Nickel-Catalyzed Aerobic Oxidative Isocyanide Insertion: Access to Benzimidazoquinazoline Derivatives via a Sequential Double Annulation Cascade (SDAC) Strategy

Article abstract of DOI:10.1021/acs.joc.6b02423

An efficient protocol for the synthesis of quinazoline derivatives through nickel-catalyzed ligand-/base-free oxidative isocyanide insertion under aerobic conditions with intramolecular bis-amine nucleophiles has been developed. A one-pot sequential double annulation cascade (SDAC) strategy involving an opening of isatoic anhydride and annulation to benzimidazole and further nickel-catalyzed intramolecular isocyanide insertion has also been demonstrated. The method is operationally simple to implement with a wide variety of substrates and represents a new approach for multiple C-N bond formations. The methodology has been successfully applied to the syntheses of hitherto unreported imidazo-fused benzimidazoquinazolines via a deprotection-GBB reaction sequence. Further, a florescence study reveals the potential of the present strategy for the discovery of highly fluorescent probes.

Full text of DOI:10.1021/acs.joc.6b02423

Subscriber access provided by Washington University | Libraries
Article
Nickel-Catalyzed Aerobic Oxidative Isocyanide Insertion:
Access to Benzimidazoquinazoline Derivatives via
Sequential Double Annulation Cascade (SDAC) strategy
Anand H Shinde, Sagar Arepally, Mayur D. Baravkar, and Duddu S. Sharada
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.6b02423 • Publication Date (Web): 30 Nov 2016
Downloaded from http://pubs.acs.org on November 30, 2016
Just Accepted
“Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted
online prior to technical editing, formatting for publication and author proofing. The American Chemical
Society provides “Just Accepted” as a free service to the research community to expedite the
dissemination of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts
appear in full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been
fully peer reviewed, but should not be considered the official version of record. They are accessible to all
readers and citable by the Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered
to authors. Therefore, the “Just Accepted” Web site may not include all articles that will be published
in the journal. After a manuscript is technically edited and formatted, it will be removed from the “Just
Accepted” Web site and published as an ASAP article. Note that technical editing may introduce minor
changes to the manuscript text and/or graphics which could affect content, and all legal disclaimers
and ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors
or consequences arising from the use of information contained in these “Just Accepted” manuscripts.
The Journal of Organic Chemistry is published by the American Chemical Society.
1155 Sixteenth Street N.W., Washington, DC 20036
Published by American Chemical Society. Copyright © American Chemical Society.
However, no copyright claim is made to original U.S. Government works, or works
produced by employees of any Commonwealth realm Crown government in the course
of their duties.

Page 1 of 32
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
NickelꢀCatalyzed Aerobic Oxidative Isocyanide Insertion: Access to
Benzimidazoquinazoline Derivatives via Sequential Double Annulation
Cascade (SDAC) strategy
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Anand H. Shinde, Sagar Arepally, Mayur D. Baravkar and Duddu S. Sharada*
Department of Chemistry, Indian Institute of Technology Hyderabad (IITH), Kandi, Sangareddy, 502 285,
Telangana, India. Eꢀmail: sharada@iith.ac.in
Abstract: An efficient protocol for the synthesis of quinazoline derivatives through nickelꢀcatalyzed
ligand/baseꢀfree oxidative isocyanide insertion under aerobic conditions with intramolecular bisꢀ
amine nucleophiles has been developed. A oneꢀpot sequential double annulation cascade (SDAC)
strategy involving an opening of isatoic anhydride and annulation to benzimidazole and further
nickelꢀcatalyzed intramolecular isocyanide insertion has also been demonstrated. The method is
operationally simple to implement with wide substrates and represents a new approach for multiple
CꢀN bond formations. The methodology has been successfully applied for the syntheses of hitherto
unreported imidazo fused benzimidazoquinazoline via deprotectionꢀGBB reaction sequence.
Further, the florescence study reveals the potential of the present strategy for discovery of highly
fluorescent probes.
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 2 of 32
1
2
3
4
Introduction
5
6
7
8
9
Transition metal catalyzed Cꢀhetero bond formation via CH/NH functionalization has attracted much
attention compared to traditional methods for heterocyclic synthesis as it provides a direct and atom
economical synthetic strategy to structurally diverse and complex molecules from simple substrate.1 The
development of new chemical approaches for in situ generation of template/substrate for rapid and
straightforward access to structurally complex molecules via CH/XH functionalization under ecoꢀbenign
conditions is one of the prime focuses in contemporary science. Directing group approaches have
achieved much progress in CH/NH functionalization. To overcome the drawbacks of directing group
approaches such as prefunctionalization, removal of directing group, various other alternative approaches
such as crossꢀdehydrogenative coupling (CDC),2 metalꢀfree redoxꢀneutral,3 nonꢀdirected CH bond
activation4 and direct atom insertion strategies5 have been explored. Among the various atom insertions5
such as nitrogen, carbon and sulphur, the carbon insertion using isocyanide is in limelight. In contrast to
reaction using other CO surrogates, isocyanide insertion offers functionally diverse molecules by
providing extra nitrogen functionality which could be diversified further and might also result in
improved activity as pharmaceuticals.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
In the past decades, precious late transition metals, for example, palladium, ruthenium, rhenium and
iridium catalysts have been shown to be effective catalytic systems for CH or XH activation. However,
cost and toxicity of these noble metals limit their practical applications. Owing to this, the development of
new catalytic routes by switching to nonꢀprecious metals such as nickel/cobalt has become a challenging
and active area of research, and drastic shift is taking place in industrial process from precious to nonꢀ
precious transition metals.6 Especially, nickel continued to shine by carrying out a broader array of
reactions, and has proved to play key role to facilitate highly efficient transformations through CꢀH
activation.6aꢀc,7
Several transition metals such as palladium, cobalt, and Lewis acid catalyzed isocyanide insertion
reactions have been reported which use various kinds of bisnucleophiles either in inter or intramolecular
ACS Paragon Plus Environment

Page 3 of 32
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
fashion.8 However, nickel catalyzed isocyanide insertions are in their infancy.9 Among various
intramolecular isocyanide insertions leading to heteroannulations, isocyanide insertion in NH bond is
unique as it provides a useful and convenient tool for the construction of Nꢀheterocycles.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Figure 1. Cyclic guanidine containing alkaloid (I) and cyclic guanidine containing bioactive
benzimidazoquinazoline skeletons (II and III).
Azaꢀheterocyclic compounds10 especially cyclic guanidine containing compounds have attracted
considerable interest due to its wide variety of biological activities.11 As a result, molecules containing
this structural motif have recently emerged as important pharmacophores in biomedical research. The
cyclic guanidine containing alkaloid Saxitoxin I (Fig 1) is a potent neurotoxin and sodium channel
blocker.12 Moreover, cyclic guanidines have also been employed as synthetically useful organocatalysts
and reagents in organic synthesis.13 Quinazoline containing cyclic guanidines such as II and III (Fig 1)
are highly potent virucidal and neoplasm inhibitors and are found to be active against breast cancer.14
Cyclic guanidine is typically synthesized from acyclic precursor or guanidinylation of amine. The
literature reveals several traditional approaches including the coupling of 2ꢀaminophenylbenzimidazole
with cyanogen bromide or alkyl nitrile,15 low valent titanium catalyzed reaction,16 and copper catalyzed
cascade.17 On the other hand, the strategies involving isocyanide insertion under transition metal catalysis
have also been reported.18 However, most precedents still rely on ligands as well as stoichiometric metal
oxidants and bases, which limits its use in organic synthesis. Although oxidants such as Cu(OAc)2,
AgOAc, K2S2O8 etc. have been proven to be excellent and practical, dioxygen is an ideal oxidant which
offers attractive industrial prospects in terms of green and sustainable chemistry.19 These reported
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 4 of 32
1
2
3
4
5
6
7
8
9
protocols also suffer from several drawbacks such as limited substrate scope, multistep processes and
poorly available starting materials. On the other hand, amine substrates could poison catalytic activity of
the metals by forming stable complexes, which in turn makes CꢀN bond formation reactions challenging
and achieving such transformations in oneꢀpot efficiently from simple substrate is even most challenging
due to the compatibility issues with further sensitive catalytic processes, which are inevitable to carry out
these cascade reactions.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
In continuation of our research interest in annulation cascade strategies20a,20b and transition metal
catalyzed isocyanide insertion,20c, 20d herein, we report for the first time a novel SDAC strategy involving
nickelꢀcatalyzed metalꢀoxidant and baseꢀfree isocyanide insertion between NH/NH under aerobic
conditions for the synthesis of benzimidazoquinazoline derivatives from isatoic anhydride in oneꢀpot
fashion (Scheme 1).
Scheme 1. Designed SDAC strategy involving nickelꢀcatalyzed isocyanide insertion between active
NH bonds.
Results and Discussion:
We initiated our study by investigating the isocyanide insertion reaction into the 2ꢀ
aminophenylbenzimidazole 3aa system. It is noted that there was no product formation in absence of the
catalyst and oxidant (Table 1, entry 1). When the model reaction was performed in the presence of
NiCl2.6H2O as catalyst, K2S2O8 as oxidant and Na2CO3 as base in DMF solvent, afforded the desired
product 5aab albeit in 42% yield and little improvement was observed in presence of anhydrous NiCl2
(Table 1, entries 2 and 3). But, unfortunately reaction under Ni(ClO4)2, Ni(C2O4) as catalyst or with
ACS Paragon Plus Environment

Page 5 of 32
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
change of base as NaOAc as well could not improve the yield (Table 1, entries 4ꢀ6). When we used
peroxide based oxidants, there was improvement in yield as well as reaction profile especially with DTPB
as oxidant (Table 1, entries 7 and 8). To our delight, the reaction under dioxygen as sole oxidant gave the
product in much better yield (55%) (Table 1, entry 9). To our surprise the reaction under Ni(acac)2
catalysis under aerobic conditions gave the product in 61% yield (Table 1, entry 10).
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Table 1. Screening of reaction conditions for Niꢀcatalysed isocyanide insertion 5aaa a
Entry Catalyst
Oxidant
Base
Solvent
Yield (%)b
1c
2
ꢀ
ꢀ
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
NaOAc
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
ꢀ
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
Toluene
DCE
trace
42
45
5
trace
42
49
40
55
61
0
30
20
trace
trace
30
65
68
NiCl2.6H2O
K2S2O8
K2S2O8
K2S2O8
K2S2O8
K2S2O8
DTPB
TBPB
O2
O2
O2
O2
O2
O2
O2
O2
O2
O2
O2
ꢀ
O2
3
NiCl2
4
5
6
Ni(ClO4)2
Ni(C2O4)
NiCl2
7
NiCl2
8
NiCl2
9
NiCl2
10
11
12
13
14
15
16
17
18d
19e,f
20 d
21g
22h
Ni(acac)2
Ni(acac)2
Ni(acac)2
Ni(acac)2
Ni(acac)2
Ni(acac)2
Ni(acac)2
Ni(acac)2
Ni(acac)2
Ni(acac)2
Ni(acac)2
Ni(acac)2
Ni(acac)2
MeCN
H2O
DMF:H2O
DMSO
DMF
DMF
DMF
DMF
DMF
DMF
ꢀ
ꢀ
ꢀ
ꢀ
60
0
60
58
ꢀ
O2
a) General conditions: amine 3aa (0.2 mmol), CyNC 4a (0.2 mmol), catalyst (20 mol%), base (1.5 equiv.), oxidant
(1.5 equiv.), and solvent (2 mL); b) Isolated yields; c) Without catalyst/oxidant; d) 15 mol% of Ni(acac)2; e) 10
o
o
mol% of Ni(acac)2; f) Reaction time = 8 h; g) Reaction temperature = 120 C; h) Reaction temperature = 80 C;
DTPB= diꢀtertꢀbutylperoxide; TBPB= tertꢀbutylperoxybenzoate; For compound 5aaa first letter refers to isatoic
anhydride part 1a, second letter refers to diamine part 2a and third letter refers to part coming from isocyanide 4a.
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 6 of 32
1
2
3
4
5
6
7
8
9
Further, reaction under various solvents such as toluene, DCE, acetonitrile, water and DMSO was
unsatisfactory (Table 1, entries 11ꢀ16). When we tested the reaction under baseꢀfree condition, resulted in
comparable yield of the product (65%) (Table 1, entry 17). Further, when we tested the effect of varied
catalyst loading (Table 1, entries 18 and 19), we found 15 mol% of Ni(acac)2 led to the best yield (68%)
of the product efficiently (Table 1, entry 18). For understanding the role of oxidant, when we performed
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Table 2. Scope of diamines 2 and Isocyanides 4 for the synthesis of quinazolines 5 a,b
a) General conditions: Amine 3 (0.2 mmol), isocyanide 4 (0.2 mmol), Ni(acac)2 (15 mol%), O2 balloon, and DMF
(2 mL); b) Isolated yields after column chromatography; c) Failed to give the intermediate 3ag; For compound 5
first letter refers to isatoic anhydride part 1aꢀ1c, second letter refers to diamine part 2aꢀ2g and third letter refers to
part coming from isocyanides 4aꢀ4d.
ACS Paragon Plus Environment

Page 7 of 32
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
the reaction using Ni(acac)2 in absence of oxidant, there was no progress in the reaction and 90% of the
starting material was recovered suggesting that the oxygen is essential for the present transformation
(Table 1, entry 20). The reaction under varying temperature could not able to improve the yield further
(Table 1, entries 21 and 22). So we chose the 15 mol% of Ni(acac)2 as catalyst and dioxygen as oxidant in
DMF solvent as optimum condition for further study.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
After having the optimized conditions in hand, we turned our attention to explore the scope of the
present methodology with respect to oꢀphenylenediamines 2 and variety of isocyanides 4. We have
successfully extended the methodology to various electron donating as well as electron withdrawing oꢀ
phenylenediamines 2 and 1o, 2o and 3o isocyanides (Table 2). When we have used the neutral
unsubstituted oꢀphenylenediamine 2a for the Niꢀcatalyzed isocyanide insertion it resulted in products with
good to high yields (Table 2, entries 5aaaꢀ5cab). The donating dimethyl substituted oꢀphenylenediamine
2b provided the desired products in high yields (Table 2, entries 5aba, 5abb and 5cba). Interestingly, 1,8
diaminonaphthalene 2e as an amine variant gave the products in moderate yields demonstrating the
diversity of our methodology (Table 2, entries 5aea, 5bea and 5cea). However, 2ꢀbromoꢀ2,3ꢀ
diaminopyridine 2g failed to give the desired product, which might be due to the side reactions involving
pyridinium complex (Table 2, entry 5aga). In general, both the 2o cyclohexyl and 3o tꢀbutyl isocyanides
worked well and provided the desired products in moderate to good yields (Table 2, entries 5aaaꢀ5abb).
Our further motto to introduce different 1o isocyanides such as ethylisocyanoacetate 4c and
benzylisocyanide 4d was successful resulting in the desired products with moderate to good yields (Table
2, entries 5aac and 5aad).
When the application of this methodology is considered for the synthesis of quinazoline 5, potential
regioselectivity issues exist in case of unsymmetrically substituted oꢀphenylenediamines. Consequently,
various unsymmetrically substituted oꢀphenylenediamines 2 were used to investigate the regioselectivity
of the process (Table 3). When electron donating methyl substituted oꢀphenylenediamine was treated with
chloro or bromo substituted isatoic anhydrides 1, to our surprise gave the desired products as a single
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 8 of 32
1
2
3
4
Table 3. Regioselectivity in Niꢀcatalyzed isocyanide insertion and scope of isatoic anhydrides 1 and
5
6
oꢀphenylenediamines 2 for the synthesis of quinazolines 5 a,b
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
a) General conditions: Amine 3 (0. 2 mmol), isocyanide 4 (0.2 mmol), Ni(acac)2 (15 mol%), O2 balloon, and DMF
(2mL); b) Isolated yields after column chromatography; c) Ratio was determined by NMR spectroscopy; For
compound 5 first letter refers to isatoic anhydride part 1aꢀ1c, second letter refers to diamine part 2aꢀ2h and third
letter refers to part coming from isocyanides 4a, 4b.
regioisomer with good yields (Table 3, entries 5ccaꢀ5bcb). However, oꢀphenylenediamines such as 2d
and 2f with electron withdrawing group at 4ꢀposition provided the unisolable mixture of regioisomers
(1:1) (Table 3, entries 5bda, 5cfa and 5cda) in good yields. A satisfactory improvement in
regioselectivity was observed in case of 5aha, 5bdb and 5bfa, which gave the desired products with good
ACS Paragon Plus Environment

Page 9 of 32
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
yields however as inseparable regioisomeric mixture (1:0.67) (Table 3, entries 5aha, 5bdb and 5bfa). The
isolable mixture of regioisomer was observed in case of 5ada and 5adaꞌ which gave the product in
overall 57% yield. The structure of the isomers 5ada and 5adaꞌ was assigned by NOE experiments. The
observed high regioselectivity in case of methyl substituted oꢀphenylenediamine 2c might be due to the
orthoꢀsubstituent effect leading to predominant existence of single tautomer. The structures of the
products were confirmed by spectral analyses and Xꢀray crystal structure analysis of one of the
compounds 5abb (see the SI† for Xꢀray data of 5abb).
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
After having successfully developed the methodology, we were keen to examine the feasibility of a
sequential double annulation cascade (SDAC) protocol for the synthesis of quinazolines 5 directly from
Table 4. Oneꢀpot synthesis of quinazolines 5 via sequential double annulation cascade (SDAC)
strategy a,b
a) General conditions: Isatoic anhydride 1 (0.25 mmol), oꢀphenylenediamine 2 (0.25 mmol), amine 3 (0. 0.25
mmol), isocyanide 4 (0.25 mmol), Ni(acac)2 (15 mol%), O2 balloon, and DMF (2 mL); b) Isolated yields after
column chromatography; For compound 5 first letter refers to isatoic anhydride part 1aꢀ1c, second letter refers to
diamine part 2a, 2e and third letter refers to part coming from isocyanides 4a, 4b.
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 10 of 32
1
2
3
4
5
6
7
8
isatoic anhydride 1 and oꢀphenylenediamine 2 involving openingꢀcyclization of isatoic anhydride and Niꢀ
catalyzed isocyanide insertion. To our delight, this oneꢀpot sequence has resulted in desired product with
moderate to good yield (30ꢀ56%, Table 4, entries 5aaaꢀ5cab).
9
Next, to illustrate the synthetic viability of our methodology, we converted the quinazoline 5 into free
aminoquinazoline 6aa and 6ba in good yields via scandium triflate mediated tertꢀbutyl deprotection
reaction (Scheme 2, eqn 1).21 These resulting compounds with aminoazine moiety could be suitable
substrate for many of the organic transformations. We have accordingly demonstrated the synthetic utility
of one of the aminoazines 6aa by employing in GroebkeꢀBlackburnꢀBienayme (GBB) reaction22 to
provide interesting hitherto unreported imidazo fused pentacyclic scaffolds 8a and 8b in good yields
under scandium triflate catalysis (Scheme 2, eqn 2).23 This isatoic openingꢀcyclization and Niꢀcatalysed
isocyanide insertion (SDAC) protocol/tꢀbutyl deprotection/GBB reaction approach can be systematically
used for the synthesis of library of privileged benzimidazoquinazoline fused imidazole hybrids 8 for the
biological screening in fourꢀstep reaction sequence.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Scheme 2. Synthetic applicability of products generated through Niꢀcatalyzed isocyanide insertion.
To gain some insights into the reaction mechanism, radical trapping experiments were carried out.
The commonly used radical scavengers such as TEMPO and BHT were introduced into the standard
reaction system to trap possible radical intermediates. Interestingly, the desired products could still be
obtained in 66% and 68% yields respectively (Scheme 3), thus, implicating the ionic mechanism.
ACS Paragon Plus Environment

Page 11 of 32
The Journal of Organic Chemistry
1
2
3
4
Scheme 3. TEMPO and BHT trapping experiments.
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Based on the literature reports,18 and TEMPO/ BHT trapping experiments, a plausible ionic
mechanism is proposed in Figure 2 in two possible pathways. Path I consists of the Ni(II) salt reacting
with isocyanide 4 to furnish complex A. Then, 3aa adds to give nickel(II) complex B (Figure 2, path I).
The other possible pathway for the formation of B involves a direct reaction of Ni(II) salt with 3aa to give
nickel(II) complex D (Figure 2, path II), which on further isocyanide insertion forms complex B. Further,
complex B undergoes aerobic oxidation to provide nickel (III) complex C, which on reductive elimination
affords the desired product 5 with further regeneration of Ni(II) catalyst via aerobic oxidation to complete
the catalytic cycle.
Figure 2. Plausible reaction mechanism for the formation of benzimidazoquinazoline 5.
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 12 of 32
1
2
3
4
5
6
7
8
9
After having developed the strategy, we were keen to study the fluorescent properties of the
synthesized molecules. The absorption and fluorescent spectra of chosen molecules were measured in
DCM as shown in Table 5 and Figure 3. Initially, when the parent compounds 5aaa and 5aab were
measured, there was only 2 nm change by changing the substituent on nitrogen (Tabel 5, entries 1 and 2).
However, in comparison to 5aab, a longer wavelength of the absorption maximum peak (λmax) was
obtained in case of free amine compound 6aa (Tabel 5, entry 3); as well a longer wavelength was
obtained when there was substituent over phenyl rings of benzimidazoquinazoline moiety irrespective of
donating or withdrawing groups (Tabel 5, entries 4ꢀ7). The napthalene fused quinazoline compound 5cea
gave a shorter wavelength of the absorption maximum peak (λmax), however, it showed the stronger
yellow fluorescence among all at 532 (λem) (Tabel 5, entry 8). The compounds 6aa and 5bfa showed
greenꢀblue fluorescence, while compounds 5aaa, 5aab and 5cbaꢀ5ada showed blue fluorescence. The
withdrawing phenoxy substituted compound 5bfa showed the higher fluorescence emission at 445 (λem)
(Tabel 5, entry 7). The compounds 5aaaꢀ5ada showed the fluorescence emission in the range of 381ꢀ407
(λem) (Tabel 5, entries 1ꢀ6). Overall, fluorescence study showed that the electron withdrawing groups on
benzimidazole and tꢀbutyl substituent on amine increases the fluorescence properties of the molecule.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Table 5. Photophysical properties of benzimidazoquinazoline 5.
entry
compd
λmax (nm)[ε (Mꢀ1 cmꢀ1)]a
λem (nm)a,b
1
2
3
4
5
6
7
8
5aaa
5aab
6aa
5cba
5bca
5ada
5bfa
5cea
271 [3115]
273 [3263]
284 [1294]
284 [3389]
283 [1320]
284 [1295]
284 [1288]
242 [2516]
388
407
381
401
400
393
445
532
a) Concentration:1x10ꢀ3 M in DCM; b) Excited at 285 nm.
ACS Paragon Plus Environment

Page 13 of 32
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Figure 3. Fluorescence spectra of the compounds 5 recorded in DCM.
In conclusion, we have developed a novel and highly efficient sequential double annulation
cascade (SDAC) protocol involving isatoic anhydride openingꢀcyclization and Ni(acac)2 catalyzed
isocyanide insertion for the synthesis of complex and diverse benzimidazoquinazoline 5. The use of
dioxygen as sole oxidant, and base/ligandꢀfree features make this strategy unique. The diverse potential of
the present SDAC strategy has been demonstrated by synthesizing naphthalene fused quinazoline
compounds. The utility of the present SDAC is showed by synthesizing privileged
benzimidazoquinazoline fused imidazole hybrids through GBB reaction and which can be further utilized
for synthesizing a library of compounds for biological screening. The present SDAC technique shows
wide substrate scope with moderate to good yields. The salient features of this method are formation of
four new CꢀN bonds in oneꢀpot, rapid access to biologically relevant heterocyclic scaffolds, short reaction
time, high bond forming index (BFI), and the use of inexpensive, readily available starting materials. The
UVꢀVisible and fluorescence studies reveal the possible application for the discovery of highly
fluorescent probes. Further, studies on nickelꢀcatalyzed isocyanide insertion and exploration of SDAC
strategy are currently under way.
Experimental Section
General Considerations
In this section the preparations of all the compounds that have been made in the course have been
discussed. For the experiments, all starting material and reagents are purchased from standard
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 14 of 32
1
2
3
4
5
6
7
8
9
commercial sources or were prepared in laboratory. All the glassware was cleaned with soap water
followed by acetone and dried in hot air oven at 100 ˚C for 2h. Solvents were distilled prior to use.
IR spectra were recorded on the FTIR spectrophotometer. 1H NMR spectra were recorded on 400
MHz spectrometer at 295K in CDCl3 or DMSO d6; chemical shifts value (δ ppm) and coupling constants
(Hz) are reported in standard fashion with reference to either tetramethylsilane (TMS) (δꢀH = 0.00 ppm)
or CHCl3 (δꢀH = 7.26 ppm). 13C NMR spectra were recorded on 100 MHz spectrometer at 298K in
CDCl3 or DMSO d6; chemical shifts (δ ppm) are reported relative to CHCl3 [(δꢀC = 77.00 ppm) central
line of triplet] or DMSO [(δꢀC = 39.52 ppm) central line of septet]. In 13C NMR the nature of carbons (C,
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1
CH, CH2, and CH3) was determined by recording the DEPTꢀ 135 spectra. In H NMR, the following
abbreviations were used throughout the experimental; s = singlet, d = doublet, t = triplet, q = quartet, qui
= quintet, m = multiplet and br. s = broad singlet. The assignment of the signals was confirmed by 1H, 13C
and DEPT spectra. Highꢀresolution mass spectra (HRꢀMS) were recorded on QꢀTOF electron spray
ionization (ESI) mode and atmospheric pressure chemical ionization (APCI) modes. Reactions were
monitored by TLC on silica gel GFꢀ254 using a combination of hexane and ethyl acetate as eluents.
(I) General Procedure 1: Synthesis of 2ꢀaminophenylbenzimidazoles 3 via opening of isatoic
anhydride with diamines 2.
To the mixture of isatoic anhydride 1 (1 mmol) and diamine 2 (1 mmol) was added glacial acetic acid (2
mL) and stirred at 90 oC for 1ꢀ3 h and monitored by TLC. After completion of the reaction the acetic acid
was evaporated. The reaction mixture was quenched with saturated solution of NaHCO3, extracted with
ethyl acetate (2 X 20 mL). The combined organic extracts were washed with brine and dried over
anhydrous Na2SO4, filtered and concentrated and then purified by silica gel column chromatography
using ethyl acetate and hexane (15:85) as eluents to afford the corresponding product 3. The compounds
(3aaꢀ3ad) are already known in the literature and compounds (3caꢀ3bf) are newly synthesized according
to general procedure 1.
(II) Spectral data for the 2ꢀaminopheylbenzimidazole compounds 3caꢀ3bf:
ACS Paragon Plus Environment

Page 15 of 32
The Journal of Organic Chemistry
1
2
3
4
2-(1H-Benzo[d]imidazol-2-yl)-4-bromoaniline (3ca): Following the general procedure 1, 3ca was
5
6
isolated as a colorless solid; Yield: 207 mg (72%); mp 184ꢀ186 °C; IR (MIRꢀATR, 4000ꢀ600cmꢀ1): νmax
=
7
8
9
3186, 2973, 2926, 1610, 1527, 1451, 1283, 811, 732 cmꢀ1; 1H NMR (DMSO d6, 400 MHz): δ ppm = 6.83
(d, J = 8.80 Hz, 1H), 7.20 ꢀ 7.31 (m, 3H), 7.60 (dd, J = 5.62 and 3.18 Hz, 2H), 8.05 (d, J = 2.45 Hz, 1H);
13C NMR (DMSO d6, 100 MHz): δ ppm = 105.4, 111.7, 118.1, 122.2, 129.1, 132.7, 147.3, 151.0; HRꢀMS
(ESI+) m/z calculated for C13H10BrN3 + [M + H+]: 288.0131; found: 288.0135.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
2-(1H-Perimidin-2-yl)aniline (3ae): Following the general procedure 1, 3ae was isolated as a yellow
solid; Yield: 168 mg (65%); mp 138ꢀ140 °C; IR (MIRꢀATR, 4000ꢀ600cmꢀ1): νmax = 3399, 3271, 3046,
1616, 1592, 1370, 1260, 821, 768 cmꢀ1; 1H NMR (CDCl3, 400 MHz): δ ppm = 5.87 (br. s., 1H), 6.46 (br.
s., 2H), 6.63 ꢀ 6.70 (m, 2H), 7.02 ꢀ 7.19 (m, 6H), 7.27 ꢀ 7.30 (m, 1H) ;13C NMR (CDCl3, 100 MHz): δ
ppm = 115.3, 117.1, 117.5, 119.6, 121.2, 126.1, 128.3, 131.7, 135.3, 147.9, 153.1; HRꢀMS (ESI+) m/z
calculated for C17H14N3 + [M + H+]: 260.1182; found: 260.1185.
4-Chloro-2-(1H-perimidin-2-yl)aniline (3be): Following the general procedure 1, 3be was isolated as a
orange solid; Yield: 176 mg (60%); mp 144ꢀ146 °C; IR (MIRꢀATR, 4000ꢀ600cmꢀ1): νmax = 3398, 3286,
1
3048, 1632, 1593, 1489, 1371, 1256, 820, 767 cmꢀ1; H NMR (CDCl3, 400 MHz): δ ppm = 5.91 (br. s.,
2H), 6.64 (d, 8.8 Hz, 2H), 7.07 ꢀ 7.14 (m, 6H), 7.28 (d, 2.4 Hz, 2H) ;13C NMR (CDCl3, 100 MHz): δ ppm
= 116.1, 118.6, 121.2, 121.4, 125.6, 131.5, 135.3, 146.5, 152.0; HRꢀMS (ESI+) m/z calculated for
+
C17H13ClN3 [M + H+]: 294.0793; found: 294.0780.
4-Bromo-2-(1H-perimidin-2-yl)aniline (3ce): Following the general procedure 1, 3ce was isolated as a
yellow solid; Yield: 222 mg (66%); mp 184ꢀ186 °C; IR (MIRꢀATR, 4000ꢀ600cmꢀ1): νmax = 3289, 3049,
1632, 1564, 1408, 1237, 822, 768 cmꢀ1; 1H NMR (CDCl3, 400 MHz): δ ppm = 5.96 (br s, 2H), 6.17 ꢀ 6.44
(m, 1H), 6.61 (d, J = 8.80 Hz, 1H), 6.69 ꢀ 6.94 (m, 1H), 7.11 (br s, 2H), 7.18 ꢀ 7.30 (m, 3H), 7.44 (d,
J=1.96 Hz, 2H) ;13C NMR (CDCl3, 100 MHz): δ ppm = 108.1, 116.6, 119.0, 121.2, 128.4, 134.3, 135.3,
+
147.0, 151.8; HRꢀMS (ESI+) m/z calculated for C17H13BrN3 [M + H+]: 338.0287; found: 338.0285.
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 16 of 32
1
2
3
4
5
6
7
8
4-Bromo-2-(5,6-dimethyl-1H-benzo[d]imidazol-2-yl)aniline (3cb): Following the general procedure 1,
3cb was isolated as a colorless solid; Yield: 198 mg (63%); mp 236ꢀ238 °C; IR (MIRꢀATR, 4000ꢀ600cmꢀ
1): νmax = 3609, 3368, 3054, 1680, 1264, 731 cmꢀ1; 1H NMR (DMSO d6, 400 MHz): δ ppm = 2.34 (s, 3H),
9
13
2.32 (s, 3H), 6.81 (s, 1H), 7.16 ꢀ 7.30 (m, 2H), 7.37 ꢀ 7.49 (m, 3H), 8.02 (br. s., 1H), 12.54 (s, 1H); C
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
NMR (DMSO d6, 100 MHz): δ ppm = 19.9, 20.0,105.3, 111.0, 112.1, 118.0, 118.4, 128.8, 129.8, 131.4,
+
132.0, 132.2, 141.4, 147.1, 150.2; HRꢀMS (ESI+) m/z calculated for C15H15BrN3 [M + H+]: 316.0444;
found: 316.0441.
2-(1H-Benzo[d]imidazol-2-yl)-4-bromoaniline (3cc): Following the general procedure 1, 3cc was
isolated as a colorless solid; Yield: 195 mg (65%); mp 158ꢀ160 °C; IR (MIRꢀATR, 4000ꢀ600cmꢀ1): νmax
=
3310, 3263, 1606, 1484, 1160, 815, 754 cmꢀ1; 1H NMR (DMSO d6, 400 MHz): δ ppm = 2.58 (s, 3H), 6.83
(dd, 8.8 and 3.9 Hz, 1H), 7.01 (t, 6.4 Hz, 1H), 7.11 (dt, 7.4 and 6.4 Hz, 1H), 7.28 (dd, 6.4 and 2.4 Hz,
1H), 7.34 (d, 8 Hz, 0.5H), 7.50 (d, 4 Hz, 2.5H), 7.47 (d, 4 Hz, 0.5H), 8.06 (d, 2 Hz, 0.5H), 8.26 (d, 2 Hz,
0.5H), 12.76 (s, 0.5H); 13C NMR (DMSO d6, 100 MHz): δ ppm 16.5, 17.2, 108.4, 115.8, 118.0, 118.1,
+
121.7, 121.8, 122.6, 123.4, 128.9, 129.4, 132.5, 132.5; HRꢀMS (ESI+) m/z calculated for C14H13BrN3 [M
+ H+]: 302.0288; found: 302.0286.
(2-(2-Amino-5-bromophenyl)-1H-benzo[d]imidazol-5-yl)(phenyl)methanone (3cf): Following the
general procedure 1, 3cf was isolated as a light yellow solid; Yield: 226 mg (58%); mp 236ꢀ238 °C; IR
1
(MIRꢀATR, 4000ꢀ600cmꢀ1): νmax = 3441, 3250, 1640, 1611, 1315, 1315, 1261, 805, 710 cmꢀ1; H NMR
(DMSO d6, 400 MHz): δ ppm = 6.85 (d, 8.8 Hz, 1H), 7.32 (dd, 8.4 and 2.4 Hz, 1H), 7.47 (br. s., 2H),
13
7.55 ꢀ 7.63 (m, 2H), 7.69 (t, 7.3 Hz, 2H), 7.74 ꢀ 7.82 (m, 3H), 8.07 (s, 1H), 13.16 (br. s., 1H); C NMR
(DMSO d6, 100 MHz): δ ppm 105.4, 110.9, 118.3, 128.4, 129.3, 129.4, 132.1, 138.1, 147.7, 195.5; HRꢀ
MS (ESI+) m/z calculated for C20H15BrN3O+ [M + H+]: 392.0393; found: 392.0384.
4-Bromo-2-(5-chloro-1H-benzo[d]imidazol-2-yl)aniline (3cd): Following the general procedure 1, 3cd
was isolated as a colorless solid; Yield: 173 mg (54%); mp 198ꢀ200 °C; IR (MIRꢀATR, 4000ꢀ600cmꢀ1):
νmax = 3302, 3198, 2925, 1603, 1482, 1406, 1233, 864, 817, 745 cmꢀ1; 1H NMR (DMSO d6, 400 MHz):
ACS Paragon Plus Environment

Page 17 of 32
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
δ ppm = 6.83 (d, 8.8 Hz, 1H), 7.24 (br. s., 1H), 7.30 (dd, 8.8 and 2 Hz, 1H), 7.43 (br. s., 2H), 7.54 (br. s.,
1H), 7.65ꢀ7.72 (m, 1H), 8.04 (d, 2 Hz, 1H), 12.99 (br. s., 1H) ; 13C NMR (DMSO d6, 100 MHz): δ ppm
105.4, 111.2, 118.2, 129.2, 133.0, 147.5; HRꢀMS (ESI+) m/z calculated for C13H10BrClN3+ [M + H+]:
321.9741; found: 321.9745.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(2-(2-Amino-5-chlorophenyl)-1H-benzo[d]imidazol-5-yl)(phenyl)methanone (3bf): Following the
general procedure 1, 3bf was isolated as a light yellow solid; Yield: 201 mg (58%); mp 222ꢀ224 °C; IR
1
(MIRꢀATR, 4000ꢀ600cmꢀ1): νmax = 3251, 2923, 1601, 1278, 805, 712 cmꢀ1; H NMR (DMSO d6, 400
MHz): δ ppm = 6.89 (d, 8.8 Hz, 1H), 7.22 (d, 8.8 Hz, 1H), 7.47 (s, 1H), 7.44 (s, 1H), 7.59 (t, 7.8 Hz, 2H),
7.69 (t, 6.8 Hz, 2H), 7.71 ꢀ 7.83 (m, 3H), 7.83 ꢀ 8.06 (m, 2H), 13.21 (br. s., 1H); 13C NMR (DMSO d6,
100 MHz): δ ppm 110.2, 111.0, 112.8, 118.0, 121.0, 123.8, 124.8, 126.5, 128.4, 129.4, 130.6, 130.8,
132.1, 133.1, 137.0, 138.1, 142.2, 147.3, 195.6; HRꢀMS (ESI+) m/z calculated for C20H15ClN3O+ [M +
H+]: 348.0899; found: 348.0890.
(III) General procedure 2: Synthesis of quinazolines 5 via Niꢀcatalyzed isocyanide insertion:
To the mixture of 2ꢀaminophenylbenzimidazole 3 (0.2 mmol), isocyanide 4 (0.2 mmol) and Ni(acac)2 (15
mol%) in an 10 mL Schlenk tube was added 2mL of DMF and the mixture was stirred at 100 oC for 2ꢀ4 h
(monitored by TLC) under oxygen balloon. After the completion of the reaction, the reaction mixture was
allowed to cool and was quenched with ice cold water. Then the reaction mixture was extracted with ethyl
acetate (3 X 10 mL). The combined organic extracts were washed with brine and dried with anhydrous
Na2SO4. The crude extract was purified by filtration through a silica gel (100ꢀ200 mesh) column using
hexane and ethyl acetate (9:1) as eluents to yield the desired products quinazolines 5.
(IV) General procedure 3: Oneꢀpot SDAC synthesis of quinazolines 5 via isatoic anhydride
opening/ring closing to 2ꢀaminophenylbenzimidazole/Niꢀcatalyzed isocyanide insertion:
To the mixture of isatoic anhydride 1 (0.25 mmol) and diamine 2 (0.25 mmol) in a 10 mL Schenk tube
o
was added glacial acetic acid (2 mL) and stirred at 90 C for 2ꢀ3 h and monitored by TLC. After
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 18 of 32
1
2
3
4
completion of the reaction the acetic acid was evaporated using rotary evaporator and dried under
5
6
vacuum. To this was added isocyanide 4 (0.25 mmol), Ni(acac)2 (15 mol%), and 2 mL of DMF and the
7
8
o
mixture was stirred at 100 C for 2ꢀ3 h (monitored by TLC) under oxygen balloon. After the completion
9
of the reaction, the reaction mixture was allowed to cool and was quenched with ice cold water. Then the
reaction mixture was extracted with ethyl acetate (3 X 10 mL). The combined organic extracts were
washed with brine and dried with anhydrous Na2SO4. The crude extract was purified by filtration through
a silica gel (100ꢀ200 mesh) column using hexane and ethyl acetate (9:1) as eluents to yield the desired
products quinazolines 5.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(V) Spectral data for the quinazolines compounds 5aaaꢀ5bfa:
N-Cyclohexylbenzo[4,5]imidazo[1,2-c]quinazolin-6-amine (5aaa): Following the general procedure 2,
5aaa was isolated as a colorless solid; Yield: 54 mg (68%); mp 158ꢀ160 °C. IR (MIRꢀATR, 4000ꢀ600cmꢀ
1
1): νmax = 3446, 3054, 2925, 2852, 1626, 1598, 1527, 1446, 1339, 758, 732 cmꢀ1; H NMR (CDCl3, 400
MHz): δ ppm = 1.53 ꢀ 1.62 (m, 5H), 1.70 ꢀ 1.76 (m, 1H), 1.82 ꢀ 1.87 (m, 2H), 2.16ꢀ2.31 (m, 2H), 4.33 (m,
1H), 5.29 (d, 1H), 7.34 ꢀ 7.43 (m, 2H), 7.54 (t, 7.6 Hz, 1H), 7.60 ꢀ 7.65 (m, 2H), 7.82 (d, 8Hz, 1H), 8.02
13
(d, 8Hz 1H), 8.54 (d, 8Hz 1H); C NMR (CDCl3, 100 MHz): δ ppm = 24.8, 25.8, 33.2, 50.3, 76.7, 77.0,
+
77.4, 112.1, 120.4, 122.6, 123.7, 124.3, 125.2, 125.4, 131.9; HRꢀMS (ESI+) m/z calculated for C20H21N4
[M + H+]: 317.1761; found: 317.1754.
2ꢀChloroꢀNꢀcyclohexylbenzo[4,5]imidazo[1,2ꢀc]quinazolinꢀ6ꢀamine (5baa): Following the general
procedure 2, 5baa was isolated as a colorless solid; Yield: 56 mg (64%); mp 178ꢀ180 °C. IR (MIRꢀATR,
4000ꢀ600cmꢀ1): νmax = 3449, 3054, 2928, 2852, 1625, 1598, 1528, 1208, 823, 731 cmꢀ1; 1H NMR (CDCl3,
400 MHz): δ ppm = 1.44 ꢀ 1.61 ppm (m, 4H), 1.73 (dt, J = 12.6, 3.7 Hz, 1H), 1.78 ꢀ 1.90 (m, 3H), 2.28
(dd, J = 12.0 and 3.2 Hz, 2H), 4.22 ꢀ 4.38 (m, 1H), 5.29 (d, J = 6.8 Hz, 1H), 7.37 ꢀ 7.45 (m, 1H), 7.48 ꢀ
7.58 (m, 3H), 7.78 (d, J = 7.8 Hz, 1H), 7.98 (d, J = 7.8 Hz, 1H), 8.47 (d, J = 2.4 Hz, 1H); 13C NMR
(CDCl3, 100 MHz): δ ppm = 24.8, 25.7, 33.1, 50.4, 112.1, 116.1, 120.5, 122.9, 123.5, 125.4, 126.9, 128.0,
ACS Paragon Plus Environment

Page 19 of 32
The Journal of Organic Chemistry
1
2
3
4
5
128.9, 132.0, 143.0, 144.5, 148.2; HRꢀMS (ESI+) m/z calculated for C20H20ClN4 [M + H+]: 351.1371;
found: 351.1375.
+
6
7
8
9
2-Bromo-N-cyclohexylbenzo[4,5]imidazo[1,2-c]quinazolin-6-amine (5caa): Following the general
procedure 2, 5caa was isolated as a colorless solid; Yield: 61 mg (62%); mp 140ꢀ142°C. IR (MIRꢀATR,
4000ꢀ600cmꢀ1): νmax = 3444, 3055, 2929, 2853, 1627, 1599, 1528, 1263, 822, 732 cmꢀ1; 1H NMR (CDCl3,
400 MHz): δ ppm = 1.32 ꢀ 1.38 ppm (m, 1H), 1.44 ꢀ 1.60 (m, 4H), 1.77 ꢀ 1.90 (m, 3H), 2.28 (dd, J = 12.0
and 3.2 Hz, 2H), 4.24 ꢀ 4.37 (m, 1 H), 5.30 (d, J = 7.3 Hz, 1H), 7.39 ꢀ 7.45 (m, 1H), 7.48 (d, J = 8.8 Hz,
1H), 7.50 ꢀ 7.56 (m, 1H), 7.65 (dd, J = 8.6 and 2.2 Hz, 1H), 7.77 (d, J = 8.3 Hz, 1H), 7.98 (d, J = 7.8 Hz,
1H), 8.64 (d, J = 2.4 Hz, 1H); 13C NMR (CDCl3, 100 MHz): δ ppm = 24.8, 25.7, 33.1, 50.4, 112.1, 116.4,
116.6, 120.6, 123.0, 125.4, 126.6, 127.1, 128.0, 134.8, 143.4, 144.5, 144.6, 148.1; HRꢀMS (ESI+) m/z
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
+
calculated for C20H20BrN4 [M + H+]: 395.0866; found:395.0860.
N-(Tert-butyl)benzo[4,5]imidazo[1,2-c]quinazolin-6-amine (5aab): Following the general procedure 2,
5aab was isolated as a colorless solid; Yield: 54 mg (75%); mp 134ꢀ136 °C. IR (MIRꢀATR, 4000ꢀ600cmꢀ
1): νmax = 3452, 3273, 3055, 2962, 2925, 1628, 1600, 1528, 731 cmꢀ1; 1H NMR (CDCl3, 400 MHz): δ ppm
= 1.72 (s, 9H), 5.29 (s, 1H), 7.44 ꢀ 7.31 (m, 2H), 7.57 ꢀ 7.48 (m, 1H), 7.68 ꢀ 7.59 (m, 2H), 7.79 (d, J = 8.3
Hz, 1H), 8.01 (d, J = 8.3 Hz, 1H), 8.53 (dd, J = 1.2 and 8.1 Hz, 1H); 13C NMR (CDCl3, 100 MHz): δ ppm
= 29.2, 53.2, 112.0, 115.2, 120.3, 122.5, 123.7, 124.2, 125.1, 125.7, 128.1, 131.8, 143.5, 144.2, 144.6,
+
149.5; HRꢀMS (ESI+) m/z calculated for C18H19N4 [M + H+]: 291.1604; found: 291.1606.
N-(Tert-butyl)-2-chlorobenzo[4,5]imidazo[1,2-c]quinazolin-6-amine (5bab): Following the general
procedure 2, 5bab was isolated as a colorless solid; Yield: 61 mg (75%); mp 168ꢀ170 °C. IR (MIRꢀATR,
1
4000ꢀ600cmꢀ1): νmax = 3451, 2961, 2924, 1626, 1529, 1470, 1197, 822, 731 cmꢀ1; H NMR (CDCl3, 400
MHz): δ ppm = 1.71 (s, 9H), 5.33 (s, 1H), 7.41 ꢀ 7.49 (m, 1H), 7.52 ꢀ 7.62 (m, 4H), 7.79 (d, J = 8.3 Hz,
1H), 8.01 (d, J = 8.3 Hz, 1H), 8.51 (d, J = 2.0 Hz, 1H); 13C NMR (CDCl3, 100 MHz): δ ppm = 29.1, 53.3,
112.0, 120.6, 122.9, 123.5, 125.4, 127.1, 128.0, 129.0, 132.0, 142.7, 143.6, 144.5; HRꢀMS (ESI+) m/z
+
calculated for C18H18ClN4 [M + H+]: 325.1215; found: 325.1214.
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 20 of 32
1
2
3
4
5
6
7
8
9
2-Bromo-N-(tert-butyl)benzo[4,5]imidazo[1,2-c]quinazolin-6-amine (5cab): Following the general
procedure 2, 5cab was isolated as a colorless solid; Yield: 60 mg (65%); mp 188ꢀ190 °C. IR (MIRꢀATR,
4000ꢀ600cmꢀ1): νmax = 3364, 2921, 2851, 1631, 1601, 1529, 814, 721 cmꢀ1; 1H NMR (CDCl3, 400 MHz): δ
ppm = 1.71 (s, 9H) 5.34 (s, 1H) 7.40 ꢀ 7.47 (m, 1H) 7.50 (d, J = 8.80 Hz, 1H) 7.55 (td, J = 7.83 and 0.98
Hz, 1H) 7.66 (dd, J = 8.56 and 2.20 Hz, 1H) 7.77 (d, J = 8.31 Hz, 1H) 8.00 (d, J = 7.82 Hz, 1H) 8.66 (d, J
= 2.45 Hz, 1H); 13C NMR (CDCl3, 100 MHz): δ ppm = 29.1, 53.3, 112.0, 116.5, 116.6, 120.6, 122.9,
125.4, 126.6, 127.4, 128.0, 134.7, 143.0, 143.7, 144.5, 148.2; HRꢀMS (ESI+) m/z calculated for
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
C18H18BrN4 [M + H+]: 369.0709; found: 369.0708.
+
N-Cyclohexyl-9,10-dimethylbenzo[4,5]imidazo[1,2-c]quinazolin-6-amine (5aba): Following the general
procedure 2, 5aba was isolated as a light yellow solid; Yield: 56 mg (65%); mp 208ꢀ210 °C. IR (MIRꢀ
ATR, 4000ꢀ600cmꢀ1): νmax = 3338, 2926, 2853, 1604, 1529, 1453, 761 cmꢀ1; 1H NMR (CDCl3, 400 MHz):
δ ppm = 1.44 ꢀ 1.65 ppm (m, 4H), 1.68 ꢀ 1.78 (m, 1H), 1.81 ꢀ 1.91 (m, 2H), 2.26 ꢀ 2.34 (m, 4H), 2.38 (d, J
= 9.8 Hz, 6H), 4.23 ꢀ 4.41 (m, 1H), 5.22 (d, J = 6.4 Hz, 1H), 7.32 (t, J = 7.3 Hz, 1H), 7.45 (br. s., 1H),
7.54 ꢀ 7.65 (m, 2H), 7.69 (br. s., 1H), 8.47 (d, J = 7.8 Hz, 1H); 13C NMR (CDCl3, 100 MHz): δ ppm =
20.5, 21.0, 24.8, 25.8, 33.2, 50.3, 112.4, 115.5, 120.4, 123.5, 124.1, 125.3, 126.4, 131.5, 131.7, 134.3,
+
143.2, 144.4, 144.5, 148.8; HRꢀMS (ESI+) m/z calculated for C22H25N4 [M + H+]: 345.2074; found:
345.2072.
N-Cyclohexylquinazolino[3,4-a]perimidin-6-amine (5aea): Following the general procedure 3, 5aea was
isolated as a yellow solid; Yield: 44 mg (48%); mp 178ꢀ180°C; IR (MIRꢀATR, 4000ꢀ600cmꢀ1): νmax
=
3432, 2928, 1609, 1496, 825, 741 cmꢀ1; 1H NMR (CDCl3, 400 MHz): δ ppm = 1.21 ꢀ 1.33 (m, 5H), 1.45 ꢀ
1.55 (m, 2H), 1.75 (dt, J = 13.6 and 4.0 Hz, 3H), 2.09 ꢀ 2.19 (m, 2H), 4.09 ꢀ 4.22 (m, 1H), 5.13 (d, J = 7.3
Hz, 1H), 7.10 ꢀ 7.19 (m, 3H), 7.26 ꢀ 7.35 (m, 3H), 7.39 ꢀ 7.45 (m, 2H), 7.49 (td, J = 7.6 and 1.5 Hz, 1H),
8.24 (dd, J = 8.3 and 1.5 Hz, 1H); 13C NMR (CDCl3, 100 MHz): δ ppm = 24.8, 25.7, 33.0, 50.1, 111.1,
117.4, 119.1, 120.7, 122.8, 122.8, 123.9, 124.0, 125.6, 126.3, 129.0, 133.1, 135.1, 140.9, 145.0, 146.1,
+
148.9; HRꢀMS (ESI+) m/z calculated for C24H23N4 [M + H+]: 367.1917; found: 367.1916.
ACS Paragon Plus Environment

Page 21 of 32
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
2-Chloro-N-cyclohexylquinazolino[3,4-a]perimidin-6-amine (5bea): Following the general procedure 2,
5bea was isolated as a yellow solid; Yield: 45 mg (45%); mp 136ꢀ138 °C. IR (MIRꢀATR, 4000ꢀ600cmꢀ1):
νmax = 3424, 2923, 2852, 1621, 1509, 823, 761 cmꢀ1; 1H NMR (CDCl3, 400 MHz): δ ppm = 1.23 ꢀ 1.30 (m,
5H), 1.41 ꢀ 1.51 (m, 3H), 1.75 (dt, J = 13.3 and 3.9 Hz, 3H), 2.12 (dd, J = 12.2 and 3.4 Hz, 2H), 7.09 ꢀ
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
13
7.22 (m, 3H), 7.28 ꢀ 7.36 (m, 2H), 7.39 ꢀ 7.46 (m, 3H), 8.20 (d, J = 2.4 Hz, 1H),; C NMR (CDCl3, 100
MHz): δ ppm = 24.8, 25.7, 32.9, 50.2, 111.2, 117.6, 120.1, 121.0, 123.0, 123.9, 124.9, 125.5, 126.3,
128.0, 129.1, 132.8, 133.1, 135.1, 140.5, 145.1; HRꢀMS (ESI+) m/z calculated for C24H22ClN4 [M + H+]:
+
401.1528; found: 401.1524.
2-Bromo-N-cyclohexylquinazolino[3,4-a]perimidin-6-amine (5cea): Following the general procedure 2,
5cea was isolated as a yellow solid; Yield: 52 mg (47%); mp 204ꢀ206 °C. IR (MIRꢀATR, 4000ꢀ600cmꢀ1):
νmax = 3420, 2926, 2852, 1619, 1566, 1509, 822, 761 cmꢀ1; H NMR (CDCl3, 400 MHz): δ ppm = 1.20 ꢀ
1
1.33 (m, 3H), 1.41 ꢀ 1.54 (m, 2H), 1.66 (dt, J = 12.84 and 4.10 Hz, 1H), 1.75 (dt, J = 13.33 and 3.85 Hz,
2H), 2.07 ꢀ 2.16 (m, 2H), 4.13 (td, J = 6.97 and 3.18 Hz, 1H), 5.18 (d, J = 7.83 Hz, 1H), 7.10 ꢀ 7.18 (m,
3H), 7.26 ꢀ 7.34 (m, 1H), 7.34 ꢀ 7.36 (m, 1H), 7.40 ꢀ 7.46 (m, 2H), 7.55 (dd, J = 8.56 and 2.20 Hz, 1H),
8.36 (d, J = 2.45 Hz, 1H); 13C NMR (CDCl3, 100 MHz): δ ppm = 24.8, 25.6, 32.9, 50.2,111.2, 115.4,
117.7, 120.3, 120.6, 121.1, 123.0, 123.9, 125.8, 126.3, 128.0, 129.1, 132.8, 135.1, 135.9, 140.5, 145.2,
147.6; HRꢀMS (ESI+) m/z calculated for C24H22BrN4 [M + H+]: 445.1022; found: 445.1020.
+
2-Bromo-N-cyclohexyl-9,10-dimethylbenzo[4,5]imidazo[1,2-c]quinazolin-6-amine (5cba): Following
the general procedure 2, 5cba was isolated as a colorless solid; Yield: 68 mg (65%); mp 216ꢀ218 °C. IR
(MIRꢀATR, 4000ꢀ600cmꢀ1): νmax = 3443, 2925, 2852, 1631, 1603, 1527, 1464, 821, 735 cmꢀ1; H NMR
1
(CDCl3, 400 MHz): δ ppm = 1.49 ꢀ 1.61 (m, 4H), 1.71 ꢀ 1.77 (m, 2H), 1.86 (dt, J = 13.1 and 3.7 Hz, 2H),
2.25 ꢀ 2.33 (m, 2H), 2.41 (s, 3H), 2.44 (s, 3H), 4.21 ꢀ 4.37 (m, 1H), 5.25 (d, J = 6.8 Hz, 1H), 7.42 ꢀ 7.49
(m, 2H), 7.63 (dd, J = 8.8 and 2.4 Hz, 1H), 7.69 (s, 1H), 8.59 (d, J = 2.0 Hz, 1H); 13C NMR (CDCl3, 100
MHz): δ ppm = 20.5, 21.0, 24.8, 25.8, 33.1, 50.4, 112.3, 116.2, 116.9, 120.4, 126.3, 126.4, 127.0, 132.2,
134.3, 134.6, 143.0, 143.2, 144.7, 147.3; HRꢀMS (ESI+) m/z calculated for C22H24BrN4 [M + H+]:
+
423.1179; found: 423.1182.
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 22 of 32
1
2
3
4
5
6
7
8
9
N-(Tert-butyl)-9,10-dimethylbenzo[4,5]imidazo[1,2-c]quinazolin-6-amine (5abb): Following the general
procedure 2, 5abb was isolated as a colorless solid; Yield: 59 mg (74%); mp 228ꢀ230 °C. IR (MIRꢀATR,
4000ꢀ600cmꢀ1): νmax = 3412, 2962, 2918, 1605, 1562, 1529, 1452, 1201, 764 cmꢀ1; 1H NMR (CDCl3, 400
MHz): δ ppm = 1.72 (s, 9H), 2.41 (d, J = 8.31 Hz, 6H), 5.25 (s, 1H), 7.34 (ddd, J = 7.95, 6.72 and 1.47
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
13
Hz, 1H), 7.46 (s, 1H), 7.55 ꢀ 7.65 (m, 2H), 7.72 (s, 1H), 8.48 (dd, J = 7.82 and 0.98 Hz, 1H); C NMR
(CDCl3, 100 MHz): δ ppm = 20.4, 21.0, 29.2, 53.0, 112.3, 115.4, 120.3, 123.5, 124.0, 125.6, 126.4, 131.3,
131.5, 134.1, 143.1, 143.6, 144.1, 148.8; HRꢀMS (ESI+) m/z calculated for C20H23N4 [M + H+]:
+
319.1917; found: 319.1909.
Ethyl 2-(benzo[4,5]imidazo[1,2-c]quinazolin-6-ylamino)acetate (5aac): Following the general procedure
2, 5aac was isolated as a colorless solid; Yield: 48 mg (60%); mp 152ꢀ154 °C. IR (MIRꢀATR, 4000ꢀ
600cmꢀ1): νmax = 3432, 2927, 1736, 1628, 1602, 1535, 1450, 1203, 737 cmꢀ1; 1H NMR (CDCl3, 400 MHz):
δ ppm = 1.39 (t, 7.3 Hz, 3H), 4.37 (q, 7.3 Hz, 2H), 4.52 (d, 4.4 Hz, 2H), 6.19 (br. s., 1H), 7.38 ꢀ 7.43 (m,
1H), 7.45 (d, 8.3 Hz, 1H), 7.50 ꢀ 7.56 (m, 1H), 7.60 ꢀ 7.65 (m, 2H), 8.01 (dd, 7.6 and 6.1 Hz, 2H), 8.53
(d, 7.6 Hz, 1H); 13C NMR (CDCl3, 100 MHz): δ ppm = 14.2, 44.0, 62.1, 112.4, 115.5, 120.3, 123.1,
124.3, 124.3, 125.4, 125.5, 128.0, 131.9, 144.0, 144.3, 144.4, 148.9, 170.6.; HRꢀMS (ESI+) m/z
+
calculated for C18H17N4O2 [M + H+]: 321.1346; found: 321.1346.
N-Benzylbenzo[4,5]imidazo[1,2-c]quinazolin-6-amine (5aad): Following the general procedure 2, 5aad
was isolated as a colorless solid; Yield: 47 mg (58%); mp 168ꢀ170 °C; IR (MIRꢀATR, 4000ꢀ600cmꢀ1):
νmax = 3398, 1626, 1599, 1530, 1447, 1264,734, 701 cmꢀ1; 1H NMR (CDCl3, 400 MHz): δ ppm = 4.98 (d,
4.9 Hz, 2H), 5.62 (br. s., 1H), 7.34 ꢀ 7.46 (m, 5H), 7.48 ꢀ 7.57 (m, 3H), 7.62 ꢀ 7.71 (m, 2H), 7.75 ꢀ 7.80
13
(m, 1H), 8.01 (d, 7.8 Hz, 1H), 8.56 (d, 6.8 Hz, 1H); C NMR (CDCl3, 100 MHz): δ ppm = 46.4, 112.2,
114.4, 114.5, 115.5, 120.4, 122.6, 122.8, 124.2, 124.3, 125.3, 125.6, 128.0, 128.1, 129.0, 131.0, 132.0,
137.9, 144.2, 145.1, 149.2; HRꢀMS (ESI+) m/z calculated for C21H17N4 [M + H+]: 325.1448; found:
+
325.1449.
2-Bromo-N-cyclohexyl-11-methylbenzo[4,5]imidazo[1,2-c]quinazolin-6-amine (5cca):
ACS Paragon Plus Environment

Page 23 of 32
The Journal of Organic Chemistry
1
2
3
4
Following the general procedure 2, 5cca was isolated as a colorless solid; Yield: 66 mg (65%); mp 208ꢀ
5
6
1
210 °C. IR (MIRꢀATR, 4000ꢀ600cmꢀ1): νmax = 3442, 2924, 2850, 1624, 1593, 820, 735 cmꢀ1; H NMR
7
8
9
(CDCl3, 400 MHz): δ ppm = 1.43 ꢀ 1.60 (m, 4H), 1.70 ꢀ 1.76 (m, 2H), 1.84 (dt, J = 13.2 and 3.9 Hz, 2H),
2.27 (dd, J = 11.7 and 2.9 Hz, 2H), 2.81 (s, 3H), 4.23 ꢀ 4.37 (m, 1H), 5.33 (d, J = 6.8 Hz, 1H), 7.30 ꢀ 7.36
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
13
(m, 2H), 7.47 (d, J = 8.8 Hz, 1H), 7.58 ꢀ 7.68 (m, 2H), 8.68 (d, J = 2.4 Hz, 1H); C NMR (CDCl3, 100
MHz): δ ppm = 17.1, 24.8, 25.8, 33.1, 50.3, 109.5, 116.2, 116.9, 122.8, 125.7, 126.6, 127.0, 127.6, 130.9,
134.5, 143.3, 143.9, 144.7, 147.3; HRꢀMS (ESI+) m/z calculated for C21H22BrN4 [M + H+]: 409.1022;
+
found: 409.1005.
2-Chloro-N-cyclohexyl-11-methylbenzo[4,5]imidazo[1,2-c]quinazolin-6-amine (5bca):
Following the general procedure 2, 5bca was isolated as a colorless solid; Yield: 65 mg (72%); mp 184ꢀ
186 °C. IR (MIRꢀATR, 4000ꢀ600cmꢀ1): νmax = 3397, 2922, 2851, 1617, 1591, 1227, 1071, 822, 733 cmꢀ1;
1H NMR (CDCl3, 400 MHz): δ ppm = 1.32 ꢀ 1.62 (m, 6H), 1.72 (m, 1H), 1.84 (m, 2H), 2.27 (m, 2H), 2.78
(s, 3H), 4.26 (td, 10.6, 6.6 and 3.2 Hz, 1H), 5.28 (d, 7.3 Hz, 1H), 7.24 ꢀ 7.31 (m, 2H), 7.44 ꢀ 7.48 (m, 1H),
7.48 ꢀ 7.52 (m, 1H), 7.54 ꢀ 7.58 (m, 1H), 8.49 (d, 1.5 Hz, 1H); 13C NMR (CDCl3, 100 MHz): δ ppm =
17.1, 24.8, 25.8, 33.1, 50.3, 109.4, 116.4, 122.7, 123.5, 125.6, 126.7, 127.5, 128.7, 130.8, 131.7, 142.9,
143.8, 144.6, 147.4; HRꢀMS (ESI+) m/z calculated for C21H22ClN4 [M + H+]: 365.1528; found:
+
365.1522.
N-(tert-butyl)-2-chloro-11-methylbenzo[4,5]imidazo[1,2-c]quinazolin-6-amine (5bcb):
Following the general procedure 2, 5bcb was isolated as a colorless solid; Yield: 62 mg (73%); mp 210ꢀ
212 °C. IR (MIRꢀATR, 4000ꢀ600cmꢀ1): νmax = 3448, 2961, 1627, 1599, 1530, 1470, 1206, 820, cmꢀ1; H
1
NMR (CDCl3, 400 MHz): δ ppm = 1.70 (s, 9H), 2.80 (s, 3H), 5.33 (s, 1H), 7.29 ꢀ 7.35 (m, 2H), 7.46 ꢀ
7.51 (m, 1H), 7.51 ꢀ 7.55 (m, 1H), 7.55 ꢀ 7.60 (m, 1H), 8.52 (s, 1H); 13C NMR (CDCl3, 100 MHz): δ ppm
= 17.1, 29.1, 53.2, 109.4, 116.3, 122.7, 123.5, 125.6, 127.0, 127.5, 128.7, 130.3, 130.8, 131.7, 142.5,
143.7, 147.5; HRꢀMS (ESI+) m/z calculated for C19H20ClN4 [M + H+]: 339.1371; found: 339.1371.
+
Mixture of 2,10-dichloro-N-cyclohexylbenzo[4,5]imidazo[1,2-c]quinazolin-6-amine and 2,9-dichloro-
N-cyclohexylbenzo[4,5]imidazo[1,2-c]quinazolin-6-amine (5bda):
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 24 of 32
1
2
3
4
5
6
Following the general procedure 2, 5bda was isolated as a colorless inseparable solid mixture; Yield: 60
mg (62%); mp 178ꢀ180 °C. IR (MIRꢀATR, 4000ꢀ600cmꢀ1): νmax = 3444, 2929, 2854, 1629, 1598, 1524,
7
8
1
934, 823 cmꢀ1; H NMR (CDCl3, 400 MHz): δ ppm = 1.42 ꢀ 1.60 (m, 4H), 1.69 ꢀ 1.81 (m, 2H), 1.86 (m,
9
2H), 2.25 ꢀ 2.34 (m, 2H), 4.21 ꢀ 4.32 (m, 1H), 5.02 (d, 6.6 Hz, 0.5H), 5.10 (d, 6.6 Hz, 0.5H), 7.28 ꢀ 7.35
(m, 0.5H), 7.43 ꢀ 7.49 (m, 0.5H), 7.49 ꢀ 7.55 (m, 2H), 7.59 ꢀ 7.65 (m, 0.5H), 7.71 (br. s., 0.5H), 7.80 ꢀ
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
13
7.86 (m, 0.5H), 7.88 (br. s., 0.5H), 8.37 (br. s., 1H); C NMR (CDCl3, 100 MHz): δ ppm = 24.8, 24.9,
25.5, 25.7, 33.1, 50.6, 50.8, 112.4, 112.7, 115.7, 115.9, 120.1, 121.1, 123.1, 123.4, 123.5, 126.0, 126.5,
127.0, 128.3, 128.4, 129.1, 129.2, 131.0, 132.3, 132.4, 142.8, 143.0, 144.1, 145.4, 148.8, 149.2; HRꢀMS
+
(ESI+) m/z calculated for C20H19Cl2N4 [M + H+]: 385.0981; found: 385.0996.
Mixture
of
(2-bromo-6-(cyclohexylamino)benzo[4,5]imidazo[1,2-c]quinazolin-10-yl
(phenyl)
methanone and (2-bromo-6-(cyclohexylamino)benzo[4,5]imidazo[1,2-c]quinazolin-9-yl)
(phenyl)methanone (5cfa):
Following the general procedure 2, 5cfa was isolated as a yellow color inseparable solid mixture; Yield:
82 mg (66%); mp 210ꢀ212 °C; IR (MIRꢀATR, 4000ꢀ600cmꢀ1): νmax = 3339, 3061, 2928, 2853, 1628, 1599,
1
1525, 1276, 823, 718 cmꢀ1; H NMR (CDCl3, 400 MHz): δ ppm = 1.32 ꢀ 1.51 (m, 1H), 1.53 ꢀ 1.56 (m,
3H), 1.71 ꢀ 1.82 (m, 3H), 1.87 (dd, J = 9.3, 3.9 Hz, 1H), 2.22 (d, J = 9.8 Hz, 1H), 2.27 ꢀ 2.36 (m, 1H),
4.32 (dd, J = 6.1, 3.2 Hz, 1H), 5.33 (d, J = 6.8 Hz, 0.5H), 5.42 (d, J = 6.8 Hz, 0.5H), 7.46 ꢀ 7.56 (m, 3H),
13
7.59 ꢀ 7.72 (m, 2H), 7.79 ꢀ 7.91 (m, 3H), 8.34 (d, J = 1.5 Hz, 1H), 8.42 (s, 1H), 8.56 ꢀ 8.66 (m, 1H); C
NMR (CDCl3, 100 MHz): δ ppm = 24.6, 24.8, 25.7, 25.7, 32.7, 33.1, 50.5, 50.7, 112.3, 114.8, 116.2,
116.3, 116.7, 116.7, 119.4, 123.2, 124.5, 126.7, 126.8, 127.3, 127.3, 128.1, 128.4, 129.9, 130.2, 130.5,
131.8, 132.4, 132.6, 134.6, 135.3, 135.6, 137.5, 137.8, 143.4, 143.8, 143.9, 144.3, 144.4, 147.7, 149.4,
195.8, 196.0 ; HRꢀMS (ESI+) m/z calculated for C27H24BrN4O+ [M + H+]: 499.1128; found: 499.1107.
Mixture of 2-bromo-10-chloro-N-cyclohexylbenzo[4,5]imidazo[1,2-c]quinazolin-6-amine and 2-bromo-
9-chloro-N-cyclohexylbenzo[4,5]imidazo[1,2-c]quinazolin-6-amine (5cda):
Following the general procedure 2, 5cda was isolated as a inseparable colorless solid mixture; Yield: 74
mg (69%); mp 190ꢀ192 °C; IR (MIRꢀATR, 4000ꢀ600cmꢀ1): νmax = 3445, 2927, 2853, 1626, 1597, 1522,
ACS Paragon Plus Environment

Page 25 of 32
The Journal of Organic Chemistry
1
2
3
4
1
1466, 1422, 1207, 821, 737 cmꢀ1; H NMR (CDCl3, 400 MHz): δ ppm = 1.33 ꢀ 1.63 ppm (m, 6H), 1.86
5
6
7
8
(td, J = 8.6 and 3.9 Hz, 2H), 2.25 ꢀ 2.36 (m, 2H), 4.27 (dd, J = 6.1 and 3.2 Hz, 1H), 5.03 (d, J = 6.8 Hz,
1H), 5.10 (d, J = 6.8 Hz, 1H), 7.42 ꢀ 7.49 (m, 1H), 7.59 ꢀ 7.67 (m, 2H), 7.70 (d, J = 2.0 Hz, 1H), 7.81 ꢀ
7.90 (m, 1H), 8.54 (t, J = 2.0 Hz, 1H); 13C NMR (CDCl3, 100 MHz): δ ppm = 149.1, 148.6, 145.4, 144.2,
144.1, 143.4, 143.2, 143.0, 135.1, 135.0, 131.0, 128.3, 128.3, 127.2, 126.5, 126.5, 126.0, 123.1, 121.1,
120.1, 116.7, 116.6, 116.4, 116.2, 112.7, 112.4, 77.3, 77.0, 76.7, 50.8, 50.6, 33.1, 25.7, 24.9, 24.8; HRꢀ
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
MS (ESI+) m/z calculated for C20H19BrClN4 [M + H+]: 429.0476; found: 429.0487.
+
Mixture of N-cyclohexyl-10-methylbenzo[4,5]imidazo[1,2-c]quinazolin-6-amine and N-cyclohexyl-9-
methylbenzo[4,5]imidazo[1,2-c]quinazolin-6-amine (5aha):
Following the general procedure 2, 5aha was isolated as a colorless inseparable solid mixture; Yield: 54
mg (65%); mp 174ꢀ176 °C. IR (MIRꢀATR, 4000ꢀ600cmꢀ1): νmax = 3408, 2920, 1607, 1482, 834, 735 cmꢀ1;
1H NMR (CDCl3, 400 MHz): δ ppm = 1.29 ꢀ 1.42 (m, 1H), 1.43 ꢀ 1.65 (m, 3H), 1.67 ꢀ 1.78 (m, 2H), 1.80
ꢀ 1.91 (m, 2H), 2.24 ꢀ 2.36 (m, 2H), 2.56 (s, 1H), 2.61 (s, 2H), 4.27 ꢀ 4.40 (m, 1H), 5.20 ꢀ 5.31 (m, 1H),
7.31 ꢀ 7.39 (m, 2H), 7.54 ꢀ 7.69 (m, 3H), 7.89 (d, 8.3 Hz, 1H), 8.47 ꢀ 8.55 (m, 1H); 13C NMR (CDCl3, 100
MHz): δ ppm = 21.7, 22.3, 24.8, 24.9, 25.8, 33.2, 50.2, 50.3, 76.7, 77.0, 77.2, 77.3, 111.5, 112.2, 115.4,
119.9, 120.2, 123.6, 123.6, 124.0, 124.1, 124.2, 125.3, 126.7, 128.3, 131.6, 131.7, 132.6, 135.2, 144.4;
+
HRꢀMS (ESI+) m/z calculated for C21H23N4 [M + H+]: 331.1917; found: 331.1917.
Isolated Mixture of 10-chloro-N-cyclohexylbenzo[4,5]imidazo[1,2-c]quinazolin-6-amine (5ada) and 9-
chloro-N-cyclohexylbenzo[4,5]imidazo[1,2-c]quinazolin-6-amine (5ada’):
Following the general procedure 2, 5ada and 5ada’ were isolated as colorless solids;
Data for 5ada: Yield: 35 mg (40%); mp 186ꢀ188 °C, IR (MIRꢀATR, 4000ꢀ600cmꢀ1): νmax = 3444, 3062,
2927, 2853, 1627, 1599, 1525, 1428, 1208, 1068, 865, 761; 1H NMR (CDCl3, 400 MHz): δ ppm = 1.32 ꢀ
1.39 (m, 1H), 1.43 ꢀ 1.52 (m, 2H), 1.55 ꢀ 1.61 (m, 2H), 1.67 ꢀ 1.79 (m, 3H), 1.85 (dt, J = 13.3 and 3.9 Hz,
2H), 2.30 (dd, J = 12.0 and 3.2 Hz, 2H), 4.32 (dtd, J = 10.1, 6.6 and 3.7 Hz, 1H), 5.10 (d, J = 6.8 Hz, 1H),
7.30 ꢀ 7.43 (m, 2H), 7.60 ꢀ 7.67 (m, 2H), 7.68 ꢀ 7.75 (m, 1H), 7.92 ꢀ 7.99 (m, 1H), 8.42 ꢀ 8.54 (m, 1H); 13C
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 26 of 32
1
2
3
4
5
6
NMR (CDCl3, 100 MHz): δ ppm = 24.8, 25.8, 33.2, 50.5, 112.7, 114.9, 120.0, 122.7, 123.9, 124.3, 125.5,
126.7, 130.8, 132.2, 144.1, 144.6, 145.6, 150.6;
7
8
9
Data for 5ada’: Yield: 22 mg (25%); mp 196ꢀ198 °C; IR (MIRꢀATR, 4000ꢀ600cmꢀ1): νmax = 3431, 2927,
2852, 1625, 1598, 1528, 1450, 1340, 814, 759 cmꢀ1; 1H NMR (CDCl3, 400 MHz): δ ppm = 1.32 ꢀ 1.42 (m,
1H), 1.45 ꢀ 1.61 (m, 4H), 1.75 (dt, J = 13.0 and 3.5 Hz, 1H), 1.87 (dt, J = 13.1 and 3.7 Hz, 2H), 2.31 (dd,
J = 12.0 and 3.2 Hz, 2H), 4.26 ꢀ 4.38 (m, 1H), 5.03 (d, J = 7.3 Hz, 1H), 7.38 (ddd, J = 8.1, 4.6 and 3.4 Hz,
1H), 7.49 ꢀ 7.52 (dd, 8.5 and 2Hz, 1H), 7.62 ꢀ 7.67 (m, 2H), 7.80 (d, J = 2.0 Hz, 1H), 7.91 (d, J = 8.5 Hz,
1H), 8.45 ꢀ 8.54 (m, 1H); 13C NMR (CDCl3, 100 MHz): δ ppm = 24.9, 25.7, 33.2, 50.6, 112.4, 115.1,
121.0, 124.0, 124.2, 125.5, 125.8, 127.9, 128.5, 132.2, 143.2, 144.0, 144.5, 150.1; HRꢀMS (ESI+) m/z
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
+
calculated for C20H20ClN4 [M + H+]: 351.1371; found: 351.1368.
Mixture of N-(tert-butyl)-2,10-dichlorobenzo[4,5]imidazo[1,2-c]quinazolin-6-amine and N-(tert-butyl)-
2,9-dichlorobenzo[4,5]imidazo[1,2-c]quinazolin-6-amine (5bdb):
Following the general procedure 2, 5bdb was isolated as colorless inseparable solid mixture; Yield: 58
mg (65%); mp 206ꢀ208 °C; IR (MIRꢀATR, 4000ꢀ600cmꢀ1): νmax = 3450, 2967, 2928, 1631, 1600, 1526,
1198, 822, 776 cmꢀ1; 1H NMR (CDCl3, 400 MHz): δ ppm = 1.71 (s, 9H), 5.1 (s, 0.4H), 5.1 (s, 0.6H), 7.39
(dd, 8.8 and 2 Hz, 0.5H), 7.50 ꢀ 7.55 (m, 0.5H), 7.55 ꢀ 7.60 (m, 2H), 7.7 (m, 0.6H), 7.7 (m, 0.4H), 7.96 (d,
8.8 Hz, 0.4H), 8.1(m, 0.6H), 8.45 ꢀ 8.49 (m, 1H); 13C NMR (CDCl3, 100 MHz): δ ppm = 29.1, 53.5, 53.5,
76.7, 77.0, 77.2, 77.3, 112.4, 112.7, 115.8, 116.0, 120.1, 121.1, 123.0, 123.4, 123.4, 125.9, 126.6, 127.2,
128.3, 128.4, 129.2, 129.2, 130.9, 132.2, 132.3, 142.5, 142.7, 143.0, 143.1, 143.2, 145.4, 148.9, 149.4;
+
HRꢀMS (ESI+) m/z calculated for C18H17Cl2N4 [M + H+]: 359.0825; found: 359.0825.
Mixture
yl)(phenyl)methanone
yl)(phenyl)methanone (5bfa):
of
(2-chloro-6-(cyclohexylamino)benzo[4,5]imidazo[1,2-c]quinazolin-10-
(2-chloro-6-(cyclohexylamino)benzo[4,5]imidazo[1,2-c]quinazolin-9-
and
Following the general procedure 2, 5bfa was isolated as a yellow inseparable solid mixture; Yield: 68 mg
(60%); mp 192ꢀ194 °C; IR (MIRꢀATR, 4000ꢀ600cmꢀ1): νmax = 3338, 3056, 2928, 2853, 1628, 1598, 1275,
824, 718 cmꢀ1; 1H NMR (CDCl3, 400 MHz): δ ppm = 1.29 ꢀ 1.42 (m, 1H), 1.42 ꢀ 1.62 (m, 4H), 1.72 ꢀ 1.83
ACS Paragon Plus Environment

Page 27 of 32
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
(m, 2H), 1.87 (m, 1H), 2.22 (m, 1H), 2.26 ꢀ 2.35 (m, 1H), 4.18 ꢀ 4.44 (m, 1H), 5.31 (s, 0.5H), 5.41 (s,
0.5H), 7.48 ꢀ 7.54 (m, 2H), 7.54 ꢀ 7.60 (m, 2H), 7.60 ꢀ 7.67 (m, 1H), 7.80 ꢀ 7.88 (m, 2H), 7.95 ꢀ 8.04 (m,
2H), 8.42 ꢀ 8.47 (m, 1H), 8.50 (t, 2 Hz, 1H); 13C NMR (CDCl3, 100 MHz): δ ppm = 24.6, 24.8, 25.7, 25.7,
32.8, 33.1, 50.4, 50.7, 76.7, 77.0, 77.2, 77.4, 112.3, 114.8, 115.7, 115.9, 119.5, 123.3, 123.6, 123.8, 124.6,
127.1, 128.1, 128.4, 129.2, 129.9, 130.2, 130.5, 131.8, 132.4, 132.6, 132.9, 134.6, 137.5, 137.9, 143.0,
143.6, 143.9, 144.2, 144.3, 147.8, 150.9, 195.9, 196.0; HRꢀMS (ESI+) m/z calculated for C27H24ClN4O+
[M + H+]: 455.1633; found: 455.1615.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(VI) General procedure 4: Synthesis of free amine 6ꢀaminobenzimidazoquinazolines 6aa and 6ba
from 5aab and 5bab by tertꢀbutyl deprotection:
In an 10 mL sealed tube was taken compounds 5aab or 5bab (0.5 mmol) and added 2 mL of nitro
o
methane followed by addition of Sc(OTf)2 (0.75 mmol). The tube was heated at 150 C for 6 h. Then the
solvent was evaporated using rotary evaporator. The crude was dissolved in ethyl acetate and filtered
through a pad of Celite and the crude was purified through a silica gel (100ꢀ200 mesh) column using
hexane and ethyl acetate (4:1) as eluents to yield the desired products 6aa or 6ba as free amines.
(VII) Spectral data for the compounds 6aa and 6ba:
Benzo[4,5]imidazo[1,2-c]quinazolin-6-amine (6aa): Following the general procedure 4, 6aa was isolated
as a colorless solid; Yield: 76 mg (65%); mp > 300 oC; IR (MIRꢀATR, 4000ꢀ600cmꢀ1): νmax = 3056, 2926,
1
2851, 1607, 1525, 1449, 1264, 736 cmꢀ1; H NMR (DMSO d6, 400 MHz): δ ppm = 7.37 (t, 7.6 Hz, 1H),
7.41 ꢀ 7.48 (m, 3H), 7.50 ꢀ 7.56 (m, 2H), 7.62 ꢀ 7.68 (m, 1H), 7.91 (d, 8.3 Hz, 1H), 8.42 (t, 8.8 Hz, 2H);
13C NMR (DMSO d6, 100 MHz): δ ppm = 114.3, 114.6, 119.0, 122.3, 123.2, 123.8, 124.3, 125.0, 128.1,
+
131.8, 143.8, 144.6, 146.5, 148.4; HRꢀMS (ESI+) m/z calculated for C14H11N4 [M + H+]: 235.0978;
found: 235.0977.
2-Chlorobenzo[4,5]imidazo[1,2-c]quinazolin-6-amine (6ba): Following the general procedure 4, 6ba
was isolated as a colorless solid; Yield: 90 mg (67%); mp 268ꢀ270 °C; IR (MIRꢀATR, 4000ꢀ600cmꢀ1):
νmax = 3398, 3057, 1658, 1518, 1258, 822, 732 cmꢀ1; 1H NMR (DMSO d6, 400 MHz): δ ppm = 7.45 ꢀ 7.54
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 28 of 32
1
2
3
4
5
6
7
8
(m, 2H), 7.54 ꢀ 7.59 (m, 3H), 7.65 (dd, 8.8 and 2.4 Hz, 1H), 7.92 (d, 7.8 Hz, 1H), 8.32 (d, 2.4 Hz, 1H),
8.44 (d, 8.3 Hz, 1H); 13C NMR (DMSO d6, 100 MHz): δ ppm = 38.8, 39.0, 39.2, 39.4, 39.6, 39.8, 40.0,
114.3, 115.7, 119.2, 122.5, 122.8, 125.3, 126.4, 126.8, 128.1, 131.7, 143.4, 143.6, 146.7, 147.3; HRꢀMS
9
+
(ESI+) m/z calculated for C14H10ClN4 [M + H+]: 269.0589; found: 269.0590
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(VIII) General procedure 5: Synthesis of compound 8a and 8b via GroebkeꢀBlackburnꢀBienayme
(GBB) type reaction:
To a mixture of amine (6, 0.2 mmol), 4ꢀchlorobenzaldehyde (7, 0.2 mmol) and tꢀbutylisocyanide (4b, 0.2
mmol) was added Scandium triflate (20 mol%) and 2 mL of DMSO and the mixture was heated at 110 oC
for 8 h. After completion of the reaction (checked by TLC), the ice cold water was added and extracted
with ethyl acetate (3x 15mL) and the extract was dried over anhydrous Na2SO4 and concentrated under
reduced pressure. The crude extract was purified by filtration through short pad of a silica gel (60ꢀ120
mesh) column using hexane/ EtOAc (5:1) to give compound 8a or 8b.
(IX) Spectral data for the compounds 8a and 8b:
N-cyclohexyl-2-(2-fluorophenyl)benzo[4,5]imidazo[1,2-c]imidazo[1,2-a]quinazolin-3-amine
(8a):
Following the general procedure 5, 8a was isolated as a yellow solid; Yield: 58 mg (65%); mp 188ꢀ190
°C; IR (MIRꢀATR, 4000ꢀ600cmꢀ1): νmax = 3334, 2960, 1609, 1478, 1374, 823, 732 cmꢀ1; 1H NMR (DMSO
d6, 400 MHz): δ ppm = 0.62 ꢀ 0.82 (m, 2H), 1.00 ꢀ 1.30 (m, 3H), 1.45 (m, 3H), 1.62 ꢀ 1.88 (m, 2H), 3.85
(t, 9.5 Hz, 1H), 7.12 (dd, 11.5 and 8.1 Hz, 1H), 7.32 ꢀ 7.54 (m, 5H), 7.66 (s, 1H), 7.72 ꢀ 7.79 (m, 1H),
7.91 (m, 1H), 7.99 ꢀ 8.10 (m, 1H), 8.27 (d, 7.8 Hz, 1H), 8.44 (m, 1H), 9.40 (d, 1H); 13C NMR (DMSO d6,
100 MHz): δ ppm = 23.6, 23.8, 25.1, 33.3, 34.1, 57.0, 62.7, 89.2, 112.2, 114.9, 115.4, 115.6, 115.9, 119.6,
1
124.3, 124.5, 124.6, 125.2, 125.5, 127.4, 129.0, 129.1, 130.2, 130.4, 132.7, 134.4, 143.8, 147.6 (d, JCꢀF
=
+
190.0 Hz), 158.2; HRꢀMS (ESI+) m/z calculated for C28H25FN5 [M + H+]: 450.2089; found: 450.2083.
N-(tert-butyl)-2-(4-chlorophenyl)benzo[4,5]imidazo[1,2-c]imidazo[1,2-a]quinazolin-3-amine
(8b):
Following the general procedure 5, 8b was isolated as a yellow solid; Yield: 53 mg (60%); mp 236ꢀ238
1
°C; IR (MIRꢀATR, 4000ꢀ600cmꢀ1): νmax = 3369, 2968, 1603, 1474, 1365, 1203, 835, 746 cmꢀ1; H NMR
ACS Paragon Plus Environment

Page 29 of 32
The Journal of Organic Chemistry
1
2
3
4
(CDCl3, 400 MHz): δ ppm 0.97 (s, 9H), 3.20 (s, 1H), 7.43 (d, 8.3 Hz, 3H), 7.46 ꢀ 7.52 (m, 2H), 7.53 ꢀ
5
6
7.59 (m, 1H), 7.80 (d, 8.3 Hz, 2H), 7.89 ꢀ 7.97 (m, 1H), 8.62 (d, 7.8 Hz, 1H), 8.65 ꢀ 8.73 (m, 1H), 9.37 (d,
7
8
13
8.3 Hz, 1H); C NMR (CDCl3, 100 MHz): δ ppm = 29.7, 57.1, 114.7, 115.1, 117.5, 119.4, 123.8, 124.9,
9
125.6, 125.9, 127.6, 128.6, 129.3, 129.9, 130.5, 133.1, 133.2, 134.5, 134.9, 143.7, 144.3; HRꢀMS (ESI+)
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
+
m/z calculated for C26H23ClN5 [M + H+]: 440.1636; found: 440.1631.
ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge on the ACS Publications website
Experimental procedures and characterization for all new compounds; NMR spectra (PDF)
Xꢀray data for 5abb (CIF)
AUTHOR INFORMATION
Corresponding Author
*Eꢀmail: sharada@iith.ac.in.
ACKNOWLEDGMENTS
We gratefully acknowledge Science & Engineering Research Board (SERB), New Delhi, India and Indian
Institute of Technology Hyderabad (IITH) for financial support. AHS thank UGC, New Delhi, India, AS
thank CSIR, New Delhi, India and MDB thank MHRD, New Delhi, India for the award of research
fellowship.
REFERENCES
1. (a) Midya, S. P.; Sahoo, M. K.; Landge, V. G.; Rajamohanan, P. R.; Balaraman Nat. Commun. 2015,
6, 8591ꢀ8501. (b) WencelꢀDelord, J.; Glorius, F. Nat. Chem. 2013, 5, 369–375. (c) McMurray, L.;
O’Hara, F.; Gaunt, M. J. Chem. Soc. Rev. 2011, 40, 1885–1898. (d) Gutekunst, W.; Baran, P. S.
ACS Paragon Plus Environment