Cobalt-catalyzed isocyanide insertion cyclization to dihydrobenzoimidazotriazins

Article abstract of DOI:10.1016/j.tetlet.2017.09.088

We have developed an isocyanide insertion reaction for the synthesis of dihydrobenzo[4,5]imidazo[1,2-a][1,3,5]triazins and imidazol-quinoxaline-5-carboxamides utilizing cobalt catalyst. Cobalt-catalyzed system is inexpensive and more acceptable from industrial point of view.

Full text of DOI:10.1016/j.tetlet.2017.09.088

Accepted Manuscript
Cobalt-catalyzed isocyanide insertion cyclization to dihydrobenzoimidazotria-
zins
Fereshteh Ahmadi, Peiman Mirzaei, Ayoob Bazgir
PII:
S0040-4039(17)31256-X
https://doi.org/10.1016/j.tetlet.2017.09.088
TETL 49358
DOI:
Reference:
To appear in:
Tetrahedron Letters
Received Date:
Revised Date:
Accepted Date:
17 July 2017
25 September 2017
29 September 2017
Please cite this article as: Ahmadi, F., Mirzaei, P., Bazgir, A., Cobalt-catalyzed isocyanide insertion cyclization to
dihydrobenzoimidazotriazins, Tetrahedron Letters (2017), doi: https://doi.org/10.1016/j.tetlet.2017.09.088
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Graphical Abstract
Cobalt-catalyzed isocyanide insertion
cyclization to dihydrobenzoimidazotriazins
Leave this area blank for abstract info.
Fereshteh Ahmadi, Peiman Mirzaei, Ayoob Bazgir

1
Tetrahedron Letters
journal homepage: www.els evier.com
Cobalt-catalyzed isocyanide insertion cyclization to
dihydrobenzoimidazotriazins
Fereshteh Ahmadi, Peiman Mirzaei, Ayoob Bazgir∗
Department of Chemistry, Shahid Beheshti University, General Campus Tehran 1983963113, Iran
ARTICLE INFO
ABSTRACT
Article history:
Received
We have developed an isocyanide insertion reaction for the synthesis of
dihydrobenzo[4,5]imidazo[1,2-a][1,3,5]triazins and imidazol-quinoxaline-5-carboxamides
utilizing cobalt catalyst. Cobalt-catalyzed system is inexpensive and more acceptable from
industrial point of view.
Received in revised form
Accepted
Available online
Keywords:
Isocyanide insertion
Cobalt-catalyzed isocyanide insertion
Benzoimidazotriazine
Triazine
1
5
Introduction
esters, aldehydes, ketones and ortoesters, the introduction of
new methods is still of much interest.
Triazines are planar six-membered benzene-like
1
systems with three nitrogens. Among triazine isomers (1,2,3-
triazine, 1,2,4-triazine and 1,3,5-triazine), the 1,3,5-triazine is
more considered duo to its unique structure and chemical and
2
therapeutical
thiazolidine-dione I and triazine dimer II have been reported as
properties.
For example,
1,3,5-triazine-
DPP-4 inhibitors with antibacterial activity for the treatment of
3
4
type 2 diabetes and antileishmanial agent, respectively (Fig. 1).
Furthermore, 4-(4-aminopyrazolotriazin-8-yl)benzamide III has
been nominated as a highly potent and selective inhibitors of
5
tyrosine threonine kinase. The antiproliferative activity of
fluorinated 1,2,4-triazolo[1,5-a][1,3,5]triazines against lung
cancer A549 and breast cancer MDA-MB-231 cell lines has been
6
established. In addition, some 1,3,5-triazines containing varied
functionalities are particularly prominent in many histamine H4
7
8
receptor ligands, human DNA topoisomerase IIα inhibitors, A1
adenosine receptor antagonists, escherichia coli dihydrofolate
Fig. 1. Some of potent pharmacological agents with 1,3,5-triazine nuclei
9
1
reductase inhibitors and anti cancer agents. Benzimidazole
0
11
New and modern synthetic methodologies that afford simple
access to a broad range of functionalized heterocycles are
critically important in advanced medicinal and combinatorial
chemistry as they allow providing compound libraries and
expanding the available drug-like compounds. The transition
metal-catalyzed C-N bond formation followed by intramolecular
cyclization has received broad attention recently compared to
triazines IV and V have been described as mammalian target of
13
1
rapamycin (mTOR) inhibitor and dual PI3K/Mtor inhibitor,
2
respectively (Fig. 1). 2, 4 or 6-Amino-1,3,5-triazin derivatives
such as furazil, tretamine and dioxadet have been known as
1
4
anticancer drugs. Although there are several conventional
methods for the synthesis of 1,3,5-triazine such as
heterocyclization of biguanides or their analogues with β-keto
1
6-20
traditional methods for the heterocyclic synthesis. The other
important and modern strategy for the heterocycles synthesis is
———
Keywords: Isocyanide insertion, Cobalt-catalyzed isocyanide insertion, Benzoimidazotriazine, Triazine.
∗
Correspondence author: Fax +98-21-22431661; E-mail: a_bazgir@sbu.ac.ir ;

2
Tetrahedron Letters
21
isocyanide insertion cyclization.
Isocyanide insertion
regioisomeric mixture was obtained in moderate isolated yields
(Scheme 1, entries 3b and 3e).
cyclization gives an atom economical, simple and direct synthetic
strategy to complex and structurally diverse molecules using
22
simple substrate. The isocyanide insertion cyclization reaction
is the metal-catalyzed direct insertion of isocyanide into a
heteroatom/carbon-hydrogen or carbon-hologen bond to give an
imidoylative intermediate which subsequently undergoes an
a
Table 1 Optimization of the reaction conditions
2
1-23
intramolecular nucleophilic reaction to give a heterocycle.
Among previous reports, palladium catalyzed isocyanide
insertion cyclization with C-X (X=H, Br or I) bond are very
2
1b-h
common
insertion reaction into the active N–H bonds are rare.
and low cost metal catalyzed direct isocyanide
21i-k
Therefore, the expansion of more inexpensive catalyst systems
for isocyanide insertions cyclization is more desirable. Ji and
coworkers reported cobalt catalyst isocyanide insertion reactions
b
Entry
Solvent
DMF
DMF
DMF
DMF
DMF
Oxidant
-
Catalyst
Yield (%)
1
2
Pd(OAc)
Pd(OAc)
Pd(OAc)
Pd(OAc)
2
22
50
37
46
63
to amine based bisnucleophiles for the synthesis of
aminobenzimidazoles, 2-aminobenzothiazoles, and
2-
2-
2
1J
K
2
S
2
O
8
2
2
2
aminobenzoxazoles. The cobalt-catalyzed isocyanide insertion
reaction to form amino methylidyneaminiums and guanidines
c
2
4,25
3
Ag
2
O
was developed by this group.
cobalt-catalyzed isocyanide insertion cyclization for the synthesis
Very recently, we reported
c
26
4
2 3
Ag CO
of benzoimidazoquinazolines. Herein, we wish to report a new
approach for the synthesis of dihydrobenzoimidazotriazins by
Co-catalyzed isocyanide insertion cyclization.
5
K
2
S
2
O
8
Co(OAc)
2
.4H
2
O
6
7
8
9
DMF
K
K
K
K
K
K
K
2
2
2
2
2
2
2
S
S
S
S
S
S
S
2
2
2
2
2
2
2
O
8
NiCl
2
37
trace
56
Result and discussion
H
2
O
O
8
Co(OAc)
Co(OAc)
Co(OAc)
Co(OAc)
Co(OAc)
Co(OAc)
2
2
2
2
2
2
.4H
2
2
2
2
2
2
O
O
O
O
O
O
The starting point of our study was the reaction of
benzo[d]imidazol-guanidine 1a and t-buthyl isocyanide 2a as
a model reaction in the presence of Pd(OAc) and potassium
carbonate as base in DMF at 80 C (Table 1, entry 1). The
reaction had some side products and the desired product 3a was
separated in 22 % isolated yield after 24 h. When the model
1
5b
PhCH
1,4-Dioxane
CH CN
3
O
8
.4H
2
o
O
8
.4H
.4H
.4H
.4H
51
1
0
3
O
8
51
reaction was performed in the presence of K
entry 2), a satisfactory improvement in the isolated yield was
observed. We also checked the another oxidant like Ag O and
Ag CO (entries 3,4), but unfortunately no improvement was
detected even after 48 h. Therefore, we decided to change the
catalyst. When we changed the catalyst to Co(OAc) .4H O,
surprisingly high conversion was observed after 24 h in DMF and
in the presence of the K (entry 5). Then, we checked the
efficiency of NiCl as catalyst in the reaction and conversion was
less than Co(OAc) .4H after 24 (entry 6). So,
Co(OAc) .4H O was chosen as the best catalyst for the reaction.
After screening the solvents such as PhMe, 1,4-dioxane, MeCN
and H O (entries 7-10), DMF was found to be the most suitable
reaction media, providing benzo[4,5]imidazo-triazine (3a) in
3% isolated yield in the presence of Co(OAc) .4H O (10
(1eq) at 80 C. To optimize the
reaction temperature, we also performed several experiments at
2 2 8
S O as oxidant
d
1
1
2
DMF
O
8
44
(
2
e
1
DMF
DMF
O
8
64
27
2
3
13
-
2 2
Co(OAc) .4H O
2
2
a
2 3
benzo[d]imidazol-guanidine 1a (0.5 mmol), t-BuNC (0.75 mmol), K CO
(
0.5 mmol), oxidant
0.5 mmol), catalyst (10 mol%), solvent (2.0 mL), 80 °C.
2 2 8
S O
(
b
2
c
Isolated yields. Reaction time = 48 h. Reaction temperature = 60 C.
d
o
e
o
Reaction temperature = 100 C.
2
2
O
h
2
2
2
The structures of products 3 were fully characterized by IR,
13
H NMR, C NMR spectroscopy, mass spectrometry, and
1
6
2
2
o
mol%), K
2
CO
3
(1eq) and K
2
S
2
O
8
elemental analysis. The mass spectrum of 3a showed the
molecular-ion peak at m/z 256. The IR spectrum of 5a exhibited
o
-1
absorption bands due to imine groups at 1633 and 1546 cm and
6
0, 80 and 100 C (entries 5, 11 and 12). As can be seen from
o
Table 1, the most suitable reaction temperature was 80 C (entry
). The K played a crucial role in this reaction and when
broad absorption bands for the NH and NH groups was observed
2
-
1
1
at 3429 and 3151 cm . The H-NMR spectrum of 5a consisted of
5
2
S
2
O
8
this reaction was carried out without K
product was 27% (entry 13).
2
S
2
8
O , the yield of the
singlet signal for the t-buthyl group (δ 1.57 ppm) and two broad
H
resonances for the NH and NH groups (δ 6.68 and 7.01 ppm).
2
H
Then, the scope of the isocyanide insertion reaction
cyclization was examined using several substituted
benzoimidazol-guanidines containing both electron-withdrawing
and electron-donating group 1 with various isocyanides 2 under
the optimized reaction conditions and the expected products 3
were obtained in 48-75% isolated yields (Scheme 1). It should
be mentioned that high conversion (>80%) were obtained by
using optimal reaction condition and to gain more isolated yields
we used different purification methods. The column
chromatography was the best purification method and the pure
products were isolated in 50-75% yield. When unsymmetrically
substituted benzoimidazol-guanidine with methyl-substituted
group (1b) was treated with isocyanides, an inseparable
The aromatic hydrogens give rise to characteristic signals in the
1 13
aromatic region of the spectrum. The H-decoupled C-NMR
spectrum of 3a showed 11 distinct signals, in agreement with the
proposed structure.
To achieve more information about the reaction mechanism, a
control radical trapping experiment was conducted using
TEMPO as a radical scavenger to trap possible radical
intermediates (Scheme 2). Surprisingly, no considerable change
took place and the desired product 3a produced in 53 % yields,
2
7
thus indicating the ionic mechanism.

3
R
R
N
N
N
Co(OAc) .4H O / K S O
2
2
2
2
8
N
N
NH
1
+
R -NC
N
H
NH
K2CO3
DMF, 80 °C, 24 h
NH2
H N
2
2
1
R HN
1
3
N
N
N
N
N
N
N
N
N
N
N
N
NH2
NH2
NH2
NH2
N
N
N
N
NH
NH
NH
NH
(3a, 64%)
(3b, 54%)
(3c, 57%)
N
N
N
N
N
N
N
N
N
N
N
N
NH2
NH2
NH2
NH2
N
N
N
N
NH
NH
NH
NH
(
3d, 68%)
(3f, 75%)
(
3e 52%)
N
N
N
Cl
Cl
NH2
N
N
C
l
N
N
N
N
NH2
N
C
l
HN
NH2
N
N
NH
Cy NH
3g, 50%)
(
3h, 53%)
(
(3i, 51%)
Scheme 1. The synthesized benzo[4,5]imidazo[1,2-a][1,3,5]triazines
Scheme 2. TEMPO trapping control experiment
2
1k,25
On the basis of the literature reports
and TEMPO trapping
desired product 3. Doing some control test showed that Path B is
more possible (see supporting information)
experiments, two possible ionic pathways mechanism is
suggested in Figure 2. In the Path A, cobalt acetate reacts with
isocyanide to form isocyanide coordinated cobalt(II) complex I.
Then, under the basic condition, reaction of imidazol guanidine 1
with I gave III. The other plausible pathway for the formation of
III, involves a direct reaction of the cobalt(II) acetate and 1 to
give complex II. Then, isocyanide insertion reaction resulted III
Encouraged by this success, the brimonidine 4 was used as a
versatile compound for isocyanide insertion reaction.
Brimonidine is a drug used as eye drops under the brand names
Alphagan and Alphagan-P to treat open-angle glaucoma or ocular
hypertension, and as a gel, Mirvaso, for facial skin redness in
2
8
rosacea. When this reaction was carried out with birmonidine 4,
it was interesting that the desired product 5 was obtained in trace,
(
Figure2, path B). After the formation of III, two different
insertions into Co-complex III are possible to generate
intermediate IV or V. Co(II) complex IV can be easily oxidized
to result cobalt(III)-complex VI or VII. The intermediates VI or
VII subsequently undergo reductive elimination to afford the
while
yl)amino)quinoxaline-5-carboxamide 6 was produced under the
same reaction conditions (Scheme 3).
N-(alkyl)-6-((4,5-dihydro-1H-imidazol-2-

4
Tetrahedron
Figure 2. Plausible reaction mechanism
Scheme 3. Isocyanide insertion reactionof Birmonidine
In this article, for the first time, an efficient and practical
3. Srivastava, J. K.; Dubey, P.; Singh, S.; Bhat, H. R.; Kumawat, M. K.;
Singh, U. P. RSC. Adv. 2015, 5, 14095.
Chauhan, K.; Sharma, M.; Shivahare, R.; Debnath, U.; Gupta, S.;
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Laufer, R.; Li, S. W.; Liu, Y.; Ng, G.; Lang, Y.; Feher, M.; Brokx, R.;
cobalt-catalyzed isocyanide insertion cyclization of 1-(1H-
benzo[d]imidazol-2-yl)guanidines and isocyanides for the
synthesis of dihydrobenzo[4,5]imidazo[1,2-a][1,3,5]triazins is
developed. Cobalt-catalyzed reaction of brimonidine with
isocyanide resulted in the formation of imidazol-2-yl-amino
quinoxaline-5-carboxamides. Further expansion of the reaction
scope and synthetic applications of this methodology are in
progress in our laboratory.
4
.
5
.
Beletskaya, I.; Hodgson, R.; Mao, G.; Plotnikova, O.; Awrey, D. E.; Mason,
J. M.; Wei, X.; Lin, D. C. C.; Che, Y.; Kiarash, R.; Madeira, B.; Fletcher, G.
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V. J. Fluorine. Chem. 2015, 175, 68.
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.
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Zygmuntc, M.; Sapac, J.; Wojciechowskad, J. K.; Starkb, H.; Kononowicza,
K. K. Eur. J. Med. Chem. 2015, 103, 238.
Acknowledgments
8
. Pogorelčnik, B.; Janežič, M.; Sosič, I.; Gobec, S.; Solmajer, T.; Perdih, A.
Bioorgan. Med. Chem. 2015, 23, 4218.
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Laneri, S.; Lavecchia, A.; Rimoli, M. G. J. Med. Chem. 2002, 45, 5030.
We gratefully acknowledge nancial support from the
Research Council of Shahid Beheshti University.
9
.
1
6
1
0. Srinivasan, B.; Navaei, S. T.; Skolnick, J. Eur. J. Med. Chem. 2015, 103,
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1. Kumar, R.; Gupta, L.; Pal, P.; Khan, S.; Singh, N.; Katiyar, S. B.; Meena,
References and notes
1
2
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Am. Chem. Soc. 2003, 125, 10288; (b) Lee, Y. H.; Kim, C. A.; Jang, W. H.;
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Adv. Drug. Deliver. Rev. 2012, 64, 826.
12. Peterson, E. A.; Boezio, A. A.; Andrews, P. S.; Boezio, C. M.; Bush, T.
L.; Cheng, A. C.; Choquette, D.; Coats, J. R.; Colletti, A. E.; Copeland, K.

5
W.; Dupont, M.; Graceffa, R.; Grubinska, B.; Kim, J. L.; Lewis, R. T.; Liu,
J.; Mullady, E. L.; Potashman, M. H.; Romero, K.; Shaffer, P. L.; Stanton, M.
K.; Stellwagen, J. C.; Teffera, Y.; Yi, S.; Cai, T.; La, D. S. Bioorg. Med.
Chem. Lett. 2012, 22, 4967.
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24. Zhu, T. H.; Xu, X. P.; Cao, J. J.; Wei, T. Q.; Wang, S. Y.; Ji, S. J.
Adv. Synth. Catal. 2014, 356, 509.
25. Zhu, T. H.; Wang, S. Y.; Wei, T. Q.; Ji, S. J. Adv. Synth. Catal. 2015,
357, 823.
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1
3. Smith, A. L.; D’Angelo, N. D.; Bo, Y. Y.; Booker, S. K.; Cee, V. J.;
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Norman, M. H. J. Med. Chem. 2012, 55, 5188.
4
27.
General
procedure
for
the
synthesis
of
N -(tert-
butyl)benzo[4,5]imidazo[1,2-a][1,3,5]triazine-2,4-diamine (3a): A mixture of
1-(1H-benzo[d]imidazol-2-yl)guanidine (0.5 mmol), t-buthyl isocyanide (0.75
2 2 2 3 2 2 8
mmol), Co(OAc) .4H O(0.05 mmol), K CO (0.5 mmol) and K S O (0.5
o
mmol) in DMF was stirred overnight at 80 C. After the completion of the
reaction, the solvent was removed and the residue was purified by column
chromatography over silica gel using Ethyl acetate/MeOH (9:1) as eluent to
1
2
1
3
4. Pomarnacka, E.; Bednarski, P.; Grunert, R.; Reszka, P. Acta. Pol. Pharm.
004, 61, 461.
o
5. (a) Martin, D.; Graubaum, H. Journal. prakt. Chemie. Band. 1981, 323,
03; Dolzhenko, A. V.; Chui, W. K. J. Heterocyclic. Chem. 2006, 43, 95; (c)
give the desired product 3a. Cream powder (64%); mp 248–250 C. IR (KBr)
-
(mmax/ cm ): 3429, 3151, 2965, 2906, 1633, 1546. MS (EI, 70 eV) m/z: 256
1
+
1
3
(ppm) 7.71 (1H, d, JHH = 9.0 Hz, H–
Badaweya, E. S. A. M.; Kappe, T. Arch. Pharm. Pharm. Med. Chem. 1959,
30, 59; (d) Soliman, A. M.; Mohamed, S. K.; El Remaily, M. A. A.; Abdel-
Ghany, H. Eur. J. Med. Chem. 2012, 47, 138.
(M ). H NMR (300 MHz, DMSO-δ
Ar), 7.45 (1H, d, JHH = 9.0 Hz, H–Ar), 7.30 (1H, t,
6
) δ
H
3
3
3
J
HH = 9.0 Hz, H–Ar),
3
7.14 (1H, t, JHH = 9.0 Hz, H–Ar), 7.01 (2H, s, NH
(9H, s, tBu). C NMR (75 MHz, DMSO-δ ): δ
6 C
2
), 6.68 (1H, s, NH), 1.57
(ppm) 162.2, 155.4, 151.4,
144.8, 126.4, 124.9, 119.3, 117.2, 113.6, 53.6, 28.8. Anal. Calcd for
13 16 6
C H N : C, 60.92; H, 6.29; N, 32.79%. Found: C, 60.81; H, 6.35; N, 32.72.
1
3
1
1
1
1
6. Wang, M.; Jin, Y.; Yang, H.; Fu, H.; Hu, L. RSC Adv. 2013, 3, 8211.
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9. Chen, D.; Chen, Q.; Liu, M.; Dai, S.; Huang, L.; Yang, J.; Bao, W.
4
7,8-dimethyl-N -(2,4,4-trimethylpentan-2-yl)benzo[4,5]imidazo[1,2-a]
o
Tetrahedron. 2013, 69, 6461.
[1,3,5]triazine-2,4-diamine (3f). Cream powder (75%); mp 255-257 C. IR
-1
(KBr) (mmax/ cm ): 3489, 3118, 2919, 1646, 1600. MS (EI, 70 eV) m/z: 340
2
2
0. Li, J.; Benard, S.; Neuville, L.; Zhu, J. Org. Lett. 2012, 14, 5980.
1. (a) Qiu, G.; Ding, Q.; Wu, J. Chem. Soc. Rev. 2013, 42, 5257; (b) Gu, Z.
+ 1
(M ). H NMR (300 MHz, DMSO-δ
s, H–Ar), 6.91 (2H, bs, NH ), 6.31 (1H, s, NH), 2.36 (3H, s, CH
s, CH ), 2.08 (2H, s, CH ),1.63 (6H, s, CH ), 0.99 (9H, s, CH- tBu). C NMR
(75 MHz, DMSO-δ ): δ (ppm) 161.4, 155.0, 151.0, 143.2, 133.1, 127.5,
124.5, 118.0, 113.5, 57.2, 50.4, 31.9, 31.6, 29.6, 20.3, 20.3. Anal. Calcd for
: C, 67.03; H, 8.29; N, 24.68%. Found: C, 67.16; H, 8.21; N, 24.58.
6
) δ
H
(ppm) 7.50 (1H, s, H–Ar), 7.25 (1H,
Y.; Zhu, T. H.; Cao, J. J.; Xu, X. P.; Wang, S. Y.; Ji, S. J. ACS. Catal. 2014,
, 49; (c) Tang, T.; Jiang, X.; Wang, J. M.; Sun, Y. X.; Zhu, Y. M.
2
3
), 2.30 (3H,
1
3
4
3
2
3
Tetrahedron. 2014, 70, 2999; (d) Wang, D.; Cai, S.; Ben, R.; Zhou, Y.; Li,
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Tetrahedron
Research Highlight
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Synthesis of dihydrobenzoimidazotriazins
Synthesis of imidazol-2-yl-amino
quinoxaline-5-carboxamides
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Cobalt-catalyzed
isocyanide
insertion
cyclization reaction
Cobalt-catalyzed direct insertion of
isocyanide into the two N-H active bonds