Synthesis of Tetracyclic 2,3-Dihydro-1,3-diazepines from a Dinitrodibenzothiophene Derivative

Article abstract of DOI:10.1021/acs.joc.8b02029

Triply fused 1,3-diazepine derivatives have been obtained by acidic reduction of rotationally locked and sterically hindered nitro groups in the presence of an aldehyde or ketone. The nitro groups are sited on adjacent rings of a dicyanodibenzothiophene-5,5-dioxide, which also displays fully reversible two-electron-accepting behavior. The synthesis, crystallographically determined molecular structures, and aspects of the electronic properties of these new molecules are presented.

Full text of DOI:10.1021/acs.joc.8b02029

Note
Cite This: J. Org. Chem. XXXX, XXX, XXX−XXX
pubs.acs.org/joc
Synthesis of Tetracyclic 2,3-Dihydro-1,3-diazepines from a
Dinitrodibenzothiophene Derivative
Stephanie Montanaro,†,‡ Iain A. Wright,* Andrei S. Batsanov, and Martin R. Bryce*,†
,‡
†
†
Department of Chemistry, Durham University, Durham, DH1 3LE, United Kingdom
‡
Department of Chemistry, Loughborough University, Loughborough, LE11 3TU, United Kingdom
*
S Supporting Information
ABSTRACT: Triply fused 1,3-diazepine derivatives have been obtained by acidic reduction of rotationally locked and sterically
hindered nitro groups in the presence of an aldehyde or ketone. The nitro groups are sited on adjacent rings of a
dicyanodibenzothiophene-5,5-dioxide, which also displays fully reversible two-electron-accepting behavior. The synthesis,
crystallographically determined molecular structures, and aspects of the electronic properties of these new molecules are
presented.
eveloping new routes to underexplored heterocyclic
motifs is a fundamental driving force in organic
Scheme 1. Synthesis of the New Acceptor 5 and Its X-ray
Molecular Structure
D
chemistry and is essential to identifying new structures of
medicinal or technological value. Diazepines are of major
1
−3
pharmaceutical importance.
1,2-Benzodiazepines and 1,4-
benzodiazepines in particular comprise entire classes of drugs,
including the antianxiety medications tofisopam (strictly a 2,3-
4
−8
diazepine) and diazepam.
1,3-Diazepines, and the saturated
analogues 1,3-diazepanes, are less prevalent; however they have
9
−14
15−20
been studied as HIV protease inhibitors,
as anticancer
and also as N-heterocyclic carbene
In comparison with 1,2- and 1,4-diazepines, routes
to 1,3-diazepines are less clearly established. Since the last
15,21−28
and antiviral agents,
2
9,30
ligands.
31
comprehensive survey of their synthesis only a handful of
new synthetic approaches have been reported for mono-
3
2−35
36−39
cyclic,
pines.
singly
or doubly ring-fused 1,3-diaze-
4
0−49
In this work, the introduction of sterically hindered nitro
groups at the 1- and 9-positions of a dibenzothiophene-5,5-
dioxide derivative provides access to a new two-electron-
accepting molecule, which is a precursor to luminescent four-
ring-fused 2,3-dihydro-1,3-diazepines 6−8 using facile proto-
cols in synthetically viable yields. To our knowledge, these
molecules represent the first examples of tetracyclic 1,3-
diazepine derivatives.
and extending the reaction time, dinitration was achieved to
produce 1,9-dinitrodibenzothiophene-5,5-dioxide-3,7-dicar-
boxylic acid 3. A byproduct containing a nitro group in the
2-position was reported for the mononitration; however, we
did not observe this during our dinitration process. Finally, the
carboxylic acid groups of 3 were easily converted to nitriles
using standard procedures. Reaction of 3 with an excess of
50
The synthesis of the new dibenzothiophene-5,5-dioxide
acceptor is shown in Scheme 1. Simultaneous cyclization and
acidic hydrolysis of dimethyl biphenyl-4,4′-dicarboxylate 1 was
achieved in refluxing chlorosulfonic acid according to the
refluxing SOCl and a catalytic amount of N,N-dimethylfor-
2
mamide (DMF) gave the presumed diacyl chloride derivative,
50
procedure of Olkhovik et al. to produce diacid 2. In the same
report, mononitration of 2 at the 1-position was performed;
therefore, by using the more concentrated fuming nitric acid
Received: August 6, 2018
©
XXXX American Chemical Society
A
DOI: 10.1021/acs.joc.8b02029
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
Scheme 2. Synthesis of Tetracyclic 1,3-Diazepines 6, 7, and 8 from 5 via Intermediate Diamine 9 and the X-ray Molecular
Structure of 6
which was reacted immediately with aqueous ammonia to
produce the diamide derivative 4, which had a low solubility.
enforced proximity of the two amino groups in 9 is required
for efficient reductive cyclization.
Compound 4 was then dehydrated with POCl to give 5. Each
The diazepines 6−8 were brightly colored and emissive in
both the solid state and in solution, unlike the precursor 5,
which is nonemissive. Absorption and emission spectra in
acetonitrile are shown in Figure 1 and summarized in Table S1.
3
step in Scheme 1 is straightforward to perform, relying upon
simple precipitation and filtration to isolate products. The
overall yield is 54% for the five-step sequence to compound 5.
Considerable twisting of the aromatic skeleton of 5 occurs
due to a combination of steric hindrance and repulsive
electronic effects between the nitro groups. Relief of this ring
strain should be a useful driving force in exploiting the
reactivity of these nitro groups toward producing new
heterocycles. Indeed, reduction of the nitro groups of 5 in
the presence of aldehydes or ketones provides convenient
access to the brightly colored 2,3-dihydro-1,3-diazepines 6−8,
featuring alkyl or aromatic substituents at the 2-position, via
the diamine 9 (Scheme 2).
Acidic reduction of 5 using SnCl ·2H O in the presence of
2
2
acetone provided the N,N′-isopropylidene-2,3-dihydro-1,3-
diazepine derivative 6. The modest yield (45%) is offset by
the straightforward practical protocol. To confirm the
intermediacy of diamine 9 in this process, a separate
experiment was performed, in which 9 was isolated, albeit in
only 14% yield, and then cyclized in acidic acetone to provide
Figure 1. Absorption (solid line) and emission spectra (dashed line)
for compounds 5−8 in MeCN solution.
6
in 78% yield. The one-pot approach is, therefore, much more
expedient than performing the reduction and cyclization
sequentially, due to difficulties in isolating diamine 9.
Analogous one-pot reactions using cyclohexanone and 4-tert-
butylbenzaldehyde gave 7 and 8, respectively, in 44% and 39%
yields.
The absorption and emission in the visible region for 6−8 are
probably due to a strong intramolecular charge transfer
between the electron-rich diazepine and electron-poor
dibenzothiophene-5,5-dioxide regions. This postulation is
strengthened by solvatochromism observed as a blue shift in
emission of up to 26 nm when moving from highly polar
We note that electrochemical reduction of 2,2′-dinitrobi-
phenyl in the presence of aldehydes and ketones has previously
acetonitrile (ε = 37.5) to less polar chloroform (ε = 4.81,
51
r
r
been used to produce 1,3-diazepines. However, the reaction
conditions reported above for converting 9 into 6 did not work
with 2,2′-dinitrobiphenyl; no diazepine was isolated, and the
only major product identified was 2,2′-diaminobiphenyl. This
agrees with a previously reported high-yielding, tin-mediated,
Figure S1 and Table S1). There is a substantial difference in
color between the ketone products 6 and 7 (orange) and
aldehyde product 8 (yellow).
The molecular structures of 5 (in three different crystal
forms) and 6 were determined by single-crystal X-ray
diffraction (see Supporting Information) and, in good
agreement, calculated using the density functional theory
(DFT, B3LYP/6-31G*). Both methods show molecule 5
adopting a twisted conformation of the dibenzothiophene
system, in order to widen the short contacts N···N and N···O
52
53,54
reduction of this and related compounds.
We are aware
of one example of a reductive cyclization of a 2,2′-dinitrobiaryl
using SnCl and an identical reaction stoichiometry to the
2
present work, which resulted in trace (5%) benzo[c]cinnoline
5
5
formation. These results indicate that the structurally
B
DOI: 10.1021/acs.joc.8b02029
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
between adjacent nitro groups (Table 1), whereas in 6 the
dibenzothiophene unit is practically planar, N(2) and N(3) are
Table 1. Experimental and Calculated Torsion Angles (Deg)
a
and Interatomic Distances (Å)
molecule
5
6
9
C5−C6−C7−C8/DFT
X-ray
C1−C6−C7−C12/DFT
X-ray
N2···N3/DFT
X-ray
N2···O5/DFT
X-ray
18.2
18.0−23.5
13.1
12.0−14.4
2.997
2.901(3)−3.001(2)
2.681
2.587(7)−2.717(2)
1.490
1.486(2)−1.494(4)
0
1.2
0
0.7
2.411
16.3
8.7
2.774
2.425(2)
Figure 3. Cyclic voltammetry of 5.
C6−C7/DFT
X-ray
1.474
1.472(2)
2,3-dihydro-1,3-diazepine system from the key dinitro
compound 5 based on a one-pot reduction followed by
reaction with aldehyde or ketone functionality. A comparison
with 2,2′-dinitrobiphenyl shows that the structurally enforced
proximity of the two amino groups in 9 is required for
diazepine formation. There is a scope to exploit this chemistry
in the synthesis of other interesting products. For example, the
close proximity of the nitro groups in 5 suggests that ring
closure to benzo[c]cinnoline-type scaffolds may also be feasible
a
For atom numbering, see Schemes 1 and 2.
coplanar with it, and their (postcyclization) separation is much
shorter than in 5, with the C6−C7 bond also shortening
slightly. The 1,3-diazepine ring of 6 adopts a half-chair
conformation with the N2−C15−N3 fragment inclined to the
dibenzothiophene plane by 51.5(1)° (cf. calculated 34.6°).
The accurate prediction of structures 5 and 6 by DFT analysis
encouraged us to perform it for 9, whose single crystals could
not be obtained. The predicted structure is intermediate
between those of 5 and 6 (Figure S5, Table 1).
57−59
using alternative reaction conditions,
while other suitably
nitrated carbo- and heterocycles such as fluorenes or
carbazoles might behave similarly to 5, providing further
structural diversity for fused-ring 1,3-diazepines.
Molecular orbital distributions for 5 and 6 (Figure 2) show a
major contribution to the LUMO of 5 from the nitro groups,
EXPERIMENTAL SECTION
■
General Methods. All reactions requiring an inert atmosphere
were performed under a blanket of argon or nitrogen gas, which was
dried though a column of phosphorus pentoxide. Anhydrous solvents
were dried through an HPLC column on an innovative Technology
Inc. solvent purification system. All reactants and reagents were
purchased from commercial suppliers and used without further
purification unless otherwise stated. Column chromatography was
carried out using silica gel 60, 40−60 μm mesh (Fluorochem).
Analytical thin-layer chromatography was performed on precoated
aluminum silica gel 60 F254 plates (Merck), which were approximately
2
cm × 6 cm in size, and visualized using ultraviolet light (254/365
nm). NMR spectra were recorded on the following specrtrometers:
Bruker Avance-400 ( H NMR (400 MHz), C NMR (101 MHz)),
1
13
1
3
Varian Inova-500 ( C NMR (125 MHz)), and Varian VNMRS-700
1
13
(
H NMR (700 MHz), C NMR (175 MHz)). Chemical shifts are
Figure 2. HOMO (lower) and LUMO (upper) contours for 5 and 6
and their calculated energies.
reported in ppm downfield of tetramethylsilane (TMS) using TMS or
the residual solvent as an internal reference. NMR spectra were
processed using MestreNova. Multiplicities are reported as singlet (s),
doublet (d), triplet (t), and multiplet (m). Melting points were
determined in open-ended capillaries using a Stuart Scientific SMP3
melting point apparatus at a ramping rate of 1 °C/min. They are
recorded to the nearest 1 °C and are uncorrected. Mass spectrometry
data were generated by Waters Ltd., U.K. (atmospheric solids analysis
probe (ASAP) mass spectrometry). IR spectra were collected on a
PerkinElmer Spectrum Two IR spectrometer. Elemental analyses were
obtained on an Exeter Analytical Inc. CE-440 elemental analyzer.
the nitrogen atoms of which subsequently become HOMO
contributors upon reduction and cyclization to 6. The results
of identical calculations for 9 are shown in Figure S6.
An interesting feature of the diazepine precursor compound
5
is its ability to accept two electrons as shown in cyclic
voltammetry (CV) experiments. The voltammogram in Figure
shows two, sequential, single-electron reductions at half-wave
3
potentials of −0.15 and −0.45 V. Both processes are cleanly
reversible, displaying a linear dependence between peak
current and the square root of the scan rate (Figures S8 and
S9) and peak separations close to the 59 mV expected for a
one-electron wave. The data are summarized in Table S4
alongside a more detailed discussion of the properties of 5 in
Cyclic voltammetry was recorded using a Princeton Applied Research
+
VersaSTAT 3. A glassy carbon disk, Pt wire, and Ag/Ag (AgNO in
3
acetonitrile) were used as the working, counter, and reference
electrodes, respectively. Measurements were corrected to the
ferrocene/ferrocenium redox couple as an internal standard and
represented versus Ag/AgCl, which occurred at −0.45 V versus Fc/
+
Fc in these conditions. Acetonitrile was used as the solvent with an
56
comparison with some related fluorenone-based acceptors.
−4
−3
analyte molarity of ca. 10 M in the presence of 1 × 10 M (n-
In conclusion, an efficient synthetic route has been
Bu N)(PF ) as a supporting electrolyte. Solutions were degassed with
4
6
established to an unusual highly functionalized fused-ring
Ar and experiments run under a blanket of Ar. UV−vis absorbance
C
DOI: 10.1021/acs.joc.8b02029
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
spectra were measured using a UV-1800 UV−vis spectrophotometer
recrystallized from acetonitrile and water to afford 5 as pale yellow
1
(
Shimadzu) and UVProbe version 2.33 software. Emission spectra
crystals (1.30 g, 90%): mp 250 °C (dec); H NMR (400 MHz,
were recorded on an SPEX Fluoromax luminescence spectrometer
using dM300 version 3.12 software. Density function theory (DFT)
acetone-d , ppm) δ 9.08 (2H, d, J = 1.5 Hz, H2/8), 9.02 (2H, d, J = 1.5
6
1
3
Hz, H4/6); C NMR (101 MHz, acetone-d , ppm) δ 147.9, 142.8,
6
60
−1
calculations were performed with ORCA v4.01 using the B3LYP
135.4, 131.6, 125.5, 119.0, 115.8; IR (νmax/cm ) 3074 (w), 2242
6
1−63
hybrid functional and 6-31G* basis set.
Ground-state structural
(CN, w), 1547 and 1352 (NO , s), 1495 (m), 1330 and 1161
2
optimizations were performed prior to frontier orbital calculations.
(SO , s), 1227 (m), 1188 (m), 778 (m), 737 (s), 694 (s), 575 (m),
2
5
0
5
,5-Dioxo-5H-dibenzo[b,d]thiophene-3,7-dicarboxylic Acid (2).
544 (s), 467 (s). Elemental Anal. Calcd for C H N O S: C, 47.20; H,
1
4
4
4
6
A solution of dimethyl biphenyl-4,4′-dicarboxylate 1 (5.00 g, 19.0
mmol) in chlorosulfonic acid (20 mL) was heated at reflux for 3 h.
The reaction mixture was cooled to room temperature and poured
over ice to precipitate the product. The white precipitate was filtered
and washed with water (50 mL), hexane (40 mL), and diethyl ether
1.13; N, 15.73. Found: C, 46.84; H, 1.12; N, 15.70. Despite repeated
attempts using a range of techniques, this molecule was not observed
by mass spectrometry. Single crystals for X-ray analysis were grown
from both ethyl acetate/hexane and THF/MeOH/H O solutions.
2
N,N′-Isopropylidene-1,9-diamino-3,7-dicyano-5,5-dioxo-5H-
(
40 mL). The white powder was recrystallized from acetone to afford
as a white crystalline solid (5.51 g, 95%): mp > 350 °C; H NMR
dibenzo[b,d]thiophene (6). To a stirred solution of SnCl ·2H O
2 2
1
2
(3.00 g, 13.4 mmol) in a mixture of methanol (8.50 mL) and aqueous
HCl (2 M, 8.5 mL) were added acetone (1.00 mL, 13.6 mmol, 16
equiv) and 5 (0.30 g, 0.84 mmol) sequentially. The mixture was then
heated to 85 °C for 2.5 h. The mixture was cooled to room
temperature and poured into aqueous HCl (2 M, 34 mL). An orange
precipitate immediately formed, which was filtered and washed with
hexane (30 mL). It was then purified by silica column chromatog-
raphy (eluent 30:70 hexane/ethyl acetate (v/v)) to afford 6 as an
(
400 MHz, DMSO-d , ppm) δ 8.43 (2H, d, J = 7.7 Hz, H1/9), 8.38
6
(
ylic Acid (3). A 1 L two-neck round-bottom flask equipped with a
water-cooled reflux condenser and a pressure equalizing dropping
funnel was charged with 2 (18.0 g, 59.2 mmol) and 95% sulfuric acid
(
(
d = 1.83, 165 mL) and placed in an ice batch. Fuming 90% nitric acid
d = 1.50, 250 mL) was added cautiously using to the stirred solution
1
orange powder (128 mg, 45%): mp 350 °C (dec); H NMR (400
through the dropping funnel, while maintaining the temperature
between 5−10 °C. The ice bath was swapped for a heating block,
which was then slowly heated to 130 °C for 48 h. To minimize
corrosive vapors escaping the reaction vessel, the top of the reflux
condenser was connected by PVC tubing to an empty 500 mL
Dreschel bottle (to avoid the risk of suck back into the reaction
vessel), which in turn was connected by another length of PVC
tubing, the end of which was submerged approximately 2 cm below
the surface of 400 mL of water in a 1 L beaker. After heating, the
mixture was allowed to cool and then was poured over ice. The white
precipitate that formed was filtered and washed with water (60 mL)
and then hexane (40 mL). The crude product was recrystallized from
MHz, acetone-d , ppm) δ 7.64 (2H, d, J = 1.3 Hz, H ), 7.44 (2H, d,
6
4/6
1
3
J = 1.3 Hz, H2/8), 6.98 (2H, s, NH), 1.63 (6H, s, CH ); C NMR
3
(101 MHz, acetone-d , ppm) δ 146.1, 140.2, 126.9, 119.1, 118.0,
6
−
1
114.6, 114.3, 67.2, 28.4; IR (νmax/cm ) 3331 (NH, m), 2917 (w),
2233 (CN, m), 1740 (m), 1606 (m), 1526 (m), 1457 (m), 1367
(m), 1308 and 1150 (SO , s), 1278 (m), 1028 (m), 876 (m), 713
2
+
(m), 624 (m), 545(s); MS (ASAP) m/z 337.1 [M + H] ; HRMS
(ASAP) m/z [M + H] calcd for C H N O S 337.0754, found
+
1
7
13
4
2
337.0753.
N,N′-Cyclohexylidene-1,9-diamino-3,7-dicyano-5,5-dioxo-5H-
dibenzo[b,d]thiophene (7). To a stirred solution of SnCl ·2H
O
2
2
(5.07 g, 22.5 mmol) in a mixture of methanol (14 mL) and aqueous
HCl (2 M, 14 mL) were added cyclohexanone (0.73 mL, 7.0 mmol)
and 5 (0.50 g, 1.40 mmol). The mixture was then heated to 85 °C for
2.5 h. The mixture was cooled to room temperature and poured into
aqueous HCl (2 M, 56 mL). An orange precipitate immediately
formed, which was filtered and washed with hexane (30 mL). It was
then purified by silica column chromatography (eluent 40:60 hexane/
acetic acid to afford 3 as a white crystalline solid (17.1 g, 73%): mp >
1
3
50 °C; H NMR (400 MHz, DMSO-d , ppm) δ 8.89 (2H, d, J = 1.5
6
1
3
Hz, H2/8), 8.71 (2H, d, J = 1.5 Hz, H4/6); C NMR (101 MHz,
DMSO-d , ppm) δ 163.6, 146.3, 141.0, 137.0, 131.1, 127.1, 123.9; IR
6
−
1
(
νmax/cm ) 3095 (w), 2523 (br), 1707 (s, CO), 1543 and 1359 (s,
NO ), 1326 and 1146 (s, SO ), 1279 (s), 1185 (s), 1172 (s), 744 (s);
MS (ASAP) m/z 395.0 [M + H] ; HRMS (ASAP) m/z [M + H]
2
2
+
+
ethyl acetate (v/v)) to afford 7 as small orange crystals (230 mg,
1
calcd for C H N O S 394.9816, found 394.9811.
44%): mp 300 °C (dec); H NMR (400 MHz, acetone-d
6
, ppm) δ
14
7
2
10
1
,9-Dinitro-5,5-dioxo-5H-dibenzo[b,d]thiophene-3,7-dicarboxa-
7.64 (2H, d, J = 1.3 Hz, H4/6), 7.59 (2H, d, J = 1.3 Hz, H2/8), 6.84
(2H s, NH), 1.92−1.84 (4H, m, CH ), 1.69−1.49 (6H, m, CH ); C
NMR (101 MHz, acetone-d , ppm) δ 145.5, 140.1, 127.2, 119.6,
118.0, 114.7, 114.3, 68.8, 36.1, 25.8, 22.4; IR (νmax/cm ) 3401 (m),
3356 (m), 3321 (NH, m), 3076 (w), 2941 (w), 2241 (CN, m),
1606 (m), 1517 (s), 1305 and 1150 (SO2, s) 852 (m), 708 (m), 620
1
3
mide (4). A few drops of DMF were added to a suspension of 3 (15.0
g, 38.0 mmol) in thionyl chloride (380 mL), which was then heated to
reflux for 3 h to form a yellow solution. After the mixture was cooled
to room temperature, the excess thionyl chloride was removed under
reduced pressure to afford a pale yellow solid (16.4 g, 38.0 mmol).
The yellow solid was then suspended in water (20 mL) with stirring
before a 35% aqueous ammonia solution (d = 0.88, 200 mL) was very
carefully added dropwise (CAUTION! gas evolution). The reaction
mixture was left to stir at room temperature for 2.5 h and then poured
over ice to produce a brown precipitate, which was filtered off and
washed with diethyl ether (50 mL) and then hexane (50 mL) to yield
2
2
6
−
1
+
(m); MS (ASAP) m/z 377.1 [M + H] ; HRMS (ASAP) m/z [M +
+
H] calcd for C H N O S 377.1067, found 377.1067.
2
0
17
4
2
N,N′-(4-tert-Butylbenzylidene)-1,9-diamino-3,7-dicyano-5,5-
dioxo-5H-dibenzo[b,d]thiophene (8). To a stirred solution of SnCl
2H O (2.02 g, 8.99 mmol) in a mixture of methanol (6 mL) and
·
2
2
aqueous HCl (2 M, 6 mL) were added 4-tert-butylbenzaldehyde (0.50
mL, 2.81 mmol) and 5 (0.20 g, 0.56 mmol). The mixture was then
heated to 85 °C for 2.5 h. The mixture was cooled to room
temperature and poured into aqueous HCl (2 M, 25 mL). The
organics were then extracted into ethyl acetate (3 × 15 mL) and
washed with water (2 × 25 mL). The organic fractions were dried
over magnesium sulfate, and ethyl acetate was removed under a
vacuum to afford an oil. The oil was dissolved in dichloromethane (30
mL), and hexane (20 mL) was added. The solvent was reduced in
volume (ca. 10 mL) to precipitate the crude product as a yellow
powder. It was then purified by silica column chromatography (eluent
70:30 hexane/ethyl acetate (v/v)) to afford 8 as a yellow crystalline
4
as a pale brown solid (12.7 g, 86%). The compound was used
1
without further purification: mp 230 °C (dec); H NMR (400 MHz,
DMSO-d , ppm) δ 8.96 (2H, d, J = 1.0 Hz, H ), 8.81 (2H, d, J = 1.0
Hz, H4/6), 8.61 (2H, s, NH), 8.12 (2H, s, NH); C NMR (101 MHz,
6
2/8
1
3
DMSO-d , ppm) δ 163.3, 146.2, 140.7, 139.6, 129.9, 125.4, 122.9; IR
6
−
1
(
νmax/cm ) 3083 (br), 2924 (w), 1693 (s, CO), 1616 (m,
amideH), 1541 and 1352 (s, NO ), 1314 and 1145 (s, SO ), 1386
2
2
+
(
m), 1192 (m); MS (ASAP) m/z 393.0 [M + H] ; HRMS (ASAP)
+
m/z [M + H] calcd for C H N O S 393.0136, found 393.0135.
1
4
9
4
8
3
,7-Dicyano-1,9-dinitro-5,5-dioxo-5H-dibenzo[b,d]thiophene
5). A solution of 4 (1.60 g, 4.08 mmol) in phosphorus oxychloride
40 mL) was heated to reflux for 3 h. The resulting dark orange
(
1
(
powder (92 mg, 39%): mp 300 °C (dec); H NMR (400 MHz,
solution was cooled to room temperature and quenched slowly with
warm water. The orange precipitate was filtered and washed with
water (50 mL) and hexane (30 mL). The crude product was
acetone-d , ppm) δ 7.69 (2H, d, J = 1.4 Hz, H4/6), 7.65 (2H, d, J = 1.4
6
4
6 4
‑t‑BuC H
Hz, H2/8), 7.58−7.48 (4H, m, H
(1H, s, CH), 1.36 (9H, s, CH ); C NMR (101 MHz, acetone-d6,
), 7.17 (2H, s, NH), 5.34
1
3
3
D
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The Journal of Organic Chemistry
Note
ppm) δ 153.2, 148.5, 140.7, 136.7, 128.3, 126.9, 126.4, 118.9, 118.0,
(6) Snieckus, V.; Streith, J. 1,2-Diazepines: A New Vista in
Heterocyclic Chemistry. Acc. Chem. Res. 1981, 14 (11), 348−355.
(7) Kaur, N.; Kishore, D. Synthetic Strategies Applicable in the
Synthesis of Privileged Scaffold: 1,4-Benzodiazepine. Synth. Commun.
2014, 44 (10), 1375−1413.
−
1
1
(
15.2, 113.8, 71.2, 35.3, 31.6; IR (νmax/cm ) 3355 (NH, w), 3063
w), 2956 (w), 2233 (CN, m), 1605 (m), 1505 (s), 1468 (s), 1305
and 1145 (SO , s), 1268 (m), 1202 (m), 886 (m), 836 (m), 707 (m),
2
+
621 (m); MS (ASAP) m/z 441.1 [M + H] ; HRMS (ASAP) m/z [M
+
+
H] calcd for C H N O S 441.1380, found 441.1374.
(8) Meanwell, N. A.; Walker, M. A. 1,4-Diazepines. In Comprehensive
Heterocyclic Chemistry III; Elsevier, 2008; pp 183−235.
25
21
4
2
1
,9-Diamino-3,7-dicyano-5,5-dioxo-5H-dibenzo[b,d]thiophene
(
9). To a stirred solution of SnCl ·2H O (5.07 g, 22.5 mmol) in a
2 2
(9) Hodge, C. N.; Lam, P. Y. S.; Eyermann, C. J.; Jadhav, P. K.; Ru,
Y.; Fernandez, C. H.; De Lucca, G. V.; Chang, C. H.; Kaltenbach, R.
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mixture of ethanol (14 mL) and aqueous HCl (2 M, 14 mL) was
added 5 (0.50 g, 1.40 mmol). The mixture was heated to 85 °C for
2.5 h, then cooled to room temperature, and poured into aqueous
HCl (2 M, 56 mL). An orange precipitate immediately formed, which
was filtered and washed with hexane (30 mL). The product was
purified by silica column chromatography (eluent 30:70 hexane/ethyl
acetate (v/v), gradually increased polarity to 100% ethyl acetate) to
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1
afford 9 as a light brown powder (60 mg, 14%): mp 300 °C (dec); H
NMR (400 MHz, DMSO-d , ppm) δ 7.79 (2H, d, J = 1.5 Hz, H4/6),
6
(
2), 181−191.
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1
3
7
.52 (2H, d, J = 1.5 Hz, H2/8), 6.60 (4H, s, NH ); C NMR (101
2
(
MHz, DMSO-d , ppm) δ 145.0, 139.1, 126.5, 118.1, 117.6, 112.9,
6
−1
1
12.6; IR (νmax/cm ) 3451 and 3360 (NH, m), 3243 (w), 3070
(
(w), 2226 (CN, s), 1632 and 1598 (NH , s), 1543 (m), 1467 (m),
2
(
1
430 (m), 1346 (m), 1299 and 1143 (SO , s), 1253 (m), 1194 (m),
2
Activity Relationship Study on Cyclic Urea Derivatives as HIV-1
Protease Inhibitors: Application of Comparative Molecular Field
Analysis. J. Med. Chem. 1999, 42 (2), 249−259.
+
881 (m), 617 (m); MS (ASAP) m/z 297.0 [M + H] ; HRMS (ASAP)
+
m/z [M + H] calcd for C H N O S 297.0441, found 297.0437.
1
4
9
4
2
(13) Lam, P. Y. S.; Ru, Y.; Jadhav, P. K.; Aldrich, P. E.; DeLucca, G.
ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.joc.8b02029.
1H and 13C NMR spectra for all new compounds,
■
V.; Eyermann, C. J.; Chang, C.-H.; Emmett, G.; Holler, E. R.;
Daneker, W. F.; et al. Cyclic HIV Protease Inhibitors: Synthesis,
Conformational Analysis, P2/P2′ Structure−Activity Relationship,
and Molecular Recognition of Cyclic Ureas. J. Med. Chem. 1996, 39
(18), 3514−3525.
*
S
(14) Lam, P. Y. S.; Jadhav, P. K.; Eyermann, C. J.; Hodge, C. N.; Ru,
absorption and emission spectra, computational details
for 5, 6, and 9, computational results for 9, electro-
chemical properties of 1, and further crystallographic
details (PDF)
Y.; Bacheler, L. T.; Meek, J. L.; Otto, M. J.; Rayner, M. M.; Wong, Y.
N.; et al. Rational Design of Potent, Bioavailable, Nonpeptide Cyclic
Ureas as HIV Protease Inhibitors. Science 1994, 263, 380−384.
(15) Wittine, K.; Poljak, K.; Kovac, M.; Makuc, D.; Plavec, J.;
Crystal data for 5, 5·1/2 THF, and 6 (CIF)
Balzarini, J.; Martinovic, T.; Pavelic, S. K.; Pavelic, K.; Mintas, M. The
Novel [4,5-e][1,3]Diazepine-4,8-Dione and Acyclic Carbamoyl
Imino-Ureido Derivatives of Imidazole: Synthesis, Anti-Viral and
Anti-Tumor Activity Evaluations. Molecules 2013, 18 (11), 13385−
AUTHOR INFORMATION
Corresponding Authors
E-mail: i.a.wright@lboro.ac.uk.
E-mail: m.r.bryce@durham.ac.uk.
ORCID
Iain A. Wright: 0000-0002-0142-2809
Andrei S. Batsanov: 0000-0002-4912-0981
Martin R. Bryce: 0000-0003-2097-7823
■
13397.
*
(16) Xie, M.; Lapidus, R. G.; Sadowska, M.; Edelman, M. J.;
*
Hosmane, R. S. Synthesis, Anticancer Activity, and SAR Analyses of
Compounds Containing the 5:7-Fused 4,6,8-triaminoimidazo[4,5-
e][1,3]diazepine Ring System. Bioorg. Med. Chem. 2016, 24 (12),
2
(
595−2602.
17) Kondaskar, A.; Kondaskar, S.; Kumar, R.; Fishbein, J. C.;
Muvarak, N.; Lapidus, R. G.; Sadowska, M.; Edelman, M. J.; Bol, G.
M.; Vesuna, F.; et al. Novel, Broad Spectrum Anticancer Agents
Containing the Tricyclic 5:7:5-Fused Diimidazodiazepine Ring
System. ACS Med. Chem. Lett. 2011, 2 (3), 252−256.
Notes
The authors declare no competing financial interest.
(18) Kondaskar, A.; Kondaskar, S.; Fishbein, J. C.; Carter-Cooper, B.
ACKNOWLEDGMENTS
M.R.B. and I.A.W. thank EPRSC for funding (EP/K016164/
). I.A.W. thanks Loughborough University and the Royal
Society of Chemistry Research Fund (RF18-5353) for funding.
■
1
A.; Lapidus, R. G.; Sadowska, M.; Edelman, M. J.; Hosmane, R. S.
Structure-Based Drug Design and Potent Anti-Cancer Activity of
Tricyclic 5:7:5-Fused diimidazo[4,5-d:4′,5′-f][1,3]diazepines. Bioorg.
Med. Chem. 2013, 21 (3), 618−631.
(19) Bellet, V.; Lichon, L.; Arama, D. P.; Gallud, A.; Lisowski, V.;
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