Synthesis of benzoimidazoquinazolines by cobalt-catalyzed isocyanide insertion-cyclization

Article abstract of DOI:10.1039/c6ra06828f

An efficient and practical protocol for the synthesis of benzoimidazoquinazoline amines in moderate to good yields by the reaction of isocyanides and benzo[d]imidazol-anilines via a cobalt-catalyzed isocyanide insertion cyclization reaction into the two N

Full text of DOI:10.1039/c6ra06828f

View Article Online
View Journal
RSC Advances
This article can be cited before page numbers have been issued, to do this please use: F. Ahmadi and A.
Bazgir, RSC Adv., 2016, DOI: 10.1039/C6RA06828F.
This is an Accepted Manuscript, which has been through the
Royal Society of Chemistry peer review process and has been
accepted for publication.
Accepted Manuscripts are published online shortly after
acceptance, before technical editing, formatting and proof reading.
Using this free service, authors can make their results available
to the community, in citable form, before we publish the edited
article. This Accepted Manuscript will be replaced by the edited,
formatted and paginated article as soon as this is available.
You can find more information about Accepted Manuscripts in the
Information for Authors.
Please note that technical editing may introduce minor changes
to the text and/or graphics, which may alter content. The journal’s
standard Terms & Conditions and the Ethical guidelines still
apply. In no event shall the Royal Society of Chemistry be held
responsible for any errors or omissions in this Accepted Manuscript
or any consequences arising from the use of any information it
contains.
www.rsc.org/advances

Page 1 of 6
RSC Advances
View Article Online
DOI: 10.1039/C6RA06828F
Journal Name
RSCPublishing
ARTICLE
Synthesis of benzoimidazoquinazolines by cobalt-
catalyzed isocyanide insertion-cyclization
Cite this: DOI: 10.1039/x0xx00000x
Fereshteh Ahmadi and Ayoob Bazgir*
Received 00th January 2012,
Accepted 00th January 2012
DOI: 10.1039/x0xx00000x
www.rsc.org/
Abstract:
An efficient and practical protocol for the synthesis of benzoimidazoquinazoline amines in
moderate to good yields by the reaction of isocyanides and benzo[d]imidazol-anilines via a
cobalt-catalyzed isocyanide insertion cyclization reaction into the two N-H active bonds is
reported.
or C–halogen bonds are very popular [5] and direct isocyanide
insertion reaction into the active N–H bonds are still rare [6]. It is
Introduction
Isocyanide core is a well known scaffold for the construction of
many building blocks and the importance of isocyanides is well
recognized because of their nucleophilicity and electrophilicity
potential in multi-component reactions [1]. Although the first
century of isocyanide chemistry was focused on multi-component
reactions, isocyanide-based reactions using transition metal catalysts
have received significant attention during the past several years [2].
Among of the metal-catalyzed isocyanide-based reactions,
isocyanide insertion (also called imidoylative reaction) is a powerful
strategy in the synthesis chemistry. The isocyanide insertion refers to
notable that the most of the previous isocyanide insertion reactions
were carried out using palladium catalysts which have exhibited high
catalytic activity for a wide range of substrates [7].
RHN
Br
N
NH2
NH2
R
NH
N
NH2
N
N
H
H
N
H
RNC
the metal-catalyzed direct insertion of isocyanide into
a
NHR O
N
O
HN
heteroatom/carbon−hydrogen or carbon−halogen bond to give an
imidoylative intermediate, which can be trapped by various
nucleophiles [3]. Recently, isocyanide insertion-cyclization reactions
with different nucleophiles have been developed for the synthesis of
various N-heterocyclic compounds [4] (Fig. 1). Among these reports,
transition-metal catalyzed isocyanide insertion-cyclization with C–H
O
NH
I
NHR
N
R
O
Figure 1. Synthesis of heterocycles via isocyanide insertion reaction.
However, the high cost of palladium has constricted a more general
use of such protocol in large scale productions. Therefore, the
development of new and more inexpensive catalyst systems and their
application on isocyanide insertions are desirable. To the best of our
knowledge, there are only a few reports of isocyanide insertion-
Department of Chemistry, Shahid Beheshti University, General Campus, Tehran
1983963113, Iran .E-mail: a_bazgir@sbu.ac.ir; Tel: +982129903104
†
Electronic Supplementary Information (ESI) available: [details of any
supplementary information available should be included here]. See
DOI: 10.1039/x0xx00000x
This journal is © The Royal Society of Chemistry 2013
J. Name., 2013, 00, 1-3 | 1

RSC Advances
Page 2 of 6
VJieowuArrtnicalelONnlainme e
ARTICLE
DOI: 10.1039/C6RA06828F
cyclization for the synthesis of heterocycles by using the other The methods for the synthesis of benzimidazoquinazoline amines are
transition metals catalysts [8]. In 2014, Shun-Jun Ji et al reported rare [21]. Most of these methods are multi-component and multi-step
NiCl2-catalyzed cascade reaction of isocyanides with functionalized process. In this context, benzoimidazoquinazoline amines show
anilines for the synthesis of 2-aminobenzimidazole, 2- interesting features that make them attractive for use in the cobalt-
aminobenzothiazole and 2-aminobenzoxazole [8a]. Since Kharaschs catalyzed isocyanide insertion reaction into the active N–H bonds.
pioneering works [9] on the homocoupling reactions of Grignard According to above reports and as part of our previous works on the
reagents, cobalt catalysts, which are widely available, not expensive, development of new method for the isocyanide-based heterocycles
and have low toxicity, have received particular attention [10]. synthesis [22], we herein investigate the feasibility of the formation
Recently, a cobalt-catalyzed insertion reaction has reported for the of benzimidazoquinazoline amines via cobalt-catalyzed isocyanide
reaction of amine-based bisnucleophiles and isocyanides [8b].
insertion-cyclization reaction into the N–H bonds.
As a privileged scaffold, benzimidazole is a ubiquitous subunit in
many medically important products with remarkable biological
activities [11] and its derivatives have been employed as antiviral
[12], antibiotic [13], antitumor [14] and antimicrobial agents [15].
Similarly, quinazolines are one of the most scaffolds which possess a
broad spectrum of biological activities [16] and especially they have
attracted considerable attention due to their diverse anticancer
activities [17]. The combined molecules of benzimidazole and
quinazoline frameworks, benzimidazoquinazoline derivatives I (Fig.
2), are valuable substrates with various biological activities, and they
exhibit a wide range of therapeutic properties [18]. On the other
hand, compounds bearing the Guanidine functional groups are found
in numerous biologically active natural products and several drugs
and drug Candidates [19]. The benzimidazoquinazolines containing
Guanidine framework have been presented significant biological
activities. For example, benzo[4,5]imidazo[1,2-c]quinazolin-6-amine
II (Fig. 1) is a new anti tumour compound and can bind to DNA by
intercalation and are cytotoxic to tumour cells in tissue culture and
bis[N-(benzimidazo[1,2-c]quinazolyl)-3-aminopropyl]methylamine
III has cytotoxicity effect on the human colon tumour cells [20].
Results and discussion
Our study commenced with the reaction of 2-(1H-benzo[d]imidazol-
2-yl)aniline (1a) and t-butyl isocyanide (2a) as a model reaction to
search for the optimal reaction conditions (Table 1). As shown in
Table 1, the best result was obtained with Co(OAc)2.4H2O (10
o
mol%), K2S2O8 (1 eq) and NaOAc (2 eq) in DMF at 80 C and N-
(tert-butyl)benzo[4,5]imidazo[1,2-c]quinazolin-6-amine (3a) was
obtained in 65% yield after 12 h (entry 5). As shown in Table 1,
different solvents were screened in the model reaction using
Co(OAc)2.4H2O/K2S2O8 system and it was found that DMF is the
optimal solvent (entry 5). It should be mentioned that when the
reaction was carried out in the absence of Co(OAc)2.4H2O or
K2S2O8 no reaction could be observed (entry 6 and 7). When this
reaction was carried out with other oxidants such as, H2O2, tBuOOH,
4-methylmorpholine 4-oxide and O2 the yield of the expected
product was reduced (entries 8-11). To study the effect of
temperature on this synthesis, we performed three experiments at
o
room temperature, 50, 80, and 100 C in Co(OAc)2.4H2O/K2S2O8
system in DMF. It was observed that a lower reaction temperature
leads to a lower yield (entry 13 and 14), while a higher reaction
temperature did not affect either the reaction time or the yield (entry
15).
quinazoline
benzimidazole
benzimidazole
quinazoline
N
N
N
N
N
Table 1 Optimization of the reaction conditionsa
N
N
N
HN
quanidine
N
N
N
Co(OAc)2.4H2O
I
H
t-BuNC
II
+
N
N
H
NH2
2a
1a
3a
quinazoline
Entry
Solvent
PhCH3
Oxidant
Base
Yield [%][b]
benzimidazole
N
H
1
2
3
4
K2S2O8
K2S2O8
K2S2O8
K2S2O8
NaOAc
NaOAc
NaOAc
NaOAc
56
60
N
N
N
N
N
N
Dioxane
CH3CN
H2O
N
HN
51
quanidine
III
Trace
Figure 2. Biologically active benzimidazoquinazoline derivatives.
2 | J. Name., 2012, 00, 1-3
This journal is © The Royal Society of Chemistry 2012

Page 3 of 6
Journal Name
RSC Advances
View Article Online
ARTICLE
DOI: 10.1039/C6RA06828F
5
6c
DMF
DMF
DMF
DMF
DMF
DMF
K2S2O8
K2S2O8
-
NaOAc
NaOAc
NaOAc
NaOAc
NaOAc
NaOAc
65
Trace
The structures of benzoimidazo[1,2-c]quinazolin-6-amines 3 were
1
fully characterized by IR, H NMR, 13C NMR spectroscopy, mass
7
Trace
45
8
H2O2
TBHP
spectrometry, and elemental analysis.
9
43
Based on literature reports [8b, 10, 23] and the chemistry of
isocyanides [6], a plausible mechanism is proposed in Scheme 1.
Catalyst I (formed in situ by the reaction of Co(OAc)2 and
isocyanide) reacts with the benzoimidazol-aniline 1 under basic
conditions to form cobalt (II)-isocyanide carbene complex II [10,
23b]. Then, the complex II was oxidize by SO4·- originating from
the decomposition of K2S2O8 [24] to give cobalt (III)-isocyanide
carbene complex III [10, 23b]. The complex III undergoes
homolysis to afford the active radical intermediate IV and the
catalyst Co(II) salt to complete the catalytic cycle. Oxidation of
intermediate IV followed by intramolecular nucleophilic addition
affords the product 3.
10
4-methylmorpholine
49
4-oxide
O2
11
12
13d
14e
15f
DMF
DMF
DMF
DMF
DMF
NaOAc
K2CO3
NaOAc
NaOAc
NaOAc
47
61
22
41
65
K2S2O8
K2S2O8
K2S2O8
K2S2O8
a Benzoimidazol-aniline 1a (1 eq), t-BuNC (1.5 eq), base (2 eq), oxidant (1
eq), Co(OAc)2.4H2O (10 mol%), 80 °C, 12 h.
b Isolated yields.
c Catalyst-free
d Room temperature.
e Reaction temperature = 50 oC
f Reaction temperature = 100 oC.
With optimal conditions in hand, we extended the cobalt-catalyzed
isocyanide insertion cyclization reaction to various isocyanides 2 and
H2N
RN
N
benzo[d]imidazol-anilines
1
to
afford
desired
of
N
C
2-
S2O8
N
benzoimidazoquinazoline amines 3a-i in moderate to good isolated
yields (Table 2).
SO4
Co(II)L
N
II
H
Base
1
NH2
Table 2 Synthesis of benzoimidazoquinazoline amines 3
H2N
RN
N
Co(II)L
C
RN
R2
R2
N
I
C
NaOAc (2 equiv)
K2S2O8 (1 equiv)
Co(OAc)2.4H2O (10 mol%)
R2
N
R2
R1NC
N
X
X
Co(III)L
SO4
N
N
H
RNC
DMF, 80°C, 12 h
III
N
NH
R1
Co(II)L
NH2
R2: H or Me
X: H or Cl
1
2
3
2-
SO4
+
N
N
H2N
RN
N
N
N
H2N
N
N
N
N
N
[O]
C
RN
C
N
NH
N
N
N
NH
IV
H
3c, 70%
3
3b, 67%
3a, 65%
Scheme 1. Proposed mechanism
N
N
N
N
N
N
As expected, when the benzoimidazol-aniline 1 was replaced by 2-
(1H-tetrazol-5-yl)aniline 4 or 2-amino-benzamides 5, the desired
tetrazolo[1,5-c]quinazolin-5-amine 6 or quinazolin-4(3H)-ones 7
were obtained in good yields under the same reaction conditions
(Scheme 2).
Cl
Cl
N
NH
N
NH
N
NH
3e, 90%
3f, 64%
3d, 67%
N
N
N
N
N
N
Cl
N
N
N
NH
N
NH
H
3i, 71%
3g, 62%
3h, 85%
This journal is © The Royal Society of Chemistry 2012
J. Name., 2012, 00, 1-3 | 3

RSC Advances
Page 4 of 6
ARTICLE
VJieowuArrtnicalelONnlainme e
DOI: 10.1039/C6RA06828F
N
2
(a) S. Long, Chem. Soc. Rev., 2013, 42, 4867; (b) G. Qiu, Q. Ding
and J. Wu, Chem. Soc. Rev., 2013, 42, 5257; (c) T. Vlaar, E.
Ruijter, B .U. W. Maes and R. V. A. Orru, Angew. Chem. Int. Ed.,
2013, 52, 7084, (d) Z. Chen, H. Q. Duan, X. Jiang, Y. M. Zhu, S. J.
Ji and S. L. Yang, J. Org. Chem., 2015, 80, 8183.
N
N
N
N
N
N
N
H
NaOAc (2 equiv)
K2S2O8 (1 equiv)
Co(OAc)2.4H2O (10 mol%)
N
N
NH2
H
6, 86%
4
+
t-BuNC
or
or
O
DMF, 80°C, 12 h
O
3
4
M. Tian, Y. He, X. Zhang and X. Fan, J. Org. Chem., 2015, 80,
7447.
R
R
N
N
N
H
(a) Z. Y. Gu, T. H. Zhu, J. J. Cao, X. P. Xu, S. Y. Wang and S. J.
Ji, ACS. Catal., 2014, 4, 49.; (b) T. Tang, X. Jiang, J. M. Wang, Y.
X. Sun and Y. M. Zhu, Tetrahedron, 2014, 70, 2999; (c) D. Wang,
S. Cai, R. Ben, Y. Zhou, X. Li, J. Zhao, W. Wei and Y. Qian,
Synthesis, 2014, 46, 2045; (d) J. M. Wanga, X. Jiang, Y. Zhang, Y.
M. Zhu and J. K. Shen, Tetrahedron Lett., 2015, 56, 2349; (e) Y.
Y. Pan, Y. N. Wu, Z. Z. Chen, W. J. Hao, G. Li, S. J. Tu and B.
Jiang, J. Org. Chem., 2015, 80, 5764; (i)
NH2
N
H
51%
R= 4Me-Ph 5a
R=PhCH2 5b
7a,
7b,
49 %
Scheme 2. Synthesis of tetrazoloquinazolin-5-amine and quinazolin-4(3H)-
one
Conclusions
5
(a) Y. Wang, H. Wang, J. Peng and Q. Zhu, Org. Lett., 2011, 13,
4604; (b), Y. Wang and Q. Zhua, Adv. Synth. Catal., 2012, 354,
1902; (c) L. Hu, W. Gui, Z. Liub and B. Jiang, RSC Adv., 2014, 4,
38258; (d) V. Estévez, G. V. Baelen, B. H. Lentferink, T. Vlaar, E.
Janssen, B .U. W. Maes, R. V. A. Orru and E. Ruijter, ACS. Catal.,
2014, 4, 40; (e) B. Jiang, L. Hu and W. Gui, RSC Adv., 2014, 4,
13850.
We disclosed an easy access to the benzoimidazoquinazoline amines
framework by direct reactions of isocyanides with compounds
containing active N–H bonds utilizing inexpensive cobalt catalyst.
The methodology is highly practical and it provides
a
straightforward approach to a series of benzoimidazoquinazoline
amines. The comparison between the present cobalt-catalyzed
system with the analogous reaction under palladium catalysis [6b]
shows that both methods have advantages and disadvantages. The
pd-catalyzed system is more expensive, needs more reaction times
and should carry out in the presence of 4 Å MS. However, it must be
mentioned that aerobic oxidation with only water as a by-product in
absence of base are advantages of Pd-system. On the other hand,
cobalt-catalyzed system is cheaper, but needs K2S2O8 (1 eq) as an
oxidant, along with NaOAc (2 eq) as a base. Consequently, the Pd-
catalyzed system is more benign from a green chemistry perspective
and cobalt-catalyzed system is more acceptable from industrial point
of view.
6
(a) R. Vlaar, R. C. Cioc, P. Mampuys, B .U. W. Maes, R. V. A.
Orru and E. Ruijter, Angew. Chem. Int. Ed., 2012, 51, 13058; (b) T.
Vlaar, L. Bensch, J. Kraakman, C. M. L. V. Velde, B .U. W. Maes,
R. V. A. Orru and E. Ruijter, Adv. Synth. Catal., 2014, 356, 1205;
(c) F. Ji, M. F. Lv, W. B. Yi and C. Cai, Org. Biomol. Chem., 2014,
12, 5766.
7
8
(a) T. Nanjo, S. Yamamoto, C. Tsukano and Y. Takemoto, Org.
Lett., 2013, 15, 3754; (b)
(a) G. N. Wang, T. H. Zhu, S. Y. Wang, T. Q. Wei and S. J. Ji,
Tetrahedron, 2014, 70, 8079; (b) T. H. Zhu, S. Y. Wang, G. N.
Wang and S. J. Ji, Chem. Eur. J., 2013, 19, 5850.
9
M. S. Kharasch and E. K. Fields, J. Am. Chem. Soc., 1941, 63,
2316.
10 T. H. Zhu, X. P. Xu, J. J. Cao, T. Q. Wei and S. Y. Wang, Adv.
Synth. Catal., 2014, 356, 509.
Acknowledgements
We gratefully acknowledge financial support from the Research
11 P. Singla, V. Luxami and K. Paul, RSC Adv., 2014, 4, 12422.
12 I. Tamm, Science, 1954, 120, 847.
Council of Shahid Beheshti University.
13 I. Yildiz-Oren, I. Yalcin, E. Aki-Sener and, N. Ucarturk, Eur. J.
Med. Chem., 2004, 39, 291.
Notes and references
1
1 (a) A. Domling, Chem. Rev., 2006, 106, 17; (b) C. D. Graaff, E.
Ruijter and R. V. A. Orru, Chem. Soc. Rev., 2012, 41, 3969; (c) H.
G. O. Alvim, D. N. S. Juniorb, B. A. D. Neto, RSC Adv., 2014, 4,
54282; (d) R. C. Cioc, E. Ruijter and R. V. A. Orru, Green Chem.,
2014, 16, 2958; (e) A. V. Gulevich, A. G. Zhdanko, R. V. A. Orru
and V. G. Nenajdenko, Chem. Rev., 2010, 110, 5235.
14 M. Hranjec, M. Kralj, I. Piantanida, M. Sedic, L. Suman, K.
Pavelic and G. K. Zamola, J. Med. Chem., 2007, 50, 5696.
15 S. Ozden, D. Atabey, S. Yıldız and H. Goker, Bioorg. Med. Chem.,
2005, 13, 1587.
16 (a) R. A. Smits, M. Adami, E. P. Istyastono, O. P. Zuiderveld, C.
M. E.V. van Dam, F. J. De Kanter, A. Jongejan, G. Coruzzi, R.
Leurs and I. J. P. deEsch, J. Med. Chem., 2010, 53, 2390; (b) K. S.
Kumar, P. M. Kumar, K. A. Kumar, M. Sreenivasulu, A. A. Jafar,
4 | J. Name., 2012, 00, 1-3
This journal is © The Royal Society of Chemistry 2012

Page 5 of 6
Journal Name
RSC Advances
View Article Online
ARTICLE
DOI: 10.1039/C6RA06828F
D. Rambabu, G. R. Krishna, M. C. Reddy, R. Kapavarapu, K.
Shivakumar, K. K. Priya, K. V. L. Parsa and M. Pal, Chem.
Commun., 2011, 47, 5010.
17 S. Nahar, D. Bose, S. K. Panja, S. Saha and S. Maiti,
Chem. Commun., 2014, 50, 4639.
18 S. Xu, J. Lu and H. Fu, Chem. Commun., 2011, 47, 5596.
19 (a) B. L. Nilsson, L. E. Overman, J. Org. Chem., 2006, 71, 7706;
(b) M. Okano, J. Mito, Y. Maruyama, H. Masuda, T. Niwa, S. I.
Nakagawa, Y. Nakamura, A. Matsuura, Bioorg. Med. Chem., 2009,
17, 119.
20 M. F. Braña, M. J. P. de Vega, D. Perron, D. Conlon, P. F.
Bousquet, S. P. Robinson, J. Heterocyclic Chem., 1997, 34, 807.
21 (a) P. Molina, M. Alajarín and A. Vidal, Tetrahedron, 1987, 45,
4263; (b) P. Molina, M. Alajarín, A. Vidal, Tetrahedron Lett.,
1988, 29, 3849; (c) G. A. M. Nawwar, M. M. E. A. Zaki, L. M.
Chabaka, Phosphorus, Sulfur, Silicon Relat. Elem., 1993, 79, 195;
(d) J. A. Bleda, P. M. Fresneda, R. Orenes and P. Molina, Eur. J.
Org. Chem., 2009, 15, 2490; (e) S. Xu, J. Lu and H. Fu, Chem.
Commun., 2011, 47,5596.
22 (a) R. Akbarzadeh, T. Amanpour and A. Bazgir, Tetrahedron,
2014, 70, 8142; (b) R. Akbarzadeh, T. Amanpour, H. R. Khavasi
and A. Bazgir, Tetrahedron, 2014, 70, 169; (c) R. Akbarzadeh, T.
Amanpour, P. Mirzaie and A. Bazgir, J. Organometall. Chem.,
2011, 696, 3421.
23 (a) M. Meier, R. van Eldik, M. Chem. – Eur. J., 1997, 3, 39; (b) T.-
H. Zhu, S.-Y. Wang, T.-Q. Wei, S.-J. Ji, Adv. Synth. Catal., 2015,
357, 823.
24 J. K. Laha, K. S. S. Tummalapalli, A. Nair, N. Patel, J. Org.
Chem., 2015, 80, 11351.
This journal is © The Royal Society of Chemistry 2012
J. Name., 2012, 00, 1-3 | 5

RSC Advances
Page 6 of 6
View Article Online
DOI: 10.1039/C6RA06828F
Table of content
R2
R2
NaOAc (2 equiv)
K2S2O8 (1 equiv)
Co(OAc)2.4H2O (10 mol%)
R2
N
R2
R1NC
N
X
X
N
H
N
DMF, 80°C, 12 h
N
NH
R1
NH2
R2: H or Me
X: H or Cl
The synthesis of benzoimidazoquinazoline amines by the reaction of isocyanides and benzo[d]imidazol-
anilines via a cobalt-catalyzed isocyanide insertion reaction into the two N-H active bonds is reported.