Regioselective piperidine-catalyzed tandem imination-isocyanate annulation to fused tricyclic triazines

Article abstract of DOI:10.1021/co400159z

A novel tandem imination-isocyanate-mediated annulation was explored. Ionic liquid-immobilized 2-aminobenzimidazoles react sequentially with aldehydes and isocyanates to give highly functionalized benzimidazole-embedded triazines. The second-stage transformation revealed that the formation of triazinone functionality is entirely regioselective to allow rapid assembly of biologically interesting tricyclic skeletons. In conjunction with the application of microwave irradiation and IL support, this method provides an efficient route to access substituted benzoimidazotriazines.

Full text of DOI:10.1021/co400159z

Research Article
pubs.acs.org/acscombsci
Regioselective Piperidine-Catalyzed Tandem Imination−Isocyanate
Annulation to Fused Tricyclic Triazines
Indrajeet J. Barve, Chih-Hau Chen, Chih-Hsien Kao, and Chung-Ming Sun*
Department of Applied Chemistry, National Chiao Tung University, Hsinchu 300-10, Taiwan
S
* Supporting Information
ABSTRACT: A novel tandem imination−isocyanate-medi-
ated annulation was explored. Ionic liquid-immobilized 2-
aminobenzimidazoles react sequentially with aldehydes and
isocyanates to give highly functionalized benzimidazole-
embedded triazines. The second-stage transformation revealed
that the formation of triazinone functionality is entirely
regioselective to allow rapid assembly of biologically
interesting tricyclic skeletons. In conjunction with the
application of microwave irradiation and IL support, this
method provides an efficient route to access substituted
benzoimidazotriazines.
KEYWORDS: tandem reaction, imination, isocyanate-mediated annulation, benzoimidazotriazine, ionic liquid, microwave
reactions because of their unique physical properties.10 Apart
from the homogeneous reaction conditions and high loading
INTRODUCTION
■
Fused polyheterocyclic ring systems have played a crucial role
capacity, the progress of IL-supported reactions can be
in medicinal chemistry. Utilization of these types of molecules
monitored by proton NMR spectroscopy without cleavage of
may facilitate the discovery of novel biologically active
the IL support. All of the IL-supported intermediates can be
molecules.1 To understand how small molecules modulate
purified by precipitation and filtration to remove excess
the functions of receptors or enzymes in living systems, the
incorporation of privileged scaffolds into novel core skeletons is
reagents.11 These promising features make ILs suitable as
soluble supports in high-throughput synthesis. The advent of
important to study biology and their treatment of disease.2
microwave-assisted organic synthesis has contributed signifi-
Benzimidazole and triazine compounds have been reported as
nociceptin/orphanin FQ receptor agonists, pan class I
cantly to the development of eco-compatible methods.12,13 The
use of microwave irradiation in combination with IL supports
phosphatidylinositol 3-kinase (PI3K) inhibitors, and thymidine
phosphorylase inhibitors (Figure 1).3−6 However, the biological
enhances energy dissipation and greatly speeds up the reaction.
In this report, we disclose a novel IL-supported synthesis of
profiles of the new scaffolds incorporating other versatile
pharmacophores are unexplored, which might be due to the
benzoimidazotriazines via tandem imination−isocyanate annu-
lation under microwave irradiation. Several synthetic strategies
lack of general methods for the synthesis of these compounds.
have been established to synthesize triazine derivatives.
Although some synthetic routes toward these hybrid cores are
known,7 novel approaches for the efficient construction of
heterocycles comprising chimeric cores with various substitu-
Houghten and co-workers reported the synthesis of 2-imino-
4-oxo-1,3,5-triazino[1,2-a]benzimidazoles using a tandem aza-
Wittig/heterocumulene-mediated annulation reaction of 2-
tions are unexplored.
aminobenzimidazole with alkyl isocyanates.7 Abbiati et al.14
Tandem reactions are multistep reactions combined into one
employed cycloaddition reactions of 2,4-diphenyl-1,3-diazabu-
synthetic operation to provide rapid access to natural and
synthetic fused polycyclic skeletons.8 Furthermore, these
ta-1,3-dienes with a variety of isocyanates and isothiocyanates
to obtain 3,4-dihydro-1H-[1,3,5]triazin-2-ones and 3,4-dihydro-
reactions are also consistent with the principles of green
1H-[1,3,5]triazin-2-thiones, respectively. Furthermore, Ward et
chemistry in that they are time- and cost-effective and more
al.15 reported the cyclization of 2-aminobenzimidazole with
environmentally friendly, consuming less material and generat-
ing less waste.9 The use of imination and isocyanate-mediated
dialkyl ketones, alkyl isocyanates, and alkyl isothiocyanates to
deliver 1,2,3,4-tetrahydro-1,3,5-triazino[1,2-a]benzimidazoles.
cyclization as a domino process has not been explored in the
literature. The purpose of this work is to demonstrate a three-
component cascade reaction for rapid assembly of complex
These synthetic methods typically suffer from a number of
limitations, including lengthy synthetic sequences, low yields,
compounds. The key step of the sequence consists of
regioselective isocyanate-mediated cyclization.
Recently, ionic liquids (ILs) have attracted broad interest as
novel green reaction media and reagents for various chemical
Received: December 10, 2013
Revised: March 9, 2014
Published: March 19, 2014
© 2014 American Chemical Society
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Research Article
Figure 1. Several interesting heterocycles containing benzimidazole and triazine frameworks.
Scheme 1. Synthesis of Benzo[4,5]imidazo[1,2-a][1,3,5]triazines 12
and narrow substrate scope. Obviously, there is no efficient
method to access these privileged scaffolds from commercially
available substrates. Thus, we were enticed to investigate the
possible utilization of imination and isocyanate-mediated
cyclization to afford benzoimidazotriazines in a concise route.
([hydemim][BF4], 1), was prepared in two steps according
to the method reported in the literature.17 Coupling of
commercially available 4-fluoro-3-nitrobenzoic acid (2) with
IL support 1 was carried out in refluxing acetonitrile using
N,N′-dicyclohexylcarbodiimide (DCC) and a catalytic amount
of 4-(N,N-dimethylamino)pyridine (DMAP) to provide IL-
anchored 4-fluoro-3-nitrobenzoate (3) in excellent yield. The
first position of diversity (R1) was introduced by nucleophilic
displacement of the fluorine atom with various amines. This
was achieved by reacting 3 with various amines 4 in refluxing
acetonitrile, affording IL-supported nitroamines 5 in good
yields. In the next step, the nitro group of IL-supported
nitroamines 5 was reduced by zinc and ammonium formate in
refluxing methanol. This zinc reduction reaction proceeded
smoothly to furnish IL-linked diamines 6 in excellent yields.
Treatment of IL-immobilized diamines 6 with cyanogen
bromide in refluxing dichloromethane provided IL-supported
2-aminobenzimidazoles 7 in good yields.
RESULTS AND DISCUSSION
■
Encouraged by the recent reports of the tandem aza-Wittig/
heterocyclization reaction of iminophosphorane18 and cyclo-
addition reactions of diazabutadienes with isocyanates,16 we
envisioned a possible route that utilizes a tandem imination−
isocyanate-mediated annulation to afford tetrasubstituted
benzoimidazotriazines. The synthetic strategy toward benzo-
[4,5]imidazo[1,2-a][1,3,5]triazine derivatives was designed to
study IL-supported synthesis under microwave irradiation. A
synthetic route for the preparation of benzo[4,5]imidazo[1,2-
a][1,3,5]triazines 12 is described in Scheme 1. The IL support,
1-(2-hydroxyethyl)-3-methylimidazolium tetrafluoroborate
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Scheme 2. Catalytic Cycle for the Piperidine-Induced Imination
In the key step of the proposed synthetic sequence, we
planned to prepare triazines 11 from 2-aminobenzimidazoles 7
by tandem imination−isocyanate-mediated annulation. Initially
we attempted imination of IL-tagged 2-aminobenzimidazoles 7
with aldehydes 8 in the presence of Brønsted or Lewis acids,
but incomplete conversion was observed under either reflux or
microwave conditions. On the basis of a previous literature
example,19 we attempted to employ piperidine as a basic
catalyst for imine formation. Condensation of IL-supported 2-
aminobenzimidazoles 7 with aldehydes 8 in the presence of a
catalytic amount of piperidine in toluene under microwave
irradiation at 120 °C for 5 min furnished diazabutadiene
conjugates 9, affording the second point of structural diversity
(R2). This imine bond formation required 18 h in refluxing
toluene, which indicated the significant impact of the
microwave irradiation. The reaction progress and stepwise
transformations on the IL support were monitored by
conventional proton NMR spectroscopy. Conjugate 7 was
reacted with 2-thiophenecarboxaldehyde to yield the corre-
sponding imine conjugate 9. A comparative proton NMR
spectrum analysis of the respective conjugates 7 and 9 revealed
that the spectrum of 9 displayed a singlet at 9.75 ppm due to
the imine proton, which was absent in the spectrum of 7. In
addition, the peaks corresponding to the protons of the
thiophene ring were observed at 7.19 and 7.65 ppm,
respectively in the spectrum of diazabutadiene conjugate 9.
A plausible mechanism for the piperidine-catalyzed imination
of 2-aminobenzimidazole conjugates 7 with aldehydes 8 is
described in Scheme 2. Condensation of aldehydes 8 and
piperidine gives piperidinium hydroxide salt B. Nucleophilic
addition of 2-aminobenzimidazole conjugates 7 to B affords IL-
supported intermediates A upon elimination of H2O. Finally,
the formation of diazabutadiene conjugates 9 is achieved by
expulsion of piperidine.20 The generated IL-bound diazabuta-
diene conjugates 9 were directly used for the next step without
further purification.
the IL-immobilized compounds 11 were purified by precip-
itation and filtration to remove excess reagents and side
products. The success of the isocyanate-mediated annulation
was also confirmed by proton NMR analysis of conjugates 9
and 11, which indicated the disappearance of the imine proton
at 9.75 ppm as well as the emergence of the proton at 6.21
ppm.
A plausible mechanistic route for piperidine-catalyzed [4 + 2]
annulation with isocyanates to give the fused tricyclic
heterocycles 11 is outlined in Scheme 3. The cyclization is
Scheme 3. Possible Mechanism of the Annulation To Give
Diazabutadiene Conjugates 11
initiated by nucleophilic attack on the isocyanate by the
benzimidazole nitrogen atom to form urea C. Subsequently, the
resulting intermediate undergoes an intramolecular heterocyc-
lization to generate the corresponding benzoimidazotriazine 11.
Therefore, the current tandem reaction provides a direct path
for the rapid and regioselective synthesis of fused heterocycles
with multiple sites of molecular diversity.
Finally, removal of the IL support from 11 was carried out in
a solution of ammonia in methanol at room temperature for 8 h
to provide benzo[4,5]imidazo[1,2-a][1,3,5]triazine methyl
esters 12 in good yields. The IL support was then precipitated
out with diethyl ether and removed by filtration. The filtrate
containing final compound was dried and subjected to HPLC
analysis (Table 1). The progress of the cleavage reaction was
monitored by proton NMR spectroscopy of the recovered IL
Exposure of IL-bound intermediates 9 to various isocyanates
10 under microwave irradiation 120 °C for 20 min afforded IL-
supported benzoimidazotriazines 11 in quantitative yield. An
additional point of diversity (R3) was introduced at this stage in
the fused tricyclic scaffold. Upon completion of the reaction,
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Table 1. Substrate Scope for the Synthesis of Benzoimidazoletriazines 12
isolated yield HPLC purity
isolated yield HPLC purity
isolated yield HPLC purity
a
b
a
b
a
b
entry
product
(%)
(%)
entry
product
(%)
(%)
entry
product
(%)
(%)
1
2
3
4
5
6
7
12{1,1,1}
12{2,2,1}
12{2,3,1}
12{3,4,1}
12{4,5,1}
12{5,2,2}
12{5,3,2}
92
89
85
83
80
90
83
86
81
97
84
81
91
82
8
9
12{7,5,2}
12{8,6,2}
12{6,2,3}
12{9,1,3}
12{6,3,3}
12{10,4,3}
84
82
95
92
88
71
82
85
98
93
92
72
14
15
16
17
18
19
12{6,7,3}
12{7,5,3}
12{1,2,4}
12{5,1,4}
12{3,1,5}
12{8,2,5}
90
87
80
89
90
82
97
91
81
92
94
85
10
11
12
13
a
b
Determined from the weight of purified compound. Determined on crude products by normal-phase HPLC analysis.
support. The upfield shift of the α-methylene protons from δ
4.3 to 3.6 confirmed the complete transformation.
To investigate the generality of this unprecedented tandem
either electron-withdrawing or electron-donating groups and a
variety of isocyanates were employed (Table 1). The electronic
effects of the substituted aldehydes have a minor impact on the
conversion. The yields were higher when electron-deficient
imination−isocyanate-mediated annulation, aldehydes having
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Figure 2. ORTEP diagram of compound 12{7,5,3} (Table 1, entry 15).
aldehydes were used. These results are attributed to the higher
reactivity of activated aldehydes. The feasibility of employing
aliphatic aldehydes in the reaction was also investigated
(compound 12{6,7,3}; Table 1, entry 14).
EXPERIMENTAL PROCEDURES
■
General Procedure for the Synthesis of Compounds
12. To a stirred solution of 4-fluoro-3-nitrobenzoic acid (2)
(1.12 mmol, 1.2 equiv) in acetonitrile was added DCC (1.12
mmol, 1.2 equiv), DMAP (0.04 mmol, 0.05 equiv), and IL
support 1 (0.93 mmol, 1 equiv). The reaction mixture was
refluxed for 16 h. After completion of the reaction,
dicyclohexylurea was filtered off, and the filtrate was
concentrated. The crude residue was washed with cold ether
(50 mL × 3) and dried in vacuo to afford 3 in 96% yield. To a
stirred solution of 3 (1.41 mmol, 1 equiv) in acetonitrile was
added amine 4 (1.7 mmol, 1.2 equiv), and the reaction mixture
was refluxed for 4 h. After completion of the reaction, the
solvent was evaporated under reduced pressure. The reaction
mixture was precipitated and washed with cold diethyl ether
(50 mL × 3). The precipitate was dried to give 5 in good yield.
To a stirred solution of 5 in methanol were added zinc (8.96
mmol, 7 equiv) and ammonium formate (19.2 mmol, 15
equiv), and the reaction mixture was refluxed for 30 min. After
completion of the reaction, the reaction mixture was filtered
through a Celite bed to remove zinc, and the filtrate was
concentrated. Dichloromethane (30 mL) was added to the
crude residue to precipitate ammonium formate, and the
mixture was again passed through a Celite bed. The filtrate was
concentrated to yield 6 in good yield. A solution of 6 (1.28
mmol, 1 equiv) and cyanogen bromide (2.56 mmol, 2 equiv) in
dichloromethane (30 mL) was refluxed for 12 h. The crude
material was washed with cold diethyl ether (50 mL × 3) to
afford IL-bound 2-aminobenzimidazole 7 in good yield.
Aldehyde 8 (0.44 mmol, 1.0 equiv) and piperidine (0.2
mmol, 0.5 equiv) were added to a solution of 7 (0.16 g, 0.44
mmol) in toluene. The reaction mixture was subjected to
microwave irradiation at 120 °C for 5 min. After formation of
iminium intermediate 9, isocyanate 10 was added to the
resulting reaction mixture, and the mixture was continuously
microwave-irradiated at 120 °C for 20 min. The reaction
progress was monitored by proton NMR spectroscopy. After
completion of the reaction, the reaction mixture was washed
and precipitated with diethyl ether (50 mL × 3). The
precipitate was filtered and dried to furnish the IL-bound
Additionally, various types of isocyanates were examined to
increase the diversity of benzoimidazotriazines 12. The
substituent on the isocyanate had no obvious influence on
the yield. The significant cooperative effect of microwave
conditions and IL support was proven to dramatically improve
the efficiency of this telescopic imination−isocyanate-mediated
cyclization. We attempted to extend this cascade reaction to
isothiocyanates as well. The reactions of imines 9 with different
isothiocyanates failed to generate benzoimidazothiotriazines
under microwave irradiation. We speculated that the low
electrophilicity of the isothiocyanates (R−NCS) inhibited
the piperidine-catalyzed [4 + 2] cyclization.
In addition to spectroscopic studies, the structure of the
representative compound 12{7,5,3} (Table 1, entry 15) was
further confirmed by single-crystal X-ray structure analysis. The
ORTEP diagram of compound 12{7,5,3} is presented in Figure
2. The tricyclic ring system is aligned in a linear conformation,
and the planar thiophene ring is perpendicular to the plane of
the fused tricycle. The allyl group on N2 and the sulfur atom of
the thiophene ring are oriented in a relative anti position.
CONCLUSION
■
We have developed a highly regioselective cascade reaction for
the synthesis of functionalized benzoimidazotriazines 12
employing 2-aminobenzimidazoles 7, aldehydes 8, and
isocyanates 10. This novel synthetic strategy utilizes an initial
imination followed by an isocyanate-mediated annulation to
deliver the tricyclic scaffold with three points of diversity. A
synergistic effect of microwave heating and the ionic liquid
support was exploited to speed up the tandem process. This
strategy offers a concise route for the convergent synthesis of
densely functionalized benzoimidazotriazines. It is anticipated
that the current method could have potential utility in chemical
synthesis and medicinal chemistry.
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benzoimidazotriazine 11 in excellent yield. A 7 M solution of
ammonia in methanol was added to 11 (0.27 g, 0.44 mmol).
The mixture was stirred at ambient temperature for 8 h. After
completion of the cleavage reaction, the solvent was evaporated
to dryness, and the polymer was precipitated with diethyl ether
(50 mL × 3). The filtrate was concentrated in vacuo, and the
crude product was subjected to HPLC analysis. The title
compound 12 was obtained in excellent yield after purification
by column chromatography.
Methyl 3-Butyl-10-cyclopentyl-2-(4-nitrophenyl)-4-
oxo-2,3,4,10- tetrahydrobenzo[4,5]imidazo[1,2-a]-
1
[1,3,5]triazin-7-ylcarboxylate (12{1,1,1}). H NMR (300
MHz, CDCl3) δ 8.55 (d, J = 1.6 Hz, 1H), 8.24 (d, J = 8.7 Hz,
2H), 7.89 (dd, J = 8.4, 1.6 Hz, 1H), 7.57 (d, J = 8.7 Hz, 2H),
6.97 (d, J = 8.4 Hz, 1H), 6.09 (s, 1H), 4.71 (m, 1H), 3.91 (m,
1H), 3.91 (s, 3H), 2.87 (m, 1H), 2.01 (m, 4H), 1.69 (m, 2H),
1.55 (m, 4H), 1.30 (m, 2H), 0.92 (t, J = 7.2 Hz, 3H); 13C NMR
(75 MHz, CDCl3) δ 167.2, 149.0, 148.6, 148.2, 148.1, 135.7,
127.7, 127.3, 126.8, 124.7, 123.7, 115.3, 108.2, 76.3, 54.4, 52.5,
45.2, 30.0, 28.3, 28.3, 25.3, 20.4, 14.1; IR (cm−1, neat) 2954,
2871, 1710; MS (ESI-MS) m/z 492 [M + H]+; HRMS calcd for
C26H29N5O5 [M + H]+ m/z 491.2169, found 492.2250.
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ASSOCIATED CONTENT
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1996, 96, 115−136.
S
* Supporting Information
Spectral data (1H and 13C NMR, IR, LRMS, HRMS) for
compounds 12 and X-ray data for compound 12{7,5,3}. This
material is available free of charge via the Internet at http://
pubs.acs.org.
(10) Zhang, Q.; Zhang, S.; Deng, Y. Recent advances in ionic liquid
catalysis. Green Chem. 2011, 13, 2619−2637.
(11) Miao, W.; Chan, T. H. Ionic-liquid-supported synthesis: A novel
liquid-phase strategy for organic synthesis. Acc. Chem. Res. 2006, 39,
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AUTHOR INFORMATION
Corresponding Author
*E-mail: cmsun@mail.nctu.edu.tw.
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(13) Kappe, C. O.; Dallinger, D. The impact of microwave synthesis
on drug discovery. Nat. Rev. Drug Discovery 2006, 5, 51−63.
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Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
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(15) Ward, C. E.; Berthold, R. V.; Koerwer, J. F.; Tomlin, J. B.;
Manning, D. T. Synthesis and herbicidal activity of 1,2,3,4-tetrahydro-
1,3,5-triazino[1,2-a]benzimidazoles. J. Agric. Food Chem. 1986, 34,
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The authors thank the National Science Council of Taiwan for
financial assistance and the authorities of the National Chiao
Tung University for providing laboratory facilities. This paper
was particularly supported by “Aim for the Top University
Plan” of the National Chiao Tung University and the Ministry
of Education, Taiwan.
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