A Novel Mechanistic Study on Ultrasound-Assisted, One-Pot Synthesis of Functionalized Benzimidazo[2,1-b]quinazolin-1(1H)-ones

Article abstract of DOI:10.1021/acscombsci.5b00186

Ultrasound-assisted synthesis of benzimidazo[2,1-b]quinazolin-1(1H)-ones was achieved via piperidine-catalyzed three-component reaction of 2-aminobenzimidazoles, an aromatic aldehyde, and 1,3-dione in aqueous isopropanol. This mechanism was first suspected following our identification of unusual reaction intermediates in a one-pot reaction. An unprecedented coupling reaction, it involved a nucleophilic attack by 2-aminobenzimidazole on in situ generated Michael adduct, followed by electrocyclic ring formation reaction. In contrast to the commonly accepted mechanism, that the direct reaction of 2-amino benzimidazole with a Knoevenagel adduct cannot deliver target compounds.

Full text of DOI:10.1021/acscombsci.5b00186

Research Article
pubs.acs.org/acscombsci
A Novel Mechanistic Study on Ultrasound-Assisted, One-Pot
Synthesis of Functionalized Benzimidazo[2,1‑b]quinazolin-1(1H)‑ones
Li-Hsun Chen,† Tsai-Wen Chung,† Bharat D. Narhe,† and Chung-Ming Sun*,†,‡
†Department of Applied Chemistry, National Chiao-Tung University, 1001 Ta-Hseuh Road, Hsinchu 300-10, Taiwan
‡Department of Medicinal and Applied Chemistry, Kaohsiung Medical University, 100, Shih-Chuan first Road, Kaohsiung 807-08,
Taiwan
S
* Supporting Information
ABSTRACT: Ultrasound-assisted synthesis of benzimidazo[2,1-b]quinazolin-1(1H)-ones was achieved via piperidine-catalyzed
three-component reaction of 2-aminobenzimidazoles, an aromatic aldehyde, and 1,3-dione in aqueous isopropanol. This
mechanism was first suspected following our identification of unusual reaction intermediates in a one-pot reaction. An
unprecedented coupling reaction, it involved a nucleophilic attack by 2-aminobenzimidazole on in situ generated Michael adduct,
followed by electrocyclic ring formation reaction. In contrast to the commonly accepted mechanism, that the direct reaction of
2-amino benzimidazole with a Knoevenagel adduct cannot deliver target compounds.
KEYWORDS: ultrasonication, multicomponent reaction, benzimidazo[2,1-b]quinazolin-1(1H)-ones
using benzimidazole was adapted for the synthesis of pyrimido-
benzimidazoles and benzimidazo-quinazoline derivatives.14
Earlier we reported a rapid reaction of polymer-bound N-alkylated
2-amino benzimidazoles, aldehydes, and 1,3-diones under micro-
wave irradiation generated triazafluor-enes.16 This transforma-
tion still remains an attraction in synthesis and in medicinal
chemistry as it produces biologically interesting benzimidazo-
dihydropyrimidine skeleton. Our search for directed green
synthesis of diverse drug-like azaheterocycles prompted us to
apply ultrasound irradiation for current three-component coupling
reaction. The results of our study reveal new insights into the
reaction mechanism. Ultrasound wave causes “acoustic cavita-
tions” to trounce molecular attractive forces and to promote
molecular mixing which increases intimate contact between
different molecules to form highly reactive species. These
activation results in acceleration of reaction and improved product
yields.16,17
INTRODUCTION
■
Multicomponent reactions (MCRs) greatly accelerate chemical
synthesis, converting three or more components into complex
molecules via simple one-pot routes.1 MCRs are frequently
associated with high atom economy since all the reactants are
incorporated in the final products. This effectively contributes
to make MCRs cost-effective, time-efficient, and eco-friendly as
compared to conventional multistep synthesis.
Fused-ring heterocyclic compounds containing nitrogen are
frequently studied owing to their diverse biological properties.2
MCRs utilizing functionalized imidazoles3 and benzimidazole4
are often employed for the synthesis of polyazaheterocycles.
Pyramido-benzimidazoles as a class of azaheterocycles are widely
investigated for their assorted biological properties, such as
antihypertensive,5 anti-inflammatory,6 antioxidant,7 and immu-
nosuppressive8 activity and DNA gyrase inhibitor.9 For example,
bicyclic pyrimidinone I is a potent HIV integrase inhibitor;11
compound II acts as an HIF prolyl hydroxylase inhibitor;12,13
benzimidazoquinazolinone III is an immune-suppressive agent;8
and quinazolinone IV shows antiproliferative activity10 (Figure 1).
A three-component MCR involving 3-aminotriazole, an
aldehyde and 1,3-dicarbonyl compounds was first reported by
Kappe et al. for microwave assisted synthesis of triazole fused
pyrimidine-6-carboxamides.14 Similar multicomponent reactions
In continuation of our research on the use of benzimidazole
skeletons to synthesize drug-like compounds, we studied a
mild reaction condition to provide a simple access toward
Received: December 13, 2015
Revised: January 29, 2016
© XXXX American Chemical Society
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DOI: 10.1021/acscombsci.5b00186
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Figure 1. Biologically active pyrimido-benzimidazoles and benzimidazo-quinazolines.
functionalized benzimidazo-quinazolinones by one pot multi-
component reaction. The substrates, substituted 2-amino-
benzimidazoles were synthesized via aromatic nucleophilic
substitution of o-nitrofluoroarenes with various amines, followed
by nitro reduction to furnish diamines 1. The diamines 1 on
cyclization with cyanogen bromide gave 2-aminobenzimidazoles
2. All these transformations were performed under ultra-
sonication to give better yields in shorter reaction time compared
to those under conventional heating conditions (Scheme 1).18a
We initiated a MCR study by treatment of 2-aminobenzimdazole
2{1,1} (R1 = 5-CO2Me, R2 = 2-(1-cyclohexenyl)ethyl)) with
equimolar quantities of 4-nitrobenzaldehyde 12{3}, 5,5-dimethyl-
1,3-hexadione 13{2}, and a catalytic amount of piperidine
(5 mol %). When the reaction was first tested under ultrasound
in dichloromethane for 2 h, it gave only a trace amount of the
desired product benzimidazo[2,1-b]quinazoli-none 3{1,3,2,1}
(Table 1, entry 1). We quickly screened solvents for this trans-
formation and found that the best conversion (92% yield) was
achieved in isopropanol. When aqueous isopropanol (IPA/H2O =
9:1) was used, this resultedinprecipitation of thecoupling product
upon its formation within 30 min (90%, entry 12).
Scheme 1. Ultrasonic Synthesis of Benzimidazo[2,1-b]-
quinazolin-1(1H)-ones
The product was then obtained in pure form simply by
washing the crude reaction mixture with cold ether. For the
same reaction stoichiometry using aqueous isopropanol, the
coupling reaction took 17 h to go to completion. However, at
room temperature the reaction never went to completion, even
after 72 h, to obtain the coupling product and only imine inter-
mediate was detected.
With the optimized conditions in hand, the scope of the
three-component reaction was studied with a number of
2-aminobenzimidazoles, substituted benzaldehydes and 1,3-diketones
(Figure 2). An electron withdrawing substituent on benzaldehyde
dramatically enhances the yields of benzimidazoquinazolinones
(e.g., 3{1,1,1,1} vs 3{1,3,2,1} in Table 2). However, an electron
a
Table 1. Reaction Optimization Studies of Three-Component Reaction
entry
solvent
time
2 h
yield of 3{1,3,2,1} (%)
1
CH2Cl2
CH2Cl2
MeOH
THF
<5
46
2
12 h
2 h
3
82
4
2 h
<10
20
5
toluene
CH3CN
DMF
2 h
6
2 h
13
7
2 h
<10
92
8
IPA
2 h
9
H2O
30 min
30 min
30 min
30 min
trace
10
11
12
MeOH
IPA
78
90
90
IPA/H2O
a
All reactions were performed on 1.0 mmol scale with equimolar quantities of benzimidazole, diketone, and benzaldehyde.
B
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Figure 2. Diversity elements employed for library synthesis. 2-aminobenzimidazole 2{1,1}−2{1,9}, 2{2,5}, 2{3,5}, 2{4,5}, aldehyde 12{1−6}, and
1,3-dicarbonyl 13{1−2}.
donating substituent on benzaldehyde has an adverse effect and
causes a very slow reaction to give desired product in low yields
(3{1,4,1,8} and 3{1,4,2,9}). The low yields with electron
donating aldehyde is a result of a competing Cannizzaro reaction
which produces 4-methoxybenzyl alcohol and 4-methoxybenzoic
acid as side products. In view of fluorinated molecules playing
an important role in development of biologically more active
and selective agents,19 we used 5-fluoro, 5-trifluoromethyl and
6-fluoro substituted benzimidazoles to obtain fluorine containing
benzimidazo[2,1-b]quinazolin-6-ones (3{2,3,2,5}−3{4,3,2,5}) in
good isolated yields. The tetracyclic triaza guanidine skeleton of
the product was confirmed unambiguously by X-ray single crystal
structure analysis (Figure 3).20
A widely accepted mechanism for such MCRs involves
formation of 3-benzylidene-2,4-pentanedione 4 via Knoevenagel
condensation of an aldehyde with 1,3-dicarbonyl compound.15
Piperidine promotes the first transformation by forming iminium
hydroxide intermediate with the aldehyde.18 In the next step,
nucleophlic attack of benzimidazole sp2 nitrogen on β-carbon of
enone 4 yields adduct 5 that subsequently undergoes cyclization
to generate intermediate 6 which after dehydration yields observed
product 3 (Scheme 2).
at δ 11.80 (−OH) and other singlet at δ 5.50 (Ph−CH) in proton
NMR. Our observation was supported by Kaupp’s work on
Knoevenagel condensation.21 The structure of Michael adduct 7
was further confirmed by single crystal X-ray analysis (Figure 4).20
The “Y” shape of the three-dimensional structure of 7 is
characterized by strong intramolecular hydrogen bonding
between the hydroxyl group of enol and the carbonyl function
on the neighboring ring. Thus, the benzylidene enone 4 is too
short-lived under current reaction conditions and undergoes
1,4 conjugate addition with enolizable ketone, that is, 1,3-dione
instantly. Further addition of dimidone (1 equiv) resulted in
complete consumption of benzaldehyde to yield 7 exclusively.
Silica gel column purification gave Michael adduct 7 as
a major product in 90% yield along with small quantity of
1,8-dioxooctahydroxanthenes 8 (∼5%) as a result of cyclization 7
with elimination of a water molecule22 (Scheme 5). The struc-
ture of 1,8-dioxooctahydroxanthenes 8 was also confirmed by
single crystal X-ray analysis (Figure 5).20
Our attempts to synthesize Knoevenagel adduct using earlier
reports also resulted into the formation of corresponding Michael
adduct only. Since Knoevenagel adduct is highly reactive, it
continues to proceed by 1,4-conjugated addition preferentially
with 1,3-dicarbonyl compounds.22−24
We next attempted to synthesize the Knoevenagel adduct
3-benzylidene-2,4-pentanedione 4 by slow addition of 5,5-
dimethylcyclohexane-1,3-dione 13{2} (1 equiv) into an ethanolic
solution of 4-methoxy benzaldehyde 12{4} (1.2 equiv) with
piperidine under ultrasonic activation for 1 h (Scheme 3). Once
a Knoevenagel adduct is isolated and purified (SI: P. 48−51),
To be able to confirm this plausible mechanism, we planned
to study a stepwise reaction between Knoevenagel adduct,
3-benzylidene-2,4-pentanedione (4) with 2-aminobenzimidazole
(2). However, treatment of benzaldehyde (1 equiv) with 5,5-
dimethylcyclohexane-1,3-dione (1 equiv) for 10 min in
isopropanol under ultrasonication gave only Michael adduct 7
rather than Knoevenagel adduct 4 as suggested by a broad singlet
C
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a
Table 2. Combinatorial Library of Benzimidazo[2,1-b]quinazolin-1(1H)-ones
a
All reactions were perfomed on 1.0 mmol scale with equimolar quanities of three reactants for 30 min under sonication in the presence of
piperidine catalyst. Isolated yields after precipitation in ether.
yield within 30 min. A similar reaction of 2{1,1} with 9-phenyl-
1,8-dioxooctahydroxanthene 8 was unrewarding since no
conversion was detected either under sonication or reflux
conditions (Scheme 5). Tolerance of 8 to nucleophilic addition
of 2-aminobenzimidazole is attributed to its higher stability
under current reaction conditions. These observations confirmed
that the true intermediate in this MCR is Michael adduct 7
instead of the claimed Knoevenagel adduct 4. Michael adduct
7 cannot convert to Knoevenagel product 4 in ultrasonic
condition.
The mechanism for the formation of tetracyclic triazafluorene
by the reaction between 2-aminobenzimidazole and Michael
Figure 3. X-ray crystal structure of 3{1,1,2,5}.
adduct could be proposed as follows. Initial nucleophilic attack
of primary sp3 nitrogen of 2-aminobenzimidazole on enol of
Michael adduct 7 yields the intermediate 9 that after dehydration
we treated it immediately with various 2-aminobenzimidazoles
by the same reaction conditions. But to our surprise, none of
gives enaminone 10a. The intramolecular hydrogen bonding of
Michael adduct 7 activates the enone toward nuleophilic attack of
2-amino-benzimidazole. Iminoenol 10b undergoes retro Michael
type reaction via keto tautomer 10c to produce diazatriene 11
and 1,3-diketone. The diazatriene 11 then undergoes six
electrons thermal electocyclic ring closure to produce observed
product 3. The sp3 nitrogen of benzimidazole ring provides a
driving force for electrocyclization (Scheme 6).25
reactions yielded MCR product. The results clearly show no
nucleophilic addition of the 2-benzimidazole on Knoevenagel
adduct and finally it was decomposed to aldehydes as well as
dimidone in all cases (Scheme 4).
This encouraged us to treat Michael adduct 7 with
2-aminobenzimidazole 2{1,1} under the same reaction con-
ditions. Smooth reaction progress was observed to deliver the
expected benzimidazoquinolinone 3{1,1,2,1} in 87% isolated
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Scheme 2. Commonly Proposed Mechanism of MCR
CONCLUSIONS
■
We disclose here a novel three-component coupling reaction
mechanism of substituted 2-aminobenzimidazoles, aromatic
aldehydes and 1,3-cyclohexadiones under ultrasonic accelera-
tion to synthesize benzimidazoquinazolinones. The detailed
mechanistic investigation of the MCR allowed us to isolate
and identify the true reaction intermediates Michael adducts 7
for the first time in the literature. It is contrary to common belief
that the key step of the reaction is regioselective nucleophilic
attack of primary amino group of 2-aminobenzimidazole on
Michael adduct instead of nucleophilic attack of sp2 nitrogen
of 2-aminobezimidazole ring on Knoevenagel adduct 4. Our
observation is expected to broaden the mechanistic under-
standing of MCRs that proposed to involve highly reactive
Knoevenagel adducts, eventually leading to development of better
synthetic strategies for other biologically interesting compounds.
Figure 4. X-ray crystal structure of 7 with intramolecular hydrogen
bonding.
EXPERIMENTAL SECTION
■
General Procedure for the Synthesis of MCR Products
(3{2,3,2,5}) under Ultrasonic Irradiation. A 50 mL round-bottom
flask was charged with 1-isobutyl-5-(trifluoromethyl)-1H-benzo[d]-
imidazol-2-amine 2{2,5} (200 mg, 1.0 equiv) in the isopropanol/water
solvent mixture (9:1, 10 mL) and 4-nitrobenzaldehyde 12{3} (117 mg,
1.0 equiv), 5,5-dimethylcyclohexane-1,3-dione 13{2} (109 mg, 1.0 equiv),
and piperidine (5 μL, 0.05 mmol) was added to the reaction mass. The
mixture was subjected to ultrasound irradiation for 30 min. The progress
of reaction was monitored by TLC. After completion, the reaction mixture
was cooled in ice cold water and filtered under vacuum. The residue
was washed by cold diethyl ether (3 × 10 mL). The isolated product
6-isobutyl-3,3-dimethyl-12-(4-nitrophenyl)-9-(trifluoromethyl)-3,4,6,12-
tetrahydro-benzo[4,5]imidazo[2,1-b]quinazolin-1(2H)-one (3{2,3,2,5})
was obtained 386 mg in 97% yield.
Figure 5. X-ray crystal structure of 1,8-dioxooctahydroxanthene 8.
Scheme 3. Preparation of Knoevenagel Adduct 4
1H NMR (300 MHz, CDCl3): δ 8.08 (d, J = 8.7 Hz, 2H), 7.54 (d, J =
8.7 Hz, 2H), 7.40 (d, J = 8.4 Hz, 1H), 7.22 (d, J = 8.4 Hz, 1H), 7.14
(s, 1H), 6.59 (s, 1H), 4.11−3.80 (m, 2H), 2.56 (d, J = 18.2 Hz, 1H), 2.47
(d, J = 18.2 Hz, 1H), 2.42−2.27 (m, 1H), 2.20 (d, J = 16.4 Hz, 2H), 2.16
(d, J = 16.4 Hz, 2H), 1.05 (s, 3H), 1.00 (d, J = 6.7 Hz, 3H), 0.98 (d, J =
6.7 Hz, 3H), 0.91 (s, 3H). 13C NMR (75 MHz, CDCl3): δ 194.7, 163.8,
151.1, 148.1, 147.8, 134.0, 129.1, 128.2, 125.3, 124.4, 121.1, 109.6, 107.7,
106.9, 55.4, 50.5, 46.7, 45.0, 32.9, 29.6, 28.3, 27.7, 22.7, 20.4, 20.4.
HRMS (ESI) Calcd m/z for C27H28F3N4O3 [M + H]+: 513.2113.
Found: 513.2114
General Procedure for the Synthesis of Michael Adduct: 2,2′-
(Phenylmethylene) Bis(3-Hydroxy-5,5-dimethylcyclohex-2-
enone) (7). A 50 mL round-bottom flask was charged with
benzaldehyde 12{1} (1.0 g, 1 equiv), 5,5-dimethylcyclohexane-1,3-
dione 13{2} (1.32 g, 1.0 equiv), and piperidine (0.04 g, 0.05 equiv) in
A regioisomeric product 3′ which could result from nucleophlic
attack of sp2 ring nitrogen of benzimidazole on Michael adduct
7 is not observed. The regioselective formation of 3 over 3′ is
attributed to minimum steric crowding during the nucleophlic
attack of primary amine as compared to that of secondary sp2 ring
nitrogen of 2-aminobenzimidazole.
Finally, we have successfully synthesized possible intermedi-
ates 9{1,1}, 9{2,2}, and 9{2,3} by trapping reaction of Michael
adduct 7 with various 2-aminobenzimidazoles (Supporting
Information, pp 52−54) (Scheme 7)
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Scheme 4. Reaction of Knoevenagel Adduct and 2-Aminobenzimidazoles
Scheme 5. Verification of Mechanistic Course of MCR
Scheme 6. Probable Mechanism of Three-Component Reaction through Michael Adduct
the isopropanol/water solvent mixture (9:1, 10 mL). The reaction
mass was subjected to ultrasound irradiation for 10 min. The progress
of reaction was monitored by TLC. After completion, the reaction
mixture was cooled in ice cold water and filtered under vacuum.
The residue was washed by cold hexane (3 × 10 mL). The obtained
product was dried under vacuum to give 2,2′-(phenylmethylene)
bis(3-hydroxy-5,5-dimethylcyclohex-2-enone) (7) 3.12 g in 90% yield.
The residual filtrate was purified via column purification to give
1,8-dioxooctahydroxanthenes (8) (∼5% yield).
1H NMR (400 MHz, CDCl3): δ 11.97 (s, 1H), 10.30 (s, 1H), 7.27 (t,
J = 7.6 Hz, 2H), 7.17 (t, J = 7.2 Hz, 1H), 7.12 (d, J = 8.0 Hz, 2H), 5.57
(s, 1H), 2.55−2.25 (m, 8H), 1.24 (s, 6H), 1.10 (s, 6H). 13C NMR
F
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Scheme 7. Isolation of Intermediates 9{1,1}, 9{2,2}, and 9{2,3}
(101 MHz, CDCl3): δ 190.4, 189.4, 138.1, 128.2, 126.8, 125.8, 115.6,
47.1, 46.4, 32.8, 31.4, 29.6, 27.4. MS (ESI): m/z 369 [M + H]+; HRMS
(ESI): calcd for C23H28O4, 369.2060, found 369.2065 [M + H]+.
General Procedure for the Synthesis of Knoevenagel Adduct:
2-(4-Methoxybenzylidene)-5,5-dimethylcyclohexane-1,3-
dione (4). A 50 mL round-bottom flask was charged with
4-methoxybenzaldehyde 12{4} (0.9 g, 1.2 equiv), ethanol (9 mL),
and piperidine (0.03 g, 0.05 equiv). The reaction mixture was added
5,5-dimethylcyclohexane-1,3-dione 13{2} (1.0 g, 1.0 equiv) slowly
portion by portion over 5−10 min and the mixture was subjected
to ultrasound irradiation for 1 h. The progress of the reaction was
monitored by TLC. After completion, the reaction mixture was
quenched with ice cold water and filtered under vacuum. The residue
was purified via flash chromarograohy (gradient elution 10:1 to 6:1 in
Hex/EtOAc). The product was obtained and dried under vacuum to
give 2-(4-methoxybenzylidene)-5,5-dimethylcyclohexane-1,3-dione (4)
was obtained 0.17 g in 10% yield.
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The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acscombs-
ci.5b00186.
General experimental methods, 1H and 13C NMR spectra
of the desired products, and X-ray characterizations
(PDF)
X-ray data for 3{1,1,2,5} (CIF)
X-ray data for 7 (CIF)
X-ray data for 8 (CIF)
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AUTHOR INFORMATION
Corresponding Author
*E-mail: cmsun@mail.nctu.edu.tw.
Notes
■
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The authors wish to thank the Ministry of Science and
Technology of Taiwan for financial support and the authorities
of the National Chiao Tung University for providing the
laboratory facilities. This study was particularly supported by the
“Centre for bioinformatics research of aiming for the Top
University Plan” of the National Chiao Tung University and
Ministry of Education, Taiwan.
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DOI: 10.1021/acscombsci.5b00186
ACS Comb. Sci. XXXX, XXX, XXX−XXX

ACS Combinatorial Science
Research Article
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DOI: 10.1021/acscombsci.5b00186
ACS Comb. Sci. XXXX, XXX, XXX−XXX