Selective one-pot synthesis of 11-arylmethylidene-11H-isoindolo-[2,1-a]benzimidazoles and 6-arylbenzimidazo[2,1-a]isoquinolines from o-alkynylbenzaldehydes and o-diaminobenzenes

Article abstract of DOI:10.1016/j.mencom.2017.05.004

Cyclization of o-alkynylbenzaldehydes with o-diaminobenzenes in DMSO under the sequential action of NH₄Br and K₂CO₃ affords 11-arylmethylidene-11H-isoindolo[2,1-a]-benzimidazoles as a result of 5-exo-dig ring closure; whereas replacement of treating with K₂CO₃ by heating at 110–115?°C results in 6-endo-dig cyclization with formation of 6-arylbenzimidazo[2,1-a]isoquinolines.

Full text of DOI:10.1016/j.mencom.2017.05.004

Mendeleev
Communications
Mendeleev Commun., 2017, 27, 231–233
Selective one-pot synthesis of 11-arylmethylidene-11H-isoindolo-
[2,1-a]benzimidazoles and 6-arylbenzimidazo[2,1-a]isoquinolines
from o-alkynylbenzaldehydes and o-diaminobenzenes
Valentin D. Gvozdev,* Konstantin N. Shavrin, Esfir G. Baskir, Mikhail P. Egorov and Oleg M. Nefedov
N. D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences, 119991 Moscow, Russian Federation.
Fax: +7 499 135 5328; e-mail: vgvozdev2006@yandex.ru
DOI: 10.1016/j.mencom.2017.05.004
R3
O
R1
R2
Cyclization of o-alkynylbenzaldehydes with o-diamino-
NH2
+
benzenes in DMSO under the sequential action of NH4Br
and K2CO3 affords 11-arylmethylidene-11H-isoindolo[2,1-a]-
benzimidazoles as a result of 5-exo-dig ring closure; whereas
replacement of treating with K2CO3 by heating at 110–115 °C
results in 6-endo-dig cyclization with formation of 6-aryl-
benzimidazo[2,1-a]isoquinolines.
R2
NH2
DMSO, NH4Br
DMSO,
20 °C
DMSO,
115 °C
K2CO3
R3
R3
R2
R2
R2
R2
N
N
N
N
R1 = Ph, 2-thienyl,
4-ButC6H4
R2, R3 = H, Me
R1
R1
48–69%
64–84%
Fused N-heterocyclic building blocks are ubiquitous in natural
products and play a significant role in the pharmaceutical and
agrochemical industries.1 Among numerous known fused hetero-
cyclic systems, benzimidazoisoquinolines attract special atten-
tion as they show important biological properties, e.g. anti-HIV-1,
anticancer, antimicrobial, and antifungal activities.2 Methods for
their synthesis are based mainly on the reactions of 2-alkynyl-
benzaldehydes with o-phenylenediamines, which require harsh
conditions.3,4 Also, efficient copper-catalyzed syntheses of benz-
imidazoisoquinolines via reactions of 2-alkynylbenzaldehydes
and benzenediamines in the presence of NBS or iodine5 as well
as underAgi catalysis in water6 were described. Recently, cascade
synthesis of alkyl 6-aminobenzimidazo[2,1-a]isoquinoline-
5-carboxylates based on the reaction between 2-(o-bromoaryl)-
benzimidazoles and cyanoacetic acid derivatives, has been
developed.7
11-Methylidene-11H-isoindolo[2,1-a]benzimidazoles, which
are isomers of benzimidazoisoquinolines, are less investigated.
A limited number of these compounds have been synthesized8
by cyclization of 2-arylbenzimidazoles with carboxylic acids in
the presence of Pd(OAc)2. However, they can serve as potential
scaffolds due to the presence of pharmacophore isoindole9 and
benzimidazole10 fragments.
Earlier we have developed a universal strategy for synthesis
of various N,N-11–13 and N,O-heterocyclic13,14 systems based
on the interaction of alk-4-ynals with corresponding diamines
or amino alcohols in DMSO under the action of bases. Further it
was found,15,16 that the use of o-diaminoarenes as binucleophilic
agents in reactions with alk-4-ynals in NH4Br–base–DMSO
system is an efficient, transition metal-free and stereoselective
procedure to access 1-arylmethylidene-2,3-dihydro-1H-pyrrolo-
[1,2-a]benzimidazoles.
Taking into account these results, we supposed that involve-
ment of o-alkynylbenzaldehydes into similar transformations
would allow one to obtain 11-arylmethylidene-11H-isoindolo-
[2,1-a]benzimidazoles or 6-arylbenzimidazo[2,1-a]isoquinolines
as a result of reaction sequence including oxidative cyclization
into the corresponding benzimidazoles and intramolecular hydro-
amination of the triple bond in 5-exo-dig or 6-endo-dig fashion.
Similar to analogous reaction of alk-4-ynals, stirring equi-
molar amounts of aldehydes 1a–c and o-diaminobenzenes 2a–c
in dry DMSO in the presence of NH4Br for 24 h at room
temperature, according to NMR spectra, selectively gives the
corresponding 2-substituted benzimidazoles 3a–e (Scheme 1).
In separate experiments, benzimidazoles 3b and 3c were individually
isolated in 67 and 78% yields, respectively.
Attempt to perform selective intramolecular cyclization of
these compounds under the action of KOH, which had been
successfully employed in analogous processes with 2-(alk-
4-ynyl)benzimidazoles,16 failed. Thus, stirring the solution of
O
R3
R1
R2
R2
NH2
NH2
DMSO, NH4Br
20 °C, 24 h
+
1a–c
2a–c
R3
6
R2
5a
9a
7
N
i
4
1
4b
4a
R2
3
2
R3
8
+ 5a–e
R2
N
11
9
11a
R2
N
R1
4a–e
N
H
R3
11
R2
11a
7a
1
2
N
12a
R1
ii
10
9
12b
4a
3
3a–e
R2
N
8
4
6
5
R1
1a R1 = Ph
5a–e
3–5: a R1 = Ph, R2 = R3 = H
1b R1 = 2-thienyl
1c R1 = 4-ButC6H4
b R1 = Ph, R2 = Me, R3 = H
c R1 = 2-thienyl, R2 = R3 = H
d R1 = 2-thienyl, R2 = H, R3 = Me
e R1 = 4-ButC6H4, R2 = R3 = H
2a R2 = R3 = H
2b R2 = Me, R3 = H
2c R2 = H, R3 = Me
Scheme 1 Reagents and conditions: i, K2CO3, DMSO, 20°C; ii, DMSO,
110–115°C.
© 2017 Mendeleev Communications. Published by ELSEVIER B.V.
on behalf of the N. D. Zelinsky Institute of Organic Chemistry of the
Russian Academy of Sciences.
– 231 –

Mendeleev Commun., 2017, 27, 231–233
3a,b,e
Table 1 Synthesis of products 4a–e and 5a–e.
– H+
R2
Reaction
Reaction
time/h
Product ratio by NMR
[isolated yield (%)]
Reactants
conditionsa
R2
N
i
ii
3
4
4a (59):5a, 5:1
5a (80)
1a + 2a
1a + 2b
1b + 2a
1b + 2c
N
i
ii
4
4
4b (52):5b, 5.5:1
5b (84)
R1
6a,b,e
i
ii
2
4
4c (69):5c, 13:1
5c (78)
i
ii
2
4
4d (65):5d, 10:1
5d (65)
i
ii
10
5
4e (48):5e, 2.9:1
5e (72)
R2
R2
1c + 2a
N
N
R2
R2
N
N
a See Scheme 1.
R1
R1
benzimidazole 3a in DMSO with twofold molar excess of powdered
KOH at room temperature, according to the NMR spectroscopic
data, caused full conversion of the starting material with forma-
tion of a complex mixture where overall content of products 4a
and 5a (1.7:1 ratio) did not exceed 50%. Luckily, replacement
of KOH by less basic K2CO3 provided better results. Stirring the
solution of benzimidazole 3a with twofold excess of this reagent
for 3 h resulted in more selective and efficient intramolecular
cyclization affording isoindolo[2,1-a]benzimidazole 4a and 6-aryl-
benzimidazo[2,1-a]isoquinoline 5a in 5:1 ratio and overall
yield of ~90%. Similar results were obtained in cyclization of
benzimidazole 3b, whereas benzimidazoles 3c,d bearing more
electronegative thienyl group at the triple bond underwent the
ring closure more regioselectively giving the corresponding
products 4c, 5c and 4d, 5d in 13:1 and 10:1 ratios, respectively.
On the contrary, reaction of benzimidazole 3e with K2CO3
appears to be less regioselective, and products 4e and 5e were
formed in 2.9:1 ratio (NMR). This can be explained by reduced
electronegativity of 4-tert-butylphenyl group compared to the
phenyl and thienyl ones, which discourages anionic 5-exo-dig-
hydroamination of the triple bond. After common aqueous
workup of reaction mixture, individual compounds 4a–e can be
isolated by column chromatography (for 4a, 4c–e) or double
recrystallization from hexane (for 4b) in 48–69% yields.†
8a,b,e
7a,b,e
5
4
Ea/kcal mol–1
E0/kcal mol–1
R1
R2
H
Me
H
6 ® 7
6 ® 8
7
8
a
b
e
Ph
Ph
22.3
21.7
22.0
18.9
18.2
19.2
6.7
6.2
6.5
11.2
10.1
12.0
4-ButC6H4
Scheme 2
ducts with Z-configured exocyclic double bond. Their identi-
fication was performed based on the 2D NOESY proton spectra,
showing correlations between methine proton at the double bond
and the proton at the 1-position, as well as between ortho-protons
in arylmethylidene substituent and the proton at the 9-position.
Also, in case of compound 4d, only one regioisomer bearing
methyl group at the 6-position was formed, which points to high
sensitivity of base-induced ring closure in benzimidazoles 3 to
steric environment of nitrogen atoms.
We have also found that minor products of the above reac-
tion, benzimidazo[2,1-a]isoquinolines 5a–e, can be selectively
obtained in 64–84% yields by simple heating solutions of benz-
imidazoles 3a–e in DMSO at 110–115°C for 4–5 h (Scheme 1).‡
Experimental data are in good agreement with B3LYP/
6+31G(d,p) calculations of intramolecular cyclization of N-anions
6a,b,e, which is a probable key step of the studied transforma-
tion. These calculations showed that 6-endo-dig-cyclization into
six-membered anions 7 (DE0 = 6.2–6.7 kcal mol–1) is thermo-
dynamically more favorable than 5-exo-dig-cyclization into anions
8 (DE0 = 10.1–12.0 kcal mol–1). However, the latter process is
characterized by lower activation barrier (18.2–19.2 kcal mol–1),
which makes it dominant reaction route (Scheme 2).
(11Z)-11-Benzylidene-11H-isoindolo[2,1-a]benzimidazole 4a was
prepared from aldehyde 1a and diamine 2a and isolated in 59% yield
by column chromatography [hexane–THF (3:1) as eluent]. 1H NMR, d:
3
3
3
5.79 (d, 1H, C9H, J 8.2 Hz), 6.87 (dd, 1H, C8H, J 8.2 Hz, J 7.5 Hz),
7.13 (s, 1H, CHPh), 7.17 (dd, 1H, C7H, 3J 8.0 Hz, 3J 7.5 Hz), 7.44–7.59
(m, 7H, C2H, C3H, Ph), 7.74 (d, 1H, C6H, 3J 8.0 Hz), 7.80–7.85 (m, 1H,
C1H), 8.01–8.09 (m, 1H, C4H). 13C NMR, d: 110.0 (CHPh), 114.2 (C9),
120.3, 120.7, 121.7 (C1, C4, C6), 122.8, 122.9 (C7, C8), 126.9 (C11a),
128.5, 129.6, 129.9 (C2, C3, C4, Ph), 128.6, 130.2 (C2, C3, C5, C6, Ph),
129.2, 132.5, 135.1, 140.7 (C11, C4a, C9a, C1, Ph), 148.8 (C5a), 158.0 (C4b).
HRMS, m/z: 295.1230 [M+H]+ (calc. for C21H14N2, m/z: 295.1231).
For characteristics of compounds 4b–e, see Online Supplementary
Materials.
Note that the formation of isoindolobenzimidazoles 4 from
aldehydes 1 proceeds stereoselectively, giving exclusively pro-
†
11-Arylmethylidene-11H-isoindolo[2,1-a]benzimidazoles 4a–e (general
procedure). A solution of o-diaminobenzene 2 (1 mmol) in anhydrous
DMSO (2 ml) was slowly added to a solution of the corresponding
aldehyde 1 (1 mmol) in DMSO (2 ml). Then, NH4Br (39 mg, 0.4 mmol)
was added and the resulting mixture was stirred in the contact with dry
air at room temperature for 24 h. Thereafter, freshly powdered anhydrous
K2CO3 (275 mg, 2 mmol) was added, and the resulting suspension was
stirred in argon atmosphere at room temperature for time specified in
Table 1 (the reaction progress was monitored by NMR). Then, water
(30 ml) and Et2O (30 ml) were added, and the organic layer was separated.
The aqueous layer was additionally extracted with Et2O (3×10 ml). The
combined organic layers were washed three times with water, dried over
anhydrous Na2SO4, and the solvent was evaporated. The residue was
subjected to column chromatography on silica gel or to double recrystal-
lization from hexane–THF to give compounds 4a–e.
‡
6-Arylbenzimidazo[2,1-a]isoquinolines 5a–e (general procedure).
A solution of o-diaminobenzene 2 (1 mmol) in anhydrous DMSO (2 ml)
was slowly added to a solution of the corresponding aldehyde 1 (1 mmol)
in DMSO (2 ml). Then, NH4Br (39 mg, 0.4 mmol) was added. The mixture
was stirred in the contact with dry air at room temperature for 24 h and
thereafter was heated at 110–115°C for 4–5 h. After cooling to room
temperature, water (30 ml) and Et2O (30 ml) were added, and the organic
layer was separated. The aqueous layer was additionally extracted with
Et2O (3×10 ml). The combined organic layers were washed three times
with water, dried over anhydrous Na2SO4, and the solvent was evaporated.
The residue was subjected to recrystallization from hexane–THF to give
products 5a–e.
– 232 –

Mendeleev Commun., 2017, 27, 231–233
2 (a) S. M. Rida, S. A. M. El-Hawash, H. T. Y. Fahmy, A. A. Hazzaa and
This reaction, in conjunction with oxidative cyclization of
aldehydes 1 with aromatic diamines 2 in DMSO in the presence
of NH4Br, represents a convenient one-pot approach to the fused
isoquinolines from available starting compounds. Compared to
known procedures which require application of transition metal
catalysts, harsh conditions (lengthy heating at high temperatures)
or toxic solvents (like nitrobenzene), it is characterized by low
cost of reagents and simple experimental technique.
In summary, we have developed new one-pot transition metal-
free syntheses of 11-arylmethylidene-11H-isoindolo[2,1-a]benz-
imidazoles and 6-arylbenzimidazo[2,1-a]isoquinolines from
o-alkynylbenzaldehydes and o-diaminobenzenes in DMSO. An
important feature of this approach is opportunity to perform
5-exo-dig or 6-endo-dig ring closure at the final stage by simple
modification of reaction conditions.
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This work was supported by the Russian Foundation for Basic
Research (grant no. 15-03-08195 A).
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Online Supplementary Materials
Supplementary data associated with this article can be found
in the online version at doi: 10.1016/j.mencom.2017.05.004.
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6-Phenylbenzimidazo[2,1-a]isoquinoline 5a was prepared from aldehyde
1a and diamine 2a in 80% yield. 1H NMR, d: 6.49 (d, 1H, C8H, 3J 8.4 Hz),
6.88 (s, 1H, C5H), 7.00 (dd, 1H, C9H, 3J 8.4 Hz, 3J 7.7 Hz), 7.39 (dd, 1H,
C10H, 3J 8.2 Hz, 3J 7.7 Hz), 7.54–7.74 (m, 8H, C2H, C3H, C4H, Ph), 8.01
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Nefedov, Russ. Chem. Bull., Int. Ed., 2016, 65, 1829 (Izv. Akad. Nauk,
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1242.
3
(d, 1H, C11H, J 8.2 Hz), 8.85–8.95 (m, 1H, C1H). 13C NMR, d: 112.6,
114.1 (C5, C8), 119.5 (C11), 121.2, 124.2 (C9, C10), 122.7 (C12b), 125.0,
126.6, 127.8, 129.8, 130.1 (C1, C2, C3, C4; C4, Ph), 128.9, 129.3 (C2, C3,
C5, C6, Ph), 130.6, 131.5, 134.5 (C7a, C11a; C1, Ph), 137.4 (C6), 144.0
(C4a), 148.1 (C12a). HRMS, m/z 295.1226 [M+H]+ (calc. for C21H14N2,
m/z: 295.1231). These data are in good agreement with the reported ones.17
For characteristics of compounds 5b–e, see Online Supplementary
Materials.
Received: 7th October 2016; Com. 16/5067
– 233 –