Synthesis and characterization of new heterocycles related to aryl[: E] [1,3]diazepinediones. rearrangement to 2,4-diamino-1,3,5-triazine derivatives

Article abstract of DOI:10.1039/d0nj01229g

Novel non-planar heterocycles make a great contribution to drug design and medicinal chemistry. Fused aryl[e][1,3]diazepinediones are a less investigated and appealing class of compounds. Herein, we designed 5 types of polynitrogen containing compounds based on 3-aminobenzo[e][1,3]diazepine-1,5-dione and undescribed 3-aminopyrido[3,4-e][1,3]diazepine-1,5-dione, 7-aminopyrido[2,3-e][1,3]diazepine-5,9-dione and 7-aminopyrazino[2,3-e][1,3]diazepine-5,9-dione. The synthesis, characterization, chemical properties, and X-ray structures are presented. Stability studies led to the identification of a novel rearrangement of 2-guanidino-benzo[e][1,3]diazepine-4,7-dione to 2,4-diamino-6-phenyl-1,3,5-triazines by hydrolytic ring-opening followed by cyclocondensation. This reactivity has been used to efficiently access, after optimization, an activated 2,2,2-trifluoroester, which was successively transformed into variously functionalized derivatives by hydrolysis, transesterification or amide formation. These latter structures present high potential as precursors of drug-like molecules.

Full text of DOI:10.1039/d0nj01229g

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Synthesis and Characterization of new Heterocycles related to
Aryl[e][1,3]diazepinediones. Rearrangement to 2,4-Diamino-1,3,5-
triazine Derivatives.
Received 00th January 20xx,
Accepted 00th January 20xx
c
d
Rostyslav Bardovskyi, a Oleksandr Grytsai,b Cyril Ronco* and Rachid Benhida*
DOI: 10.1039/x0xx00000x
ABSTRACT: Novel non-planar heterocycles make a great contribution to drug design and medicinal chemistry. Fused
aryl[e][1,3]diazepinediones are a less investigated and appealing class of compounds. Herein, we designed 5 types of
polynitrogen containing compounds based on 3-aminobenzo[e][1,3]diazepine-1,5-dione and undescribed 3-
aminopyrido[3,4-e][1,3]diazepine-1,5-dione, 7-aminopyrido[2,3-e][1,3]diazepine-5,9-dione and 7-aminopyrazino[2,3-
e][1,3]diazepine-5,9-dione. The synthesis, characterization, chemical properties, and X-ray structures are presented.
Stability studies led to the identification of a novel rearrangement of 2-guanidino-benzo[e][1,3]diazepine-4,7-dione to 2,4-
diamino-6-phenyl-1,3,5-triazines by hydrolytic ring-opening followed by cyclocondensation. This reactivity has been used to
efficiently access, after optimization, an “activated” 2,2,2-trifluoroester, which was successively transformed into variously
functionalized derivatives by hydrolysis, transesterification or amide formation. These latter structures present high
potential as precursors of drug-like molecules.
combining both features, biguanide and benzodiazepinedione
cores (molecules of type C, Figure 2), is highly appealing to
consider hybrid/dual molecules.
Herein, we present several original classes of molecules
based on 3-amino-benzo[e][1,3]diazepine-1,5-dione1, and we
report the syntheses of three new heterocycles, namely 7-
Introduction
The fused aryl[e][1,3]diazepinediones are an original
heterocyclic scaffold. It shows attractivestructural features
with a favorable balance between size, rigidity, and number of
potential H-bonding sites. Moreover, related fused
aryldiazepine derivatives are present in well-known drugs, as
demonstrated by the successful family of benzo[1,4]
diazepin(on)es that efficiently inhibit GABA receptors in the
central nervous system,1 and were proposed recently for other
biomedical applications.2 5-Member-ring fused diazepinediones
are mainly represented by imidazole-fused or 1,2,3-triazole-
fused structures used as purine extended analogs. Among these
compounds, some molecules show interesting inhibition of
several viruses by targeting NTPase and helicase enzymes, while
other derivatives exert modest cytotoxic effects against certain
cancer cell lines.3–7 On the other hand, to the best of our
knowledge, there are almost no reports of 6-member-ring fused
diazepinediones, which are basically restricted to only two
examples.8,9 Furthermore, the pyridine- and pyrazine-fused 1,3-
diazepinedione scaffolds are unknown from the literature yet
(Figure 1).
amino-pyrido[2,3-e][1,3]diazepine-5,9-dione
pyrido[3,4-e][1,3]diazepine-1,5-dione 3, 2-amino-pyrido[3,4-
e][1,3]diazepine-4,7-dione and 7-amino-pyrazino[2,3-
2,
3-amino-
e][1,3]diazepine-5,9-dione 4, as well as analogs thereof. In total,
28 new derivatives have been prepared and fully characterized
(Figure 2). The structural properties, solubility and stability
profiles and X-ray crystal structures of representative
compounds were studied. In addition, a rearrangement by
cyclocondensation of bisamidine derivatives toward
phenyltriazines was remarkably observed, which was then
extended through several representative examples.
New heterocycles
O
O
O
N
N
NH
N
NH
N
NH
N
NH2
NH2
NH2
N
N
O
O
O
4
2
3
Recently, biguanide derivatives have received increasing
attention because of their potent pharmacological properties in
line with metformin and its analogs, which have many clinical
applications in metabolic and cancer diseases.10 Therefore,
7-amino-5H-pyrazino[2,3-e]
[1,3]diazepine-5,9(6H)-dione
7-amino-5H-pyrido[2,3-e]
[1,3]diazepine-5,9(6H)-dione [1,3]diazepine-1,5(2H)-dione
3-amino-1H-pyrido[3,4-e]
Figure 1. New heterocycles based on fused aryl[e][1,3]diazepinediones.
a, b, c, d. Université Côte d’Azur, CNRS, Institut de Chimie de Nice UMR 7272, 06108,
Nice, France.
c.
E-mail: cyril.ronco@univ-cotedazur.fr
E-mail: rachid.benhida@univ-cotedazur.fr
d.
* corresponding authors
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Figure 2. Synthesis of the aryl[e][1,3]diazepinedione analogs. Conditions: i) guanidine derivative (1 eq.), tert-BuOK (3eq.), DMF, 0°C to r.t., 2h-24h; ii) Arylisocyanate
(1eq.), DMF, 0°C to r.t., 24-48h.
As shown in Figure 2, five types of structures based on the deprotonated beforehand by a strong base (t-BuOK, DMF, r.t.).
four different heterocycles were prepared. They encompass an Neither Brønsted acid activation (AcOH, H2SO4), nor non-
amino group in position 3 (Type A), a cyanamide (Type B), a deprotonative basic conditions (DBU) or higher temperatures
guanidine (Type C), an aminobenzazole moiety (Type D) or an could afford satisfactory conversion. The counter cation was
arylurea (Type E). All compounds were synthesized from the also found to have a significant effect since the guanidine
reaction between phthalic diesters (or their pyrido-/pyrazo- sodium salt gave a lower yield than the potassium salt under the
analogs) and guanidine derivatives (guanidine, cyanoguanidine, same reaction conditions (60% vs. 82% for compound 1).
biguanides, heteroarylguanidines).
Compounds from Type A-B-C-D were obtained after careful
neutralization and recrystallization in good yields (see general
procedures). Type E derivatives were prepared from the already
formed heterocycle 1, by reaction with arylisocyanates.
Results and discussion
The heterocycles 1-4 (Type A) were isolated as crystalline
powders, poorly soluble in water with slow decomposition, but
A survey of the reaction conditions proved that the optimal
method to produce heterocycles 1-4 is a double ester
condensation in the presence of the guanidine derivative,
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easily dissolved in 1 M aqueous NaOH, which might indicate a
pKa < 14.
The moderate yields obtained with some compounds are
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mainly due to the isolation and puriDfiOcaI:t1i0o.n103p9r/Do0toNcJo0l1s229bGy
The cyanamide derivatives 5-7 (Type B) were synthesized in recrystallization, which could be optimized for each compound.
a similar way from cyanoguanidine in moderate to good yields. The polarity of the synthesized compounds (as spotted by the
Surprisingly, the neutralization of the reaction media at pH 5 retention times of the monoprotonated forms in HPLC) proved
resulted only in isolation products in the form of potassium salt. as follows: A ≈ B > C > D > E and the solubility properties of these
This suggests a high acidity of the proton on the conjugated compounds are summarized in Table 1.
5
6
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cyanoamine group. The presence of the cyanoamine group was
Concerning the stability of this core, these
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attested by a typical strong band at 2180 cm-1 by IR analysis and aryl[e][1,3]aryldiazepinediones proved to be generally highly
the potassium was dosed by atomic absorption spectrometry. stable in aprotic solvents. However, in acidic water (pH = 1) or
Consequently, these compounds evince high solubility in water alcohols,
a slow ring-opening occurred, leading to the
(~1 g/L), but are easily decomposed in 1 M aqueous NaOH, corresponding guanidine-ester or guanidine-acid derivatives.
diluted aqueous NH3 or 1 M aqueous HCl solutions.
Under these conditions, the relative stability was as follows:
Type A. For defined Type, the
B
>
C
>
D
≈
a
Table 1. Aqueous solubility and solubility in DMF of synthesized aryl[e][
[1,3]diazepinedione analogs of Type A-B-C-D-E
aryl[e][1,3]benzodiazepinediones also proved somewhat more
stable than the corresponding pyridine or pyrazine derivatives.
The thermal stability also proved to be high, so that some
compounds could be obtained after recrystallization in hot DMF
(100°C), and all of them present high melting points above
180°C.
To further investigate the properties of these heterocycles,
the crystal structures of compounds 1, 8, 10 and 14 were
resolved. The position of all hydrogen atoms was determined
following the interatomic distances corresponding to the atoms
hybridization. The X-ray molecular structures, depicted in
Figure 3, revealed first the non-planarity of the diazepinedione
core. The dihedral angle between the aryl ring of aryl[e]
[1,3]diazepinedione and the guanidine fragment including
atoms N(1), N(2), N(3) and C(1) was determined to be 34.8°-
38.9° (Figure 3b).
Aqueous
solubility
-
Solubility in
DMF
+
++
++
+
Compound
Type A
Type B
Type C
Type D
Type E
+
+
[a]
-
-
++
[a] except for compounds 9, 12, 14 and 17: solubility: +/-.
The guanidine derivatives 8-18 (Type C) were synthesized
following the same protocol (t-BuOK/DMF) from biguanide
reagents. These biguanide intermediates were prepared by
reaction of amines with cyanoguanidine under TMSCl/THF
conditions adapted from the literature,11 except for N,N-
dimethylbiguanide hydrochloride and o-tolylbiguanide that
were commercially available. In all cases, the addition proved
selective to the nitrogen atom in  position of the substituted
nitrogen, leading to the compounds displayed in Figure 2 with
substitutions in terminal position of the guanidine.
In addition, an intramolecular hydrogen bond
Then, we tested the addition of substituted guanidines to
produce N-benzazoyl derivatives 19-25 (Type D). The
guanidinobenzazole intermediates were prepared according to
adapted described procedures.12,13 Attempts to produce the
benzoxazole derivatives failed because of hydrolytic ring-
opening upon work-up.
Derivatives from Type E were synthesized by substitution of
the already formed aryl[e][1,3]diazepinedione compound 1
with phenylisocyanates at room temperature in DMF. The
selective addition of the isocyanates to the exocyclic nitrogen of
1, followed by prototropy, delivered urea compounds 26-28 in
moderate yields, after extended reaction time (24-48 h).
a
b
1
8
10
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c
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DOI: 10.1039/D0NJ01229G
Angle
D–H···A,
deg
Distances, Å
H···A
Contact
D–H···A
#
D–H
D···A
8
10
14
N(4)–H4B···N(2)
0.860 2.075 2.676(2)
N(4)–H4A···N(2) 0.914 1.962 2.682(2)
N(4)–H4B···N(2) 0.952 1.994 2.704(3)
126.4
134.3
129.8
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10
14
Figure 3. a) X-ray structures of compounds 1, 8, 10 and 14. The crystals of compound 12 display organic solvent molecules (CH3COCH3) in the unit cell. Compounds 8,
10 and 12, are connected by intermolecular bonding between O(1)···H–N(1)–H···O(1) and O(2)···H–N(4) – H···O(2).. Compound 1 presents O(1)···H–N(3)–H··· O(1) and
O(2)···H–N(3)–H···O(2) bonds. b) Bis-planar organization of the structure with representative compound 8. c) Geometric characteristics of intramolecular hydrogen
bonds.
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a
We deduced from this observation that the addition of
alcohol nucleophiles could result in the formation of the related
triazine-esters. A screening of conditions identified 2,2,2-
trifluoroethanol (TFE) as a good reactant to proceed to this
O
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O
NH
N
N
N
N
N
N
NH
N
N
H
H
O
H
8
H
b
O
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N
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NH2
NH2
NH
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O
c
Compound
d(N(1)-C(1)), Å
1.387(2)
d(N(2)-C(1), Å
1.313(2)
d(N(3)-C(1), Å
1.320(2)
1
8
10
14
1.400(2)
1.406(2)
1.399(3)
1.314(2)
1.311(2)
1.311(2)
1.334(2)
1.330(2)
1.333(3)
Figure 4. Structure and tautomers in solution: a). Compound 8 offers an
intramolecular H-bonding possibility that congeals the equilibrium toward one
tautomer and breaks the symmetry of the molecule b). Compound 1 is in
permanent equilibrium between two tautomers and displays symmetric signals in
1H NMR. c). C-N bond lengths of the guanidine within compounds 1, 8, 10 and 14
in crystal solid state.
N(4) –H···N(2) is observed for 8, 10 and 14 (Figure 3c). This
interaction, stabilizing one tautomer form, could explain the
asymmetric shifts observed in the 1H NMR spectra for the
benzene ring: 8.03 – 7.87 (m, 1H) and 7.81 – 7.57 (m, 3H) (Figure
4a). On the contrary, compound 1, devoid of intramolecular
bond possibility, presents in solution an equilibrium between
two tautomer forms and shows symmetric signals for the
benzene ring: 7.85 (br s, 2H) and 7.70 (dd, J = 5.6, 3.4 Hz, 2H)
(Figure 4b). The respective C-N bond lengths of the guanidine
group display smaller relative difference for compound 1, than
for 8, 10 and 14 (Figure 4c). This supports a higher delocalization
within the guanidine for compound 1, despite undeniable
different behaviors between crystal solid state and solution.
The diazepinedione moiety always presented two C=O bonds,
correlating with 13C NMR shifts for all compounds in the range
of 175-165 ppm (to be compared to the shifts for the N=C–OH
tautomer described around 158 ppm in the literature). 14
Investigating the chemical stability of the guanidine
derivatives of Type C, we identified surprising side-products.
First, we demonstrated that compound 8 degrades in acidic
water at pH = 1 by hydrolysis, with ring-opening of the
diazepinedione to the corresponding carboxylic acid 29 (Figure
5). Then, after leaving this hydrolyzed product for several days,
we progressively observed the formation of the 1,3,5-triazine
30. This compound could originate from a cyclocondensation of
the biguanide onto the carbonyl.
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Therefore, this sequence opens access to a varieVtiyewoAfrtioclreigOinnlinael
“drug-like” compounds with two deDriOvaI:t1i0za.1t0i3o9n/D0sNitJe0s1,229bGy
modulating of the biguanide substitution pattern and by
substitution of the trifluoroester with different nucleophiles.
Here, we provide an exemplification with alcohols; and primary
or secondary, aromatic or aliphatic amines, eventually bearing
additional functionalization like 35.
O
O
O
H2N
N
N
O
OH
NH2
NH
N
H3O+
-H2O
25°C, 14 days
N
N
NH
HN
N
pH 1 water
NH
N
OH
O
N
HN
29
30
8
Figure 5. Degradation pathway of compound 8 in acidic water. After 1 day, almost
full hydrolysis to acid 29 is observed. Then slow cyclocondensation to triazine 30
occurred (25% conversion after 14 days
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rearrangement, and optimized conditions delivered the desired
triazine-trifluoroester 31 under mild conditions (25°C, 24h) with
excellent 97% yield. Then, we took advantage of the lability of
2,2,2-trifluoroesters to use this molecule as a versatile
precursor to produce analogs: the corresponding acid 30 by
hydrolysis, the esters 32 and 33 by transesterification, or the
amides 34-37 by amide condensation (Figure 6). These
reactions proceeded cleanly with a full conversion. From those
compounds, only the acid 30 was known, prepared
conventionally(condensation of biguanide and ortho-ester).15
Conclusions
In conclusion, we described the synthesis and characterization
of 5 types of original polynitrogen-containing compounds,
based on 4 different aryl[e][1,3]diazepinedione cores. Three of
them, the pyrido- and pyrazino- derivatives constitute
unprecedented heterocycles. The chemical properties, X-ray
structures of 4 derivatives were studied, and the investigation
of their stability led to the of an original rearrangement to 1,3,5-
triazine
compounds.
The
30:
31:
32:
33:
34:
35:
36:
37:
84%
R = OH,
R = OCH2CF3,
R = OCH3,
R = OCH2CH3,
O
H2N
N
N
O
97%
91%
H2N
N
N
O
88%
NH
N
i)
ii)
N
N
N
N
NH
HN
96%
R = N(CH3)2,
R = NHCH2CH2OH,
59%
N
F
F
69%
O
R
O
R = NHPh,
R = NHCH2Ph,
F
34%
Figure 6. Synthesis of 2,2,2-trifluoroester rearranged product 31 and derivatization to analogs 30 and 32-37 by the introduction of various nucleophiles. Conditions: i)
2,2,2-trifluoroethanol, 25°C, 24h. ii) alcohol or water, reflux, 15h; or amine (3 eq), dioxane, reflux, 15h.
6 | J. Name., 2012, 00, 1-3
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optimization of this last transformation has been used to create
Benhida, Tetrahedron Lett., 2018, 59, 1642–1645.
a versatile “activated” 2,2,2-trifluoroester which can be 14
derivatized into various functionalized 1,3,5-triazine-based bis-
aryl products. In total, 36 new drug-like heterocyclic structures
have been prepared, useful as derivatization platforms towards 15
biologically active molecules, e.g. antimetabolic or anticancer
drugs.
N. A. Al-Masoudi, W. Pfleiderer and C. Pannecouque,
Zeitschrift fur Naturforsch. - Sect. B J. Chem. Sci., 2012, 67,
835–842.
T. TSUJI, H. MOMONA and T. UEDA, Chem. Pharm. Bull.,
1968, 16, 799–805.
Acknowledgments
The authors are grateful for the financial support from Research
fund of the Cancéropôle PACA and the SATT-Sud Est (EmA grant
– Emergence et Accompagnement), as well as for the grant of
R. Bardovskyi. CNRS, Université Côte d’Azur, ANR and INCA are
also acknowledged for additional funding. The authors also
thank Dr. Michel Giorgi for his support on X-ray crystallography.
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New Journal of Chemistry
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DOI: 10.1039/D0NJ01229G
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Divergence-oriented synthesis of new heterocycles relevant for medicinal chemistry
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