2 H, CH2, J = 16.2 Hz); 2.56, 2.62 (both d, 2 H, CH2, J = 16.8 Hz);
3.40 (s, 3 H, OCH3); 5.42 (s, 1 H, NH); 5.76 (d, 1 H, C(1)H,
J = 2.4 Hz); 6.56 (dd, 1 H, C(3)H, 3J = 8.4 Hz, 4J = 2.4 Hz);
6.63 (m, 2 H, CHarom); 6.74 (t, 1 H, CHarom, J = 7.5 Hz); 6.84
(t, 1 H, CHarom, J = 7.5 Hz); 7.11 (d, 1 H, CHarom, J = 7.8 Hz);
9.02 (s, 1 H, NH); 9.97 (s, 1 H, NH). MS, m/z: 389 [M]+. At
280 C, disintegrates to two compounds, viz., phenazine 7 and
oxindole 8c, m/z 163 [M]+.
Compound 4 was synthesized according to the procedure
described in the work.10 Commercial samples of isatines 5a—f
were used in the syntheses. References for the preparation of
isatines 5g,h are given in the descriptions of the experiments.
Synthesis of spirooxindolodibenzodiazepines (general proceꢀ
dure). An equimolar mixture of compounds 4 and 5 (1—2 mmol
of each) was dissolved in EtOH upon reflux, followed by the
addition of several drops of CF3COOH, then the mixture was
allowed to stand at room temperature for several hours. The
reaction proceeded rapidly. In some cases, crystallization began
within first 10 min, in others only after several hours of standing.
A reaction product could be precipitated with water.
3,3ꢀDimethylꢀ2,3,4,5,10,11ꢀhexahydrospiro[1Hꢀdibenzoꢀ
[b,e][1,4]diazepineꢀ11,3´ꢀ2Hꢀindole]ꢀ1,2´ꢀdione (6a). A mixꢀ
ture of 4 (0.46 g, 2 mmol) and 5a (0.3 g, 2 mmol) in EtOH
(10 mL) with two drops of CF3COOH was heated to boiling and
allowed to stand for 3 h. Trituration with a glass rod was used,
after 2 h the mixture was placed on ice and after another 1 h
filtered, washed with cold EtOH and light petroleum, and dried
at 100 C. The yield of 6a was 0.36 g (50%). Colorless compound
with m.p. 203—207 C (from EtOH). Additional amount of the
product (0.29 g) was precipitated from the filtrate with water,
which had practically identical IR spectrum. The structure was
confirmed by Xꢀray crystallography. IR, /cm–1: 3298, 3237,
3188 (NH), 1712 (CO); 1616, 1599, 1518, 1506 (arom.). 1H NMR
(DMSOꢀd6), : 1.02, 1.15 (both s, 6 H, CH3); 1.88, 2.06 (both d,
2 H, CH2, J = 16.2 Hz); 2.54, 2.64 (both d, 2 H, CH2, J = 16.2 Hz);
5.14 (s, 1 H, NH); 6.21 (d, 1 H, CHarom, J = 7.2 Hz); 6.50 (t, 1 H,
CHarom, J = 7.5 Hz); 6.62—6.84 (m, 3 H, CHarom); 6.96 (t, 1 H,
CHarom, J = 7.5 Hz); 7.08 (d, 1 H, CHarom, J = 7.8 Hz); 8.88
(s, 1 H, NH); 10.07 (s, 1 H, NH). MS, m/z: 359 [M]+. At 280 C,
compound 6a disintegrates to two compounds, viz., phenazine 7
and oxindole 8a, m/z 133 [M]+.
5´ꢀFluoroꢀ3,3ꢀdimethylꢀ2,3,4,5,10,11ꢀhexahydrospiro[1Hꢀ
dibenzo[b,e][1,4]diazepineꢀ11,3´ꢀ2Hꢀindole]ꢀ1,2´ꢀdione (6d)
was obtained from 4 (0.23 g, 1 mmol) and 5d (0.165 g, 1 mmol)
in EtOH (4 mL) with one drop of CF3COOH. After 2 h, the
mixture was cooled on ice, triturating with a rod. A precipitate
formed was filtered off, washed with light petroleum, and
dried. The yield was 0.244 g (65%). Colorless compound, m.p.
200—205 C. Crystallized from CH3NO2 as a solvate with
CH3NO2, whose structure was confirmed by Xꢀray crysꢀ
tallography. IR, /cm–1: 3293, 3242, 3197 (NH); 1711 (CO);
1627, 1601, 1587, 1509, 1491, 1482 (arom.). 1H NMR of the
solvate 6d with CH3NO2 (DMSOꢀd6), : 0.96, 1.08 (both s, 6 H,
CH3); 1.89, 2.00 (both d, 2 H, CH2, J = 15.9 Hz); 2.59 (s, 2 H,
CH2); 4.41 (s, 3 H, CH3NO2); 5.54 (s, 1 H, NH); 5.89 (dd,
1 H, CHarom,
3J = 8.1 Hz, 4J = 2.4 Hz); 6.50—7.00 (m, 5 H,
CHarom); 7.12 (d, 1 H, CHarom, J = 7.8 Hz); 9.08 (s, 1 H, NH);
10.17 (s, 1 H, NH). MS, m/z: 377 [M]+. At 280 C, disinteꢀ
grates to two compounds, viz., phenazine 7 and oxindole 8d,
m/z 151 [M]+.
5´ꢀChloroꢀ3,3ꢀdimethylꢀ2,3,4,5,10,11ꢀhexahydrospiro[1Hꢀ
dibenzo[b,e][1,4]diazepineꢀ11,3´ꢀ2Hꢀindole]ꢀ1,2´ꢀdione (6e)
was obtained from 4 (0.23 g, 1 mmol) and 5e (0.18 g, 1 mmol) in
EtOH (8 mL) with one drop of CF3COOH. After 2 h, the reacꢀ

Derivatives of spirooxindolodibenzodiazepine
Russ.Chem.Bull., Int.Ed., Vol. 62, No. 6, June, 2013
1415
tion mixture with a precipitate was cooled on ice. The precipiꢀ
tate was filtered off, washed with cold EtOH and light petroꢀ
leum, and dried. The yield was 0.33 g (84%). Colorless comꢀ
pound, m.p. 207—210 C. Crystallized from CH3NO2 as a solꢀ
vate with CH3NO2, whose structure was confirmed by Xꢀray
crystallography. IR, /cm–1: 3304, 3240, 3150 (NH); 1717 (CO);
1604, 1583, 1534, 1506, 1493, 1475 (arom.). 1H NMR (DMSOꢀd6),
: 0.97, 1.08 (both s, 6 H, CH3); 1.91, 2.00 (both d, 2 H, CH2,
J = 16.0 Hz); 2.60 (s, 2 H, CH2); 5.57 (s, 1 H, NH); 6.08 (d, 1 H,
CHarom, J = 2.4 Hz); 6.65 (dd, 1 H, CHarom
4J = 1.5 Hz); 6.74 (m, 2 H, CHarom); 6.87 (tt, 1 H, CHarom
,
3J = 7.8 Hz,
,
3J = 7.5 Hz, J = 1.5 Hz); 7.05 (dd, 1 H, CHarom, J = 8.1 Hz,
4J = 2.1 Hz), 7.14 (dd, 1 H, CHarom, 3J = 8.1 Hz, 4J = 1.5 Hz);
9.09 (s, 1 H, NH); 10.29 (s, 1 H, NH). MS, m/z: 393 [M]+. At
280 C, disintegrates to two compounds, viz., phenazine 7 and
oxindole 8e, m/z 167 [M]+.
4
3
1´ꢀHydroxymethylꢀ3,3ꢀdimethylꢀ2,3,4,5,10,11ꢀhexahydroꢀ
spiro[1Hꢀdibenzo[b,e][1,4]diazepineꢀ11,3´ꢀ2Hꢀindole]ꢀ1,2´ꢀdiꢀ
one (6h). A mixture of 4 (0.23 g, 1 mmol) and 5h (0.18 g, 1 mmol)
(see Ref. 12) was dissolved with reflux in EtOH (5 mL), followed
by the addition of one drop of CF3COOH. After ~1 h, a crystalꢀ
line precipitate (a solvate with EtOH 1 : 1) began to form. After
trituration with a glass rod and cooling on ice, the precipitate
was filtered off, washed with cold EtOH and light petroleum,
and dried. The yield was 0.16 g (37%). After recrystallization
from PrOH (25 mL), 0.13 g (33%) of compound 6h was obꢀ
tained, m.p. 230—240 C. IR, /cm–1: 3293, 3249, 3146 (OH,
NH); 1717 (CO); 1607, 1585, 1540, 1511 (arom.). 1H NMR
(DMSOꢀd6), : 0.95, 1.08 (both s, 6 H, CH3); 1.87, 2.00 (both d,
2 H, CH2, J = 15.9 Hz); 2.57, 2.64 (both d, 2 H, CH2, J = 15.9 Hz);
5.03, 5.13 (both d, 2 H, CH2, J = 10.5 Hz); 5.31 (s, 1 H, NH);
5.95 (br.s, 1 H, OH); 6.21 (d, 1 H, CHarom, J = 7.2 Hz); 6.54
(d, 1 H, CHarom, J = 7.8 Hz); 6.63 (t, 1 H, CHarom, J = 7.2 Hz);
5´ꢀBromoꢀ3,3ꢀdimethylꢀ2,3,4,5,10,11ꢀhexahydrospiro[1Hꢀ
dibenzo[b,e][1,4]diazepineꢀ11,3´ꢀ2Hꢀindole]ꢀ1,2´ꢀdione (6f).
A mixture of 4 (0.46 g, 2 mmol) and 5f (0.45 g, 2 mmol) in
EtOH (10 mL) was heated to boiling point, two drops of
CF3COOH was added, and reflux was continued until dissoluꢀ
tion (1—2 min). After cooling to room temperature (~15 min),
the mixture was treated with water, a precipitate formed
was filtered off, washed with water, and dried. The yield of
crude product was 0.7 g (80%), m.p. 205—212 C (from EtOH).
For elemental analysis and spectroscopic studies, the prodꢀ
uct was recrystallized from EtOH, with which it formed a solvate
1 : 1. Found (%): C, 59.16; H, 6.03; Br, 16.22. C24H26N3O3Br.
Calculated (%): C, 59.51; H, 5.41; Br, 16.50. IR, /cm–1
:
3285, 3244, 3197 (NH); 1721, 1699 (CO); 1614, 1602,
1
1586, 1508, 1492, 1471 (arom.). H NMR (DMSOꢀd6), : 0.97
(s, 3 H, CH3); 1.05 (t, 3 H, CH3, J = 6.9 Hz); 1.09 (s, 3 H, CH3);
1.92, 2.00 (both d, 2 H, CH2, J = 16.2 Hz); 2.60 (s, 2 H, CH2);
3.43 (m, 2 H, CH2); 4.36 (t, 1 H, OH, J = 5.1 Hz); 5.57 (s, 1 H,
6.73 (t, 1 H, CHarom, J = 7.5 Hz); 6.86 (t, 1 H, CHarom
,
J = 7.5 Hz); 6.90—7.20 (m, 3 H, CHarom); 9.10 (s, 1 H, NH).
MS (m/z): the compound did not produce molecular ion, giving
upon electron impact a fragment with the mass of 371 and water.
The structure of 6h was confirmed by Xꢀray diffraction
analysis.
NH); 6.20 (d, 1 H, C(1)H, J = 1.8 Hz); 6.65 (t, 1 H, CHarom
,
J = 7.5 Hz); 6.70 (d, 1 H, CHarom, J = 8.4 Hz). MS, m/z:
493 [M]+.
3,3ꢀDimethylꢀ5´ꢀmorpholinosulfonylꢀ2,3,4,5,10,11ꢀhexaꢀ
hydrospiro[1Hꢀdibenzo[b,e][1,4]diazepineꢀ11,3´ꢀ2Hꢀindole]ꢀ
1,2´ꢀdione (6g). A mixture of 4 (0.23 g, 1 mmol) and 5g (0.3 g,
1 mmol) (see Ref. 11) was dissolved with reflux in EtOH (20 mL),
hot filtered through a dense filter, one drop of CF3COOH was
added, heated to the boiling point, and left to stand for 12 h.
A precipitate formed was filtered off, washed with cold EtOH,
and dried. The yield of crude product was 0.32 g (63%). After
recrystallization from PrOH (25 mL), 0.17 g (33%) of chemically
pure compound was obtained. Colorless compound with m.p.
244—245 C. Found (%): C, 61.22; H, 5.25; S, 6.10. C26H28N4O5S.
Thermal autoꢀredox rearrangement of 6a. Compound 6a
(0.3 g, 0.84 mmol) was heated at 250 C until it completely
melted. The dark brown melt was dissolved with heating in
CHCl3 and subjected to column chromatography on Al2O3 (eluꢀ
ent CHCl3), collecting the head yellow fraction. The solvent
was evaporated, the residue was triturated with light petroleum
to obtain phenazine 7 (0.12 g, 63%). Yellow compound with
m.p. 172—174 C (from acetone) (cf. Ref. 13: m.p. 172—175 C).
MS: m/z = 226. The solvent was evaporated from the second
fraction (eluent CHCl3 : EtOH, 9 : 1), the oily residue was trituꢀ
rated with light petroleum to obtain a solid compound (0.084 g),
in which the presence of oxindole 8a was detected by mass specꢀ
trometry: m/z = 133.
Xꢀray diffraction studies of compounds 6a, 6b, 6d, and 6h.
Single crystals of compound 6a suitable for Xꢀray diffraction
experiment were obtained by slow evaporation of the solution in
CH3CN, or solutions in CH3NO2 were used to grow crystals of
compounds 6b,d,h. The experimental intensities of reflections
were measured on a SMART APEX2 CCD diffractometer
((MoꢀK) = 0.71073 Å, graphite monochromator, ꢀscan techꢀ
nique) at 100 К. The starting massifs of measured intensities
were processed using the SAINT and SADABS programs inꢀ
cluded into the APEX2 software.14 The structures were solved by
direct method and refined by the fullꢀmatrix least squares methꢀ
Calculated (%): C, 61.40; H, 5.55; S, 6.30. IR, /cm–1
:
3365, 3287, 3231 (NH); 1736 (CO); 1614, 1595, 1584, 1502
(arom.); 1348, 1155 (SO2). 1H NMR (DMSOꢀd6), : 0.94,
1.10 (both s, 6 H, CH3); 1.93, 2.03 (both d, 2 H, CH2,
J = 16.2 Hz); 2.31 (m, 4 H, CH2N); 2.63 (s, 2 H, CH2); 3.50
(m, 4 H, CH2O); 5.78 (s, 1 H, NH); 6.45 (d, 1 H, CHarom
J = 1.5 Hz); 6.66 (m, 1 H, CHarom); 6.73 (t, 1 H, CHarom
,
,
J = 7.5 Hz); 6.88 (t, 1 H, CHarom, J = 7.5 Hz); 6.97 (d, 1 H,
CHarom, J = 8.1 Hz); 7.15 (d, 1 H, CHarom, J = 8.1 Hz); 7.41
(dd, 1 H, CHarom, 3J = 8.1 Hz, 4J = 1.8 Hz); 9.19 (s, 1 H, NH);
10.73 (s, 1 H, NH). MS (m/z): the compound did not give moꢀ
lecular ion, however, the fragmentation confirmed the suggestꢀ
ed structure:

1416 Russ.Chem.Bull., Int.Ed., Vol. 62, No. 6, June, 2013
Orlova et al.
Table 3. Crystalographic data and parameters of Xꢀray diffraction experiment for compounds 6a, 6e, 6d, and 6h
Parameter
6a
6e
6d
6h
Molecular formula
C22H21N3O2•
2.375C2H3N
456.92
C22H20ClN3O2•
2CH3NO2
515.95
C22H20FN3O2•
CH3NO2
438.45
C23H23N3O3•
1.36CH3NO2
472.46
Molecular weight
Crystal color
Crystal form
Crystal size/mm
Crystal system
Bright yellow
Plates
0.21×0.17×0.02
Monoclinic
P21/n
Bright yellow
Plates
0.260.230.04
Monoclinic
P21/n
Bright yellow
Prisms
0.260.220.16
Monoclinic
P21/n
Bright yellow
Needles
0.170.030.02
Monoclinic
P21/с
Space group
a/Å
b/Å
c/Å
19.545(4)
11.812(2)
22.704(4)
110.811(3)
4899.4(15)
8
1.239
0.081
1938
12.1667(16)
11.2698(15)
19.113(2)
106.712(3)
2510.1(6)
4
18.4759(10)
11.9740(6)
20.4035(11)
105.2410(10)
4355.1(4)
8
10.5411(8)
15.4198(12)
14.2520(11)
94.647(2)
2308.9(3)
4
/deg
V/Å3
Z
dcalc/g cm–3
1.365
0.201
1080
1.337
0.099
1840
1.359
0.098
998
Absorption coefficient /mm–1
F(000)
Intensity of scaning on /deg
Number of measured reflections
Number of independent reflections
Rint
1.92—28.00
53098
11824
0.0436
1.78—29.00
29218
6664
0.0389
1.99—28.00
47342
10467
0.0705
1.94—30.00
30265
6727
0.0377
Number of refined parameters
Number of reflection with I 2(I)
Completeness of reflection massif (%)
GOOF
601
5275
99.8
0.960
292
4605
99.8
1.040
602
6611
99.6
1.031
264
3610
99.9
0.983
Refinement convergence (R1(F))a
on reflections with I  2(I)
Refinement convergence
on all the reflections (wR2(F2)b
0.0796
0.0542
0.0499
0.0661
0.2050
0.1332
0.1406
0.1538
3
Residual max/min, e/Å
0.454/–0.381
0.496/–0.441
0.437/–0.326
0.337/–0.256
a R1 = |Fo – |Fc||/(Fo). b wR2 = ([w(Fo2 – Fc2)2]/[w(Fo2)2]1/2
.
od in anisotropic approximation for nonhydrogen atoms on F2
.
(Int. Ed.), 2011, 60, 1729 [Izv. Akad. Nauk, Ser. Khim.,
2011, 1703].
8. L. Yu. Ukhin, K. Yu. Suponitsky, E. N. Shepelenko, L. V.
Belousova, G. S. Borodkin, Absr. of VI Intern. Conf. High
Spin Molecules and Molecular Magnets, September 8—13,
2012, Rostov on Don, 149.
9. L. Yu. Ukhin, K. Yu. Suponitsky, E. N. Shepelenko, L. V.
Belousova, G. S. Borodkin, Tetrahedron Lett., 2012, 53, 67.
10. N. Bennamane, R. Kaoua, L. Hammal, B. NedjarꢀKolli,
Org. Commun., 2008, 1:3, 62.
hkl
The solution and refinement of structures were carried out using
the SHELXTL program.15 The principal crystallographic data
and parameters of Xꢀray diffraction experiments are given in
Table 3. The atom coordinates and the temperature factors,
as well as the details of the refinement of the solvent moleꢀ
cules were deposited with the Cambridge Structural Database
(http://www.ccdc.cam.ac.uk/products/csd/request/, CCDC
912574—912577 for 6a, 6e, 6b, and 6h, respectively).
11. Venhua Chu, J. Rothfuss, Yunxiang Chu, Dong Zhou, R. H.
Mach, J. Med. Chem., 2009, 52, 2188.
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Belousova, Zh. I. Orlova, G. S. Borodkin, Russ. Chem. Bull.
Received January 17, 2013;
in revised form March 15, 2013