Synthesis of 1-aryl-3H-[1,2,5]triazepino[5,4-a]benzimidazol-4(5H)-ones and quantum chemical investigation of the rotamers of the Boc-protected hydrazide key intermediate

Article abstract of DOI:10.1016/j.mencom.2019.05.017

3H-[1,2,5]Triazepino[5,4-a]benzimidazol-4(5H)-ones were obtained in five steps involving C-acylation of benzimidazole, its N-alkylation with ethyl bromoacetate, the ester hydrolysis, condensation with BocNHNH₂, and the acid-catalyzed heterocycl

Full text of DOI:10.1016/j.mencom.2019.05.017

Mendeleev
Communications
Mendeleev Commun., 2019, 29, 294–295
Synthesis of 1-aryl-3H-[1,2,5]triazepino[5,4-a]benzimidazol-4(5H)-ones
and quantum chemical investigation of the rotamers
of the Boc-protected hydrazide key intermediate
a
a
a
b
a
Mátyás Milen,* Tímea Szabó, András Dancsó, Péter Ábrányi-Balogh* and Balázs Volk
a
b
Directorate of Drug Substance Development, Egis Pharmaceuticals Plc., 1475 Budapest, POB 100, Hungary.
E-mail: milen.matyas@egis.hu
Research Centre for Natural Sciences, Hungarian Academy of Sciences, 1519 Budapest, POB 286, Hungary.
E-mail: abranyi-balogh.peter@ttk.mta.hu
DOI: 10.1016/j.mencom.2019.05.017
3
H-[1,2,5]Triazepino[5,4-a]benzimidazol-4(5H)-ones were
obtained in five steps involving C-acylation of benzimidazole,
its N-alkylation with ethyl bromoacetate, the ester hydrolysis,
N
N
O
N
N
Ar
ring
closure
N
4
steps
condensation with BocNHNH , and the acid-catalyzed hetero-
Ar
N
2
N
H
NH
cyclization of thus obtained 2-(2-aroyl-1H-benzimidazol-1-yl)-
N'-(tert-butoxycarbonyl)acetohydrazides. The geometry of
tert-butyl carbazate rotamers was estimated with quantum
chemical calculations.
O
NH
O
5
examples
HN
Boc
Benzimidazole derivatives play a significant role in organic and
reaction of the carboxylic acids 3a–e with tert-butyl carbazate
1–7
medicinal chemistry. In continuation of our effort to synthesize
triazepine derivatives,8 we report here the preparation of a
novel ring system containing two important cores, namely,
benzimidazole and triazepinone ones.
(BocNHNH ) in the presence of 1-[bis(dimethylamino)methylene]-
2
–10
1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate
(HATU) coupling reagent afforded hydrazides 4a–e in good
overall yields. Protected hydrazide 4b (Ar = Ph) was treated with
a catalytic amount of 10% aqueous solution of HCl in boiling
Initially, 2-aroylbenzimidazoles 1a–e were prepared from
benzimidazole and benzoyl chlorides under basic conditions
according to the reported procedure11 (Scheme 1). Compounds
9
ethanol according to our earlier procedure, however, complete
decomposition was observed and product 5b was not detected by
HPLC-MS. Unfortunately, similar results were obtained when
sulfuric, p-toluenesulfonic and trifluoroacetic acids were tested
as catalysts. Finally, when solutions of protected hydrazides 4
and pyridinium p-toluenesulfonate (PPTS) in ethanol were
refluxed for 48 h, one-pot deprotection and ring closure reaction
took place. The target compounds, 1-aryl-3H-[1,2,5]triazepino-
1
a–e were alkylated with ethyl bromoacetate in the presence of
1
2
Cs CO to give intermediates 2a–e. Mild hydrolysis of ethyl
2
3
esters 2a–e with 5% aqueous solution of NaOH and subsequent
N
N
Ar
O
N
N
Ar
O
i
ii
[
5,4-a]benzimidazol-4(5H)-ones 5 were obtained in low to
6
7–90%
72–98%
N
H
N
H
moderate yields after chromatographic purifications.
O
The synthesis of the desired 1-aryl-3H-[1,2,5]triazepino[5,4-a]-
benzimidazol-4(5H)-ones 5 was also attempted in a different
pathway (Scheme 2). This synthetic approach commenced with
a p-toluenesulfonic acid catalyzed protection of the carbonyl
group of 2-(4-fluorobenzoyl)-1H-benzimidazole 1a with ethylene
1
a–e
OR
2
a–e R = Et
iii
0–95%
6
N
N
Ar
O
3a–e R = H
Ar
13
N
N
glycol to give dioxolane 6. The N-alkylation of intermediate 6
12
with ethyl 2-bromoacetate in the presence of Cs CO led to
2
3
O
N
iv
0–91%
v
the corresponding ethyl benzimidazole-1-acetate derivative whose
hydrazinolysis afforded hydrazide 7. Unfortunately, the anticipated
cleavage of the dioxolane ring and the subsequent cyclization
did not occur upon applying the usual acid-catalyzed methods14
the starting compound 7 remained unchanged.
7
NH
9–32%
NH
HN
O
Boc
a–e
5a–e
4
The structures of the new compounds were confirmed by
IR, H and C NMR measurements as well as by HRMS. In the
a Ar = 4-FC6H4
b Ar = Ph
c Ar = 3-ClC6H4
6 4
d Ar = 4-ClC H
1
13
e Ar = 4-MeOC H
6
4
1
H NMR spectrum (DMSO-d ) of Boc-hydrazides 4, the Boc
6
methyl groups resonated as an interesting non-symmetric multiplet
that was a result of a non-equivalence of protons due to retarded
rotation. For all five hydrazides 4a–e three rotamers could be
Scheme 1 Reagents and conditions: i, ArCOCl, Py, Et N, room temperature,
3
3
h, then 40% NaOH, reflux, 1 h; ii, BrCH CO Et, Cs CO , MeCN/CH Cl ,
2 2 2 3 2 2
room temperature, ~18 h; iii, 5% NaOH, THF/EtOH, room temperature,
0 min, then 1 m HCl; iv, BocNHNH , HATU, DIPEA, THF, room tem-
1
detected in a ratio of 67:18:15 based on the H NMR measure-
2
2
perature, 2 h; v, PPTS, EtOH, reflux, 48 h.
ments. The structure of the possible conformational isomers was
©
2019 Mendeleev Communications. Published by ELSEVIER B.V.
–
294 –
on behalf of the N. D. Zelinsky Institute of Organic Chemistry of the
Russian Academy of Sciences.

Mendeleev Commun., 2019, 29, 294–295
F
group in an intensity ratio of 67:18:15. The three peaks at 1.504,
.335 and 1.253 ppm could be attributed to the 15, 67 and 18%
1
conformers, respectively. We have assumed that the different
t
chemical shifts of the Bu hydrogen atoms were influenced by
N
i
O
ii, iii
45%
the different electron withdrawing effect of the oxygen atom
connected to the Bu group. Considering the atomic charge
distributions in terms of Natural Population Analysis (NPA), one
might see that the relative charge of the C(=O)–O–CMe is
1
a
9
4%
t
N
H
O
6
3
F
changing in the order 4'''b (–0.586), 4'b (–0.582), 4''''b
(
–0.578), 4''b (–0.573). It shows that the relative charge of the
oxygen atom is the least negative in rotamer 4''b, therefore it
draws less electron density from the alkyl group thus causing the
most upfiled chemical shift (calculated amount: 19%, measured:
18% at 1.253 ppm). On the contrary, conformer 4'''b (calculated:
N
N
O
iv (H+)
O
5
a
1
1%) has the largest negative charge causing the most downfield
O
chemical shift (measured: 15% at 1.504 ppm). It is assumed that
the other two conformers (4'b and 4''''b, calculated populations:
60 and 10%, respectively) having similar charges (–0.578 and
NH
H N
2
7
–0.582, respectively) between those of 4''b and 4'''b, are detected
Scheme 2 Reagents and conditions: i, HOCH CH OH, p-TsOH, 120°C,
2
2
as one peak at 1.335 ppm (measured: 67%).
7
h; ii, BrCH CO Et, Cs CO , MeCN/CH Cl , room temperature, ~18 h;
2 2 2 3 2 2
+
In summary, five representatives of 1-aryl-3H-[1,2,5]triazepino-
iii, N H ·H O, EtOH, reflux, 48 h; iv, H O (HCl/H O/EtOH/reflux, or
HClO /CH Cl /room temperature, or H SO /H O/CH Cl /SiO /room
2
4
2
3
2
[5,4-a]benzimidazol-4(5H)-ones 5a–e containing a novel benzene-
4
2
2
2
4
2
2
2
2
temperature, cf. ref. 14).
fused triazepino imidazole ring system have been synthesized.
The H and C NMR spectra of their precursors 4 showed
1
13
investigated in detail for compound 4b with quantum chemical
calculations. The geometry of the conformers was based on the
assumed rotation around the two amide bonds, leading to four
corresponding conformers (Figure 1). The geometries of the
conformers were optimized, and the distribution of the conformers
was determined (for details, see Online Supplementary Materials).
The wB97XD/6-311G++(2d,2p) method considering the implicit
DMSO solvent model together with two explicit DMSO molecules
gave the nearest distribution values compared to the experimental
values (see Online Supplementary Materials, Table S2). When
taking a closer look at the conformers, two times two pairs
can be considered depending on the bonds rotated: 4'b–4''''b,
distinct rotamers in DMSO-d . The conformers were examined
6
with quantum chemical computations and the calculated distribu-
tion based on the conformational analyses and NBO population
analysis corresponded to the experimentally observed ratio of
the conformers, and moreover, the distribution of the chemical
shifts was explained as well.
Online Supplementary Materials
Supplementary data associated with this article (experimental
and computational details, NMR and IR spectra) can be found in
the online version at doi: 10.1016/j.mencom.2019.05.017.
4
''b–4'''b, or 4'b–4'''b, and 4''b–4''''b. Regarding the experi-
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Received: 11th October 2018; Com. 18/5717
295 –
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