One-pot synthesis of benzo[4,5]imidazo[1,2- a ]quinazoline derivatives via facile transition-metal-free tandem process

Article abstract of DOI:10.1021/co500001u

A one-pot transition metal-free method for synthesizing benzo[4,5]imidazo[1,2-a]quinazoline and imidazo[1,2-a]quinazoline derivatives has been developed. The approach is widely applicable to 2-fluoro-, 2-chloro-, 2-bromo- and 2-nitro-substituted aryl aldehyde and ketone substrates. The fluorescence properties of target compounds were studied.

Full text of DOI:10.1021/co500001u

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Article
One-Pot Regioselective Synthesis of Benzo[4,5]imidazo[1,2-
a]quinazoline Derivatives via Facile Transition Metal-Free Tandem Process
Shuai Fang, Xiaoyi Niu, Bingchuan Yang, Yanqiu Li, Xiaomeng Si, Lei Feng, and Chen Ma
ACS Comb. Sci., Just Accepted Manuscript • Publication Date (Web): 11 Jun 2014
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Oneꢀpot Synthesis of Benzo[4,5]imidazo[1,2ꢀ
a]quinazoline Derivatives via Facile Transition
Metalꢀfree Tandem Process
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Shuai Fanga, Xiaoyi Niua, Bingchuan Yanga, Yanqiu Lia, Xiaomeng Sia, Lei Fenga, Chen Ma*a,b
a
Key Laboratory of Special Functional Aggregated Materials, Ministry of Education, School of
Chemistry and Chemical Engineering, Shandong University, Jinan, 250100, P. R. China.
b
State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of
Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College,
Beijing 100050, P. R. China.
KEYWORDS
Oneꢀpot synthesis, transition metalꢀfree, benzo[4,5]imidazo[1,2ꢀa]quinazoline derivatives ，
fluorescence property.
ABSTRACT
A oneꢀpot transition metalꢀfree method for synthesizing benzo[4,5]imidazo[1,2ꢀa]quinazoline
and imidazo[1,2ꢀa]quinazoline derivatives has been developed. The approach is widely
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applicable to 2ꢀfluoroꢀ, 2ꢀchloroꢀ, 2ꢀbromoꢀ and 2ꢀnitroꢀsubstituted aryl aldehyde and ketone
substrates. The fluorescence properties of target compounds were studied.
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R2
N
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N
N
Base, heat
Solvent
O
N
R2
NH2
R1
+
N
H
X
X = F, Cl, Br, NO2
R1
INTRODUCTION
Heterocyclic compounds containing nitrogenꢀatoms have been broadly applied in
pharmaceuticals, and designing novel heterocyclic motifs has become an increasingly urgent
mission for chemists.1 Recently, attention has been paid to benzo[4,5]imidazo[1,2ꢀa]pyrimidine
derivatives due to their biological activities (Fig. 1). For instance, compound A exhibits antiꢀ
inflammatory activity against TNFꢀα and ILꢀ6,2 compound B has anticancer activity,3 compound
C (T808) can work as a specific PET tracer for imaging of Tau Pathologies,4 and compound D
shows anticancer and analgesic/antiꢀinflammatory activities.5 Moreover, benzo[4,5]imidazo[1,2ꢀ
a]pyrimidine derivatives also behave as antimicrobial agents.6 In addition, imidazo[1,2ꢀ
a]quinazoline also has some effective biological activities. Compound E is the inhibitor of
apoptosis,7 and it acts as potent farnesyl protein transferase inhibitor (Fig. 2).8
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Figure 1. The structure of benzo[4,5]imidazo[1,2ꢀa]quinazoline
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We expect that benzo[4,5]imidazo[1,2ꢀa]quinazoline derivatives, the combined skeleton of
benzo[4,5]imidazo[1,2ꢀa]pyrimidine and imidazo[1,2ꢀa]quinazoline (Fig. 1), might exert certain
biological activities. Therefore, it is meaningful to explore a variety of benzo[4,5]imidazo[1,2ꢀ
a]quinazoline scaffolds.
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A
B
C
D
E
Figure 2. Some biologically important compounds.
The traditional way to obtain benzo[4,5]imidazo[1,2ꢀa]quinazoline derivatives generally
requires a multiꢀstep synthesis and harsh conditions. Marini and coꢀworkers utilized 1Hꢀ
benzo[d]imidazolꢀ2ꢀamine and 2ꢀbromobenzoic acid as reactants. Ultimately, target compounds
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were obtained through a threeꢀstep process via Ullman reaction.9 Pozharskii used 1,8ꢀ
bis(dimethylamino)ꢀ2ꢀnaphthaldehyde and 2ꢀaminobenzimidazole as the starting material to gain
the desirable compounds, but yields were less than satisfactory.10
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Notably, the previous literature methods to obtain these heterocyclic compounds were rare,
and were not adequate in meeting the demands to research structureꢀactivity relationships.
Coincidentally, we engaged in constructing these heterocyclic scaffolds11 and created a novel
and efficient oneꢀpot approach to assemble benzo[4,5]imidazo[1,2ꢀa]quinazoline derivatives
through an additionꢀelimination/SNAr process. 1HꢀBenzo[d]imidazolꢀ2ꢀamine and 2ꢀfluoroꢀ, 2ꢀ
chloroꢀ, 2ꢀbromoꢀ and 2ꢀnitroꢀsubstituted aryl aldehydes and ketones were used as substrates in
this process.
RESULTS AND DISCUSSION
Initially, we optimized the reaction conditions with 1Hꢀbenzo[d]imidazolꢀ2ꢀamine 1 and 2ꢀ
fluorobenzaldehyde 2a. As shown in Table 1, K2CO3 in DMF provided the best condition for this
transformation (entry 6). Reaction temperature played a key role in the reaction, with the yield
being excellent at 135 °C. Moreover, Cs2CO3 was equally efficient as K2CO3 (entry 1) and a
stronger base like NaOH did not favor the reaction (entry 5). In entry 7, the effect of 4Å
molecular sieves was inconspicuous in this reaction system. Solvents were screened as well:
NMP and DMSO generated moderate yields, but the reaction in 1,4ꢀdioxane failed to form the
product (entries 10ꢀ12).
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Table 1. Optimization of reaction conditionsa
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Entry
1
Solvent
DMF
Base
Time/h
Yield/%b
75
T/°C
Cs2CO3
NaOH
K2CO3
Cs2CO3
NaOH
K2CO3
K2CO3
K2CO3
Cs2CO3
Cs2CO3
K2CO3
Cs2CO3
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120
120
135
135
135
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135
135
110
135
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DMF
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DMF
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DMF
93
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DMF
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DMF
DMF
97
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93c
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DMF
55
9
DMF
76
10
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12
NMP
86
Dioxane
Trace
DMSO
68
aReaction conditions: 2ꢀaminobenzimidazole 1a (1.0 equiv) ,2ꢀfluorobenzaldehyde 2a
(1.2 equiv) and base (3.0 equiv) under a nitrogen atmosphere. Isolated yields. Reaction
with 4Å molecular series.
b
c
To verify the generality of this reaction, a variety of electron deficient 2ꢀhaloꢀ and 2ꢀnitroꢀ
substituted aryl aldehydes were tested and found to work efficiently (Table 2, entries 1ꢀ4).
Particularly, 2ꢀbromobenzaldehyde derivatives coupled efficiently in the absence of a transition
metal (entry 3).12 Interestingly, an excellent yield resulted from the reaction of 1Hꢀ
benzo[d]imidazolꢀamine 1 and 2ꢀnitrobenzaldehyde 2d (entry 4). The nitro group has rarely been
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utilized as a leaving group.13 The yield from compounds with an electronꢀdonating group was
better than those with an electronꢀwithdrawing group (for example, entries 7 and 8). Except for
2ꢀfluoroꢀ5ꢀnitrobenzaldehyde 2m (entry 13), all the compounds afforded excellent yields.
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Table 2. Reaction of 1Hꢀbenzo[d]imidazolꢀ2ꢀamine with 2ꢀsubstituted aryl aldehydesa
Entry
1
Substrate
Product
Yield/%b
97
2a
3a
3a
3a
3a
2
3
4
63c
70c
90
2b
2c
2d
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2g
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92
2i
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63c
2j
2k
2l
3g
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59c
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3h
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N
NO2
O
Trace
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96
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2m
NO2
3i
2n
3c
3j
2o
Trace
3t
3n
aReaction conditions: 2ꢀaminobenzimidazole
1
(1.0 equiv) ,
2
(1.2 equiv) and K2CO3 (3.0
equiv) under a nitrogen atmosphere. Isolated yields. cReaction condition: Cs2CO3, DMF,
b
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145 °C, 2h.
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To extend the reaction scope, aryl ketone derivatives were tested (Table 3). Although the
reaction between aryl ketone derivatives and arylamines generally demand harsh conditions, 14
reactions worked well for both alkyl aryl ketones (entries 1–4) and diaryl ketones (entry 4).
Steric hindrance had no effect on the yield (entry 4).
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Table 3. Reaction of 1Hꢀbenzo[d]imidazolꢀ2ꢀamine with 2ꢀ substituted aryl ketonesa
Entry
1
Substrate
Product
Yield/%b
84
O
F
2p
3k
3k
O
2
3
4
56c
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Br
2q
2r
3l
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2s
3m
(1.0 equiv) ,
aReaction conditions: 2ꢀaminobenzimidazole
1
2
(1.2 equiv) and K2CO3 (3.0
equiv) under a nitrogen atmosphere. Isolated yields. cReaction condition: Cs2CO3, DMF,
b
145 °C, 2h.
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The reaction between 2ꢀaminoimidazole sulfate and 2ꢀsubstituted aryl aldehydes was also
explored and target products were obtained with moderate yields (Table 4). As previously noted,
2ꢀfluorobenzaldehyde with an electronꢀdonating group achieved a better yield than that with an
electronꢀwithdrawing group (entries 5 and 6). Overall, 2ꢀaminoimidazole sulfate 5 (Table 4) was
not as efficient as 1Hꢀbenzo[d]imidazolꢀamine 1 (Table 2 and 3).
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Table 4. Reaction of 2ꢀaminoimidazole sulfate with 2ꢀsubstituted aryl aldehydesa
Entry
1
Substrate
Product
Yield/%b
70
5a
6a
2
45c
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5c
6a
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4
52c
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N
N
N
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67
5f
O
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aReaction conditions: 2ꢀaminoimidazole sulfate
(4.0 equiv) under a nitrogen atmosphere. Isolated yields. Reaction condition: Cs2CO3,
5
(1.0 equiv) ,
2
(1.2 equiv) and K2CO3
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b
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DMF, 135 °C, 2h.
To exam the mechanism of these cascade reactions, 1Hꢀbenzo[d]imidazolꢀ2ꢀamine 1 and 2ꢀ
fluorobenzaldehyde 2a were reacted as substrates under optimized condition but at room
temperature (Scheme 1). Not surprisingly, intermediate 4a was detected by High Resolution
Mass Spectrum (HRMS) after 30min. Indeed, Schiff base was produced in the first step of this
cascade process. From this intermediate, a plausible mechanism is proposed (Scheme 2), wherein
intramolecular nucleophilic aromatic substitution reaction (SNAr) delivers 3.
Scheme 1. Reaction of 1Hꢀbenzo[d]imidazolꢀ2ꢀamine and 2ꢀfluorobenzaldehyde
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Scheme 2. Plausible mechanism
The UV/vis absorption and emission spectra of 3a, 3d, 3h and 3j in highly dilute solution were
collected (Figure 3). The longest absorption of these products was at 350 nm and the longest
emission was at 475 nm. Solution luminescence of 3a upon irradiation at 365 nm was displayed.
The fluorescence efficiency of 3d is 0.95 in DCM, compared to the quinine sulfate dehydrate.
a
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Figure 3. (a) Absorption spectra of 3a, 3d, 3h and 3j in DCM. (b) Fluorescence spectra of 3a, 3d,
3h and 3j in DCM. (c) Solution luminescence of 3a in DCM (upon irradiation at 365 nm).
CONCLUSION
We have developed an efficient method to synthesize a variety of benzo[4,5]imidazo[1,2ꢀ
a]quinazoline and imidazo[1,2ꢀa]quinazoline derivatives via a transition metalꢀfree cascade
process. A wide range of 2ꢀfluoroꢀ, 2ꢀchloroꢀ, 2ꢀbromoꢀ and 2ꢀnitroꢀsubstituted aryl aldehyde
and ketone substrates performed well in this process. In addition, we tested the fluorescence
properties of these compounds. Further pharmaceuticals and materials studies are in process.
EXPERIMENTAL
General experimental procedure for 3a
A mixture of 1Hꢀbenzo[d]imidazolꢀ2ꢀamine 1 (1.0 mmol), 2ꢀfluorobenzaldehyde 2a （ 1.2
mmol） and K2CO3 (3 mmol) in DMF (5 mL) was stirred at 135 °C under a nitrogen atmosphere.
TLC was employed to monitor the end of the reaction. After the mixture was cooled, water was
added. The solution was extracted with ethyl acetate (20 ml × 3). The combined organic phase
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was dried with MgSO4 and the solvent was removed in vacuo to obtain the residue. The residue
was purified by column chromatography on silica gel to afford 3a.
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ASSOCIATED CONTENT
Acknowledgment
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We are grateful to the National Science Foundation of China (No. 21172131) and State Key
Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia
Medica, Chinese Academy of Medical Sciences and Peking Union Medical College (No.
GTZK201405) for financial support of this research.
Supporting Information
Representative experimental procedures, copies of HRMS, 1H NMR and 13C NMR spectra of all
compounds. This information is available free of charge via the Internet at http://pubs.acs.org/.
AUTHOR INFORMATION
Corresponding Author
*Eꢀmail: chenma@sdu.edu.cn.
Funding
We are grateful to the National Science Foundation of China (No. 21172131) and State Key
Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia
Medica, Chinese Academy of Medical Sciences and Peking Union Medical College (No.
GTZK201405) for financial support of this research.
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The authors declare no competing financial interest.
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Vries, J. G. d. Iridium/Monodentate Phosphoramidite Catalyzed Asymmetric Hydrogenation of
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Oneꢀpot Synthesis of Benzo[4,5]imidazo[1,2ꢀ
a]quinazoline Derivatives via Facile Transition
Metalꢀfree Tandem Process
Shuai Fanga, Xiaoyi Niua, Bingchuan Yanga, Yanqiu Lia, Xiaomeng Sia, Lei Fenga, Chen Ma*a,b
For Table of Contents Use Only
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