Molybdate sulfuric acid (MSA): An efficient solid acid catalyst for the synthesis of diversely functionalized fused imidazo[1,2-a]pyrimidines under solvent-free conditions

Article abstract of DOI:10.1039/c5nj00516g

A one-pot multi-component, green, and highly efficient protocol has been developed for the synthesis of imidazo[1,2-a]pyrimidines annulated heterocyclic scaffolds (4a-4ab) using molybdate sulfuric acid (MSA) as an eco-friendly and reusable catalyst in goo

Full text of DOI:10.1039/c5nj00516g

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Molybdate sulfuric acid (MSA): an efficient solid
acid catalyst for the synthesis of diversely
functionalized fused imidazo[1,2-a]pyrimidines
under solvent-free conditions†
Cite this:DOI: 10.1039/c5nj00516g
Vijay Vilas Shinde and Yeon Tae Jeong*
A one-pot multi-component, green, and highly efficient protocol has been developed for the synthesis
of imidazo[1,2-a]pyrimidines annulated heterocyclic scaffolds (4a–4ab) using molybdate sulfuric acid
(MSA) as an eco-friendly and reusable catalyst in good to excellent yields under solvent-free conditions
that efficiently produced three new bonds (two C–N and one C–C) in a single operation. Other remarkable
features of this environmentally benign protocol are a short reaction time, a wide range of functional
group tolerance, use of an inexpensive heterogeneous catalyst, and high yield of products via a simple
experimental and work-up procedure. The catalyst can be recovered and reused for at least four runs
without any significant impact on the product yields.
Received (in Montpellier, France)
2nd March 2015,
Accepted 16th April 2015
DOI: 10.1039/c5nj00516g
www.rsc.org/njc
1. Introduction
There is a growing demand for complex functionalized mole-
cules for high-throughput screening (HTS) to find valuable
biological probes and lead molecules for drug discovery.1
A survey of recent literature reveals several synthesis and
pharmacological properties of ring junction heterocyclic
(bridge headed heterocyclic) compounds. In particular, aryl
and heteroaryl imidazo[1,2-a]pyrimidines have significant
Fig. 1 Examples of biologically active imidazo-fused pyrimidine
derivatives.
There is a strong need to develop quick and efficient
importance in the pharmaceutical industry owing to their synthetic methods to access a large variety of complex function-
broad range of interesting pharmacological activity.2 Contra- alized molecules. Multicomponent coupling reactions (MCRs)
rily, the natural abundance of nitrogen ring junction hetero- are known as a powerful tool for the construction of novel and
cycles is low but with the available moiety many studies have been structurally complex molecules in a single pot ensuring high
reported. Imidazo-fused heterocyclic derivatives are complex func- atom economy, good overall yields with high selectivity, lower
tionalized molecules, which have attracted considerable synthetic costs, shorter reaction times, avoidance of expensive purifica-
interest in pharmaceutical and biomedical studies. These deriva- tion processes and minimized waste, labour and energy.4
tives are found in several natural and biologically active molecules Recently, a few efficient synthetic methods of imidazo-fused
and they exhibit a remarkable biological profile that includes derivatives have been developed, including the Cu-promoted
being antimicrobial, anticancer, and antitubercular agents, benzo- synthesis of imidazopyridine via exo-dig cycloisomerization
diazepine receptor agonists, and calcium channel blockers.3 using aldehydes, 2-aminopyridines, and alkynes,5 the synthesis
Currently, several marketed drugs constitute an imidazo-fused of imidazo-fused heterocycles involving 2-aminopyridines,
fragment in the main core structure. In Fig. 1, three representa- alkynes, and aldehydes using copper sulfate/glucose as a
tive pharmacologically active imidazo-fused pyrimidine deriva- catalyst via exo-dig cyclization,6 and the synthesis of imidazo-
tives are shown, namely, fasiplon, taniplon, and divaplon, which pyridine compounds in the presence of 2-aminopyridines,
are used as anxiolytic drugs in many clinics.
alkynes, and aldehydes using Cu-MOF catalysts.7 Sivaramakrishna
Reddy et al. described a InBr3-catalyzed synthesis of imidazo[1,2-a]-
pyridines.8 All these reported methodologies lead to the formation
of five-membered ring systems.
To the best of our knowledge, only Mukesh Kumar et al.
have reported a three-component reaction including alkyne,
Department of Image Science and Engineering, Pukyong National University, Busan
608-737, Republic of Korea. E-mail: ytjeong@pknu.ac.kr; Fax: +82 51 629 6408
† Electronic supplementary information (ESI) available. See DOI: 10.1039/
c5nj00516g
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Table 1 Influence of the catalyst for the synthesis of 2-(3,4,5-trimethoxy-
phenyl)-4-p-tolylbenzo[4,5]imidazo[1,2-a]-pyrimidine (4a)a
Scheme 1 Synthesis of imidazo[1,2-a]pyrimidines derivative catalyzed by
MSA under solvent-free conditions.
Entry Catalyst (mol%)
Time (h) Temperature (1C) Yieldb (%)
1c
2
3
4
5
Neat
TSA (5)
GSA (5)
PS-PTSA (20 mg)
PSA (5)
PEG-SO3H (30 mg) 3.5
MSA (15)
MSA (5)
MSA (10)
MSA (20)
10
4
2.8
3.1
2.7
85
85
85
85
85
85
85
85
85
85
NR
38
65
58
66
54
2-aminobenzimidazole and aldehyde in the presence of
CuI/silver carbonate as a dual catalyst in acetonitrile as a solvent
to obtain multisubstituted imidazopyrimidines via 6-endo-dig
cyclization (six-membered ring).9 However, they unfortunately
used a homogenous catalyst and the organic solvent was not
recyclable. On the other hand, a huge amount of effort has been
dedicated to the development of chemical reactions in agree-
ment with the principles of green chemistry. Although various
green solvents, such as ionic liquids and water, have been
extensively studied, not using a solvent at all is definitely the
best option, which makes the development of solvent-free reac-
tions a high priority. The progress in the field of solvent and
heterogenous acid catalyst10 reactions is gaining considerable
attention because of their low cost, safety, and eco-friendliness.
Acid-catalyzed reactions have been widely used in the pro-
duction of chemicals. Homogenous mineral liquid acids, such
as HCl, H2SO4, and HF, are efficient acid catalysts due to their
uniform acidic sites and strong acid strength. However, the
employment of liquid acids in industry often faces problems of
wastewater generation, equipment corrosion, and recycling
difficulty.11 The development of solid acids as replacements
for liquid acids has received growing research attention. These
considerations are currently driving our effort to develop hetero-
geneous organic transformations. Molybdate sulfuric acid (MSA)
is an alternative to sulfuric acid, which was synthesized by the
reaction of anhydrous sodium molybdate with chlorosulfonic
acid. This new inorganic solid acid has been applied as an
efficient catalyst to a variety of organic transformations.12 It
has many advantages over conventional acid catalysts, such as
ease of handling, stability, lower cost and easy recyclability due
to its insolubility in most organic solvents.
6
7d
8
2
87, 87, 82, 80
2.5
2.3
2
65
78
87
9
10
a
Reaction of 1H-benzo[d]imidazol-2-amine (1, 1 mmol), 3,4,5-trimethoxy-
benzaldehyde (2a, 1 mmol) and 1-ethynyl-4-methylbenzene (3a, 1.5 mmol)
under neat conditions. b Isolated yield. No reaction. d Catalyst was reused
c
four times.
and 1-ethynyl-4-methylbenzene (3a, 1.5 mmol) under neat condi-
tions at 85 1C (Scheme 1) was carried out to standardize the
experimental conditions. In the absence of catalyst, we could not
isolate any desired product even after 10 h of stirring. Sub-
sequently, the same set of reaction conditions were used in the
presence of 5 mol% of the tungstate sulfuric acid (TSA). Within
4 h, the corresponding title product 4a, was isolated in 38%
product yield (Table 1, entry 2). The product 4a was confirmed by
the usual spectroscopic techniques. Encouraged by this result, we
attempted to optimize the yield of the reaction by screening the
same set of reactions with various sulfonic acid containing
Table 2 Optimization of reaction conditions of solvent and temperature for
the synthesis of 2-(3,4,5-trimethoxyphenyl)-4-p-tolylbenzo[4,5]imidazo[1,2-a]-
pyrimidine (4a)a
In connection with our consistent interest in the development
of practical strategies for the selective synthesis of various
functional heterocycles, we used heterogeneous acid catalysts
under solvent-free conditions.13 Herein, we communicate our
discovery of a molybdate sulfuric acid (MSA) mediated synthesis
of imidazo[1,2-a]pyrimidines (4a–4ab) in a one pot coupling of
1H-benzo[d]imidazol-2-amine (1), aldehydes (2) and alkyne (3)
via intramolecular C–N bond formation and 6-endo-dig cyclo-
isomerization at 85 1C under solvent-free conditions (Scheme 1).
Entry
Solvent
Temperature
Time (h)
Yieldb (%)
1
2
3
4
5
6
7
8
Toluene
Chlorobenzene
CH2Cl2
CCl4
THF
110
120
75
75
65
65
85
85
50
3.7
3.5
4.7
4.7
3.75
4.3
3.53
2
48
55
58
45
54
55
74
87
48
61
87
86
Ethanol
Acetonitrile
Solvent-free
Solvent-free
Solvent-free
Solvent-free
Solvent-free
9
3.2
3
2
10
11
12
75
90
100
2
2. Results and discussion
a
Reaction of 1H-benzo[d]imidazol-2-amine (1,
1
mmol), 3,4,5-tri-
For our initial investigation, the reaction of 1H-benzo[d]imidazol-
2-amine (1, 1 mmol), 3,4,5-trimethoxybenzaldehyde (2a, 1 mmol) (3a, 1.5 mmol), MSA (15 mol%). isolated yield.
methoxybenzaldehyde (2a, 1 mmol) and 1-ethynyl-4-methylbenzene
b
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Table 3 MSA catalyzed multi-component synthesis of imidazo[1,2-a]pyrimidines derivativesa
Entry
1
R
R1
Product
Time (h)
Yieldb (%)
M.p. (1C) ref.
3,4,5-OCH3C6H2
CH3
2
87
258–260
2
3
4
5
6
7
8
9
2-BrC6H4
CH3
CH3
CH3
CH3
CH3
CH3
CH3
2.1
2.03
2.25
2
82
81
86
80
78
81
84
81
220–222
162–164
166–168
238–240
156–158
240–242
240–242
206–2088
2-CH3C6H4
4-C(CH3)2C6H4
4-CH3C6H4
2-OCH3C6H4
4-FC6H4
2.05
2.1
1.9
2.1
4-BrC6H4
4-ClC6H4
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Table 3 (continued)
Entry
10
R
R1
H
Product
Time (h)
Yieldb (%)
M.p. (1C) ref.
4-FC6H4
2
80
197–1998
11
12
13
14
15
16
2,6-MeC6H3
2,4-FC6H3
H
H
H
H
H
H
2.3
2.6
2.3
2.6
2.1
2.2
76
74
81
75
82
79
190–192
252–254
166–168
248–250
248–250
156–158
4-C(CH3)2C6H4
2-Cl-6-FC6H3
3-CH3C6H4
2,5-CH3C6H3
17
18
3,4,5-OCH3C6H2
4-OC2H5C6H4
H
H
2
84
82
230–232
202–204
2.2
19
2-NO2C6H4
H
2.6
71
218–220
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Table 3 (continued)
Entry
20
R
R1
H
Product
Time (h)
2.2
Yieldb (%)
M.p. (1C) ref.
2-OCH3C6H4
79
160–162
21
22
23
24
25
26
4-ClC6H4
H
H
H
H
H
2
85
81
80
78
83
198–2008
195–197
188–190
172–174
190–192
2-F-5-BrC6H3
2-BrC6H4
2-FC6H4
2.3
2.1
2.1
2
4-CH3C6H4
4-BrC6H4
H
H
2
84
52
210–2128
193–1958
27
–CH(CH3)2
2.6
a
Reaction of 1H-benzo[d]imidazol-2-amine (1, 1 mmol), aldehydes (2a, 1 mmol) and alkynes (3a, 1.5 mmol) catalyzed by MSA under solvent-free
b
conditions at 85 1C. isolated yield.
catalysts, such as polystyrene supported p-toluenesulfonic acid amount of MSA loaded. When 5 mol%, 10 mol%, 15 mol% and
(PS-PTSA), glucose sulfonic acid (GSA), phosphosulfonic acid 20 mol% of MSA were used, the yields were 65%, 78%, 87% and
(PSA), PEG–SO3H and molybdate sulfuric acid (MSA), for even 87%, respectively (Table 1, entries 7–10). Therefore, 15 mol%
less than 3 h and the results are summarized in Table 1. Among of MSA was found to be sufficient and no more significant
all the screened catalysts, MSA was found to be superior with improvement in the reaction rate and product yield was observed
respect to reaction time and product yield (Table 1, entry 7). on increasing the amount of the catalyst from 5 to 15 mol%
Moreover, we found that the yields were obviously affected by the (Table 1, entry 7).
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Scheme 2 Plausible mechanism for the formation of imidazo[1,2-a]pyrimidines derivatives.
Then, we investigated the influence of various organic solvents which produced imidazo[1,2-a]pyrimidines in good to excellent
at different reaction temperatures on the model reaction with yields. Therefore, the present protocol has general applicability,
15 mol% of MSA. Among the various solvents, such as toluene, accommodating a variety of substitution patterns.
ethanol, THF, CH2Cl2, and DMF, the rate of the reaction was very
The reported as well as synthesized novel compounds
1
slow and resulted in lower product yields (Table 2, entries 1–6). (4a–4ab) have been characterised on the basis of H NMR, 13C
Conducting the same reaction in acetonitrile improved both the NMR and HRMS data.
reaction rate as well as the product yield (Table 2, entry 7). We also
To investigate the catalytic activity and the possibility of the
investigated different temperatures for the model reaction catalyst recyclability and reusability, the MSA was recovered from
(Table 2, entries 8–12). It was observed that the reaction occurred the reaction mixture by simple filtration in ethyl acetate. The
rapidly on increasing the temperature from 50 1C to 85 1C, and separated catalyst was dried in vacuum oven at 100 1C and was
the yield of preferred product increased significantly. We were reused as such for subsequent experiments under similar reac-
satisfied to find that the reaction proceeded smoothly and almost tion conditions (Table 1, entry 7). The results showed that the
a complete conversion of reactants was observed at 85 1C to afford catalyst could be effectively reused for at least four consecutive
the desired product (4a) in 87% yield within 2 h under solvent-free cycles without much appreciable loss in its catalytic activity. The
conditions (Table 2, entry 8). Further increasing the temperature recyclability data demonstrated the high stability of the catalyst
did not affect the product yield.
under the reaction conditions (see in ESI,† Fig. S2).
However, better product yield was observed in solvent-free
A possible mechanism of this one-pot reaction is based on
conditions (Table 2, entry 8) and could be explained by the fact previously reported literature.8 A possible mechanism for the
that a uniform distribution of the eutectic mixture of reactants imidazo[1,2-a]pyrimidines via 6-endo-dig cyclization ring forma-
was in closer proximity to react. From all these observations, tion of three-component coupling reactions using molybdate
we concluded that 15 mol% of MSA, 85 1C and solvent-free sulfuric acid (MSA) as a catalyst is outlined in Scheme 2.
condition are the optimized reaction conditions.
The reported as well as synthesized novel compounds were
Subsequently, the generality of this novel three component further characterized by their spectral properties (1H, 13C NMR,
reaction was examined (Table 3). To our delight, we found this and HRMS).
transformation to be very general for a wide range of aldehydes
and two different alkynes; it provided easy access to densely
substituted imidazo[1,2-a]pyrimidine derivatives 4. Aldehydes
displayed good reactivity in this reaction. A variety of functional
3. Conclusion
groups substituted at the aromatic ring of the aldehyde substrate, In conclusion, we have successfully developed a facile and
including electron-withdrawing groups such as chloro, bromo, highly selective synthesis of novel imidazo[1,2-a]pyrimidines
fluoro and nitro (Table 3, entries 2, 7, 8, 10, 12, 14 and 21–24) and via molybdate sulfuric acid (MSA)-mediated oxidative C–H
electron-donating groups such as methoxy, ethoxy, isopropyl and functionalization and 6-endo-dig cyclization from readily avail-
methyl (Table 3, entries 1, 3–6, 11, 13, 15–18, 20 and 25) were able starting materials. This methodology provides a simple and
tolerated. The reaction with isopropyl aldehyde gave lower yields direct way to access derivatives of the biologically important
(Table 3, entry 27), we also employed two different alkyne sub- heterocycles. These reaction conditions display a wide range of
strates, namely, 1-ethynylbenzene and 1-ethynyl-4-methylbenzene, functional group tolerance. From an environmental point of view,
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this protocol represents good atom economy, i.e., the expended 3.93 (s, 3H), 2.56 (s, 3H), 13C NMR (100 MHz, CDCl3): d 160.30,
MSA can be recycled and reused to mediate this reaction.
153.53, 149.45, 145.50, 141.49, 131.97, 130.07, 128.35, 125.89,
121.08, 120.03, 114.63, 105.04, 61.04, 56.45, 21.72; HRMS
(ESI, m/z): calcd for C26H23N3O3 (M + H+) 425.1739, found: 425.1738.
4.3.2. 2-(2-Bromophenyl)-4-p-tolylbenzo[4,5]imidazo[1,2-a]-
4. Experimental
4.1 Material and methods
1
pyrimidine. Yield 82%; yellow solid; Mp: 220–222 1C; H NMR
(400 MHz, CDCl3): d 7.99 (d, J = 8.1 Hz, 1H), 7.85 (d, J = 7.7 Hz,
1H), 7.67 (d, J = 8.1 Hz, 1H), 7.53 (d, J = 8.1 Hz, 2H), 7.43–7.48
(m, 4H), 7.31 (t, J = 7.5 Hz, 1H), 7.17 (s, 1H), 7.06 (t, J = 6.9 Hz,
1H), 6.87 (d, J = 8.4 Hz, 1H), 2.54 (s, 3H), 13C NMR (100 MHz,
CDCl3): d 162.85, 148.58, 145.43, 141.55, 139.32, 133.63, 132.04,
131.15, 130.08, 129.47, 128.31, 127.88, 127.43, 126.02, 121.47,
121.32, 120.46, 114.95, 109.89, 21.74; HRMS (ESI, m/z): calcd for
C23H16BrN3 (M + H+) 413.0527, found: 413.0528.
Chemicals were purchased from Aldrich and Alfa Aesar
Chemical Companies and used without further purification.
NMR spectra were recorded in parts per million (ppm) in CDCl3
on a Jeol JNM ECP 400 NMR instrument using TMS as an
internal standard. Standard abbreviations are used to denote
signal multiplicities (s = singlet, d = doublet, t = triplet, q = quartet,
m = multiplet). Mass spectra were recorded on a Jeol JMS-700 mass
spectrometer. All melting points were determined using open
capillaries on an Electrothermal-9100 (Japan) instrument and
are uncorrected.
4.3.3. 2-(2-Methylphenyl)-4-p-tolylbenzo[4,5]imidazo[1,2-a]-
1
pyrimidine. Yield 81%; yellow solid; Mp: 162–164 1C; H NMR
(400 MHz, CDCl3): d 7.96 (d, J = 8.1 Hz, 1H), 7.62 (d, J = 7.7 Hz,
1H), 7.50 (d, J = 8.1 Hz, 2H), 7.42 (d, J = 7.7 Hz, 3H), 7.23–7.35
(m, 3H), 7.02 (t, J = 7.7 Hz, 1H), 6.92 (s, 1H), 6.82 (d, J = 8.1 Hz,
1H), 2.63 (s, 3H), 2.52 (s, 3H), 13C NMR (100 MHz, CDCl3): d
164.57, 149.10, 145.35, 141.42, 137.87, 137.08, 131.48, 130.00,
129.78, 129.70, 129.48, 128.21, 126.02, 125.80, 121.01, 120.19,
114.78, 109.16, 21.65, 21.05; HRMS (ESI, m/z): calcd for
C24H19N3 (M + H+) 349.1579, found: 349.1580.
4.2 Preparation of MSA
To dry n-hexane (25 mL) in a 100 mL round bottomed flask
equipped with an overhead stirrer and kept in an ice bath, a
suspension of anhydrous sodium molybdate (20 mmol, 4.118 g)
was added. To this solution, chlorosulfonic acid (0.266 mL,
40 mmol) was added dropwise over 30 min and stirred for 1.5 h
(Scheme 3). The reaction mixture was gradually poured into
25 mL of chilled distilled water with stirring. MSA was separated by
filtration and was washed 5–6 times with cold distilled water until
its filtrate showed negative results for chloride ions. It was dried at
120 1C for 5 h and obtained in 91% yield as a bluish powder.
4.3.4. 2-(4-Isopropylphenyl)-4-p-tolylbenzo[4,5]imidazo[1,2-a]-
1
pyrimidine. Yield 86%; yellow solid; Mp: 166–168 1C; H NMR
(400 MHz, CDCl3): d 8.21 (d, J = 8.4 Hz, 2H), 7.94 (s, 1H), 7.50
(d, J = 8.1 Hz, 2H), 7.44 (d, J = 7.7 Hz, 2H), 7.40 (d, J = 7.3 Hz, 1H),
7.35 (d, J = 8.1 Hz, 2H), 7.18 (s, 1H), 6.99 (t, J = 7.3 Hz, 1H), 6.75
(d, J = 8.1 Hz, 1H), 2.93–3.00 (m, 1H), 2.54 (s, 3H), 1.28 (d, J =
7.0 Hz, 6H), 13C NMR (100 MHz, CDCl3): d 161.06, 152.63, 141.37,
134.38, 130.04, 128.34, 127.94, 127.10, 125.76, 120.93, 120.08,
114.69, 105.30, 34.18, 23.86, 21.72; HRMS (ESI, m/z): calcd for
C26H23N3 (M + H+) 377.1892, found: 377.1894.
4.3 Synthesis of 2-(3,4,5-trimethoxyphenyl)-4-p-tolylbenzo[4,5]-
imidazo[1,2-a]-pyrimidine (4a)
A mixture of 1H-benzo[d]imidazol-2-amine (1, 1 mmol), 3,4,5-
trimethoxybenzaldehyde (2a, 1 mmol) and 1-ethynyl-4-methyl-
benzene (3a, 1.5 mmol) and MSA (15 mol%) was stirred at 85 1C
under solvent-free conditions for 2 h (Table 3, entry 1). The
progress of the reaction was monitored by TLC. After the
completion of the reaction, the mixture was washed with ethyl
acetate and filtered to recover the catalyst. The filtrate was
evaporated, and the crude product was purified by flash column
chromatography on silica gel (200–300 mesh) with ethyl acetate
and hexane as an eluent to afford the product 4a in an excellent
yield (87%). The MSA catalyst was reused by the way of addition
of ethyl acetate to the reaction mixture and filtration followed by
drying in a vacuum oven every time. Compounds 4b–4ab were
also synthesized by adopting the same procedure.
4.3.5. 2-(4-Methylphenyl)-4-p-tolylbenzo[4,5]imidazo[1,2-a]-
1
pyrimidine. Yield 80%; yellow solid; Mp: 238–240 1C; H NMR
(400 MHz, CDCl3): d 8.14 (d, J = 8.1 Hz, 2H), 7.92 (d, J = 8.1 Hz,
1H), 7.49 (d, J = 8.1 Hz, 2H), 7.43 (d, J = 8.1 Hz, 2H), 7.38 (d, J =
7.7 Hz, 1H), 7.24 (d, J = 8.1 Hz, 2H), 7.14 (s, 1H), 6.98 (t, J =
8.1 Hz, 1H), 6.73 (d, J = 8.1 Hz, 1H), 2.53 (s, 3H), 2.36 (s, 3H), 13
C
NMR (100 MHz, CDCl3): d 160.95, 149.39, 141.73, 141.33, 133.90,
129.99, 129.74, 129.63, 128.30, 127.72, 125.71, 120.86, 120.03,
114.65, 105.20, 21.69, 21.52; HRMS (ESI, m/z): calcd for
C24H19N3 (M + H+) 349.1579, found: 349.1579.
4.3.6. 2-(2-Methoxyphenyl)-4-p-tolylbenzo[4,5]imidazo[1,2-a]-
pyrimidine. Yield 78%; yellow solid; Mp: 156–158 1C; 1H NMR
(400 MHz, CDCl3): d 8.26 (d, J = 8.1, 1H), 7.95 (d, J = 8.1 Hz, 1H),
7.51 (d, J = 8.1 Hz, 2H), 7.48 (s, 1H), 7.41–7.44 (m, 4H), 7.11 (t, J =
7.3 Hz, 1H), 7.02 (d, J = 7.7 Hz, 1H), 6.98 (d, J = 8.1 Hz, 1H), 6.77
(d, J = 8.1 Hz, 1H), 3.88 (s, 3H), 2.53 (s, 3H), 13C NMR (100 MHz,
CDCl3): d 161.23, 158.06, 147.93, 145.36, 141.14, 132.14, 131.99,
129.95, 128.41, 126.68, 125.64, 121.32, 120.76, 120.05, 114.75,
111.53, 110.16, 55.70, 21.68; HRMS (ESI, m/z): calcd for
4.3.1. 2-(3,4,5-Trimethoxyphenyl)-4-p-tolylbenzo[4,5]imidazo-
[1,2-a]-pyrimidine. Yield 87%; yellow solid; Mp: 258–260 1C;
1H NMR (400 MHz, CDCl3): d 7.91 (d, J = 8.1, 1H), 7.54–7.56
(m, 4H), 7.47 (d, J = 8.1 Hz, 2H), 7.42 (t, J = 7.7 Hz, 1H), 7.16
(s, 1H), 7.01 (t, J = 7.6 Hz, 1H), 6.73 (d, J = 8.1 Hz, 1H), 3.97 (s, 6H),
C
24H19N3O (M + H+) 365.1528, found: 365.1529.
4.3.7. 2-(4-Fluorophenyl)-4-p-tolylbenzo[4,5]imidazo[1,2-a]-
1
Scheme 3 Synthesis of MSA.
pyrimidine. Yield 81%; yellow solid; Mp: 240–242 1C; H NMR
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(400 MHz, CDCl3): d 8.21–8.24 (m, 2H), 7.90 (d, J = 7.3 Hz, 1H), 1H), 7.61–7.71 (m, 5H), 7.40 (t, J = 7.7 Hz, 1H), 7.35 (d, J =
7.51 (d, J = 7.7 Hz, 2H), 7.44 (d, J = 7.7 Hz, 2H), 7.39 (t, J = 7.7 Hz, 8.1 Hz, 2H), 7.20 (s, 1H), 6.98 (t, J = 7.7 Hz, 1H), 6.65 (d, J =
1H), 7.11 (t, J = 7.3 Hz, 3H), 6.98 (t, J = 7.3 Hz, 1H), 6.73 (d, J = 8.4 8.4 Hz, 1H), 2.93–3.0 (m, 1H), 1.28 (d, J = 6.6 Hz, 6H), 13C NMR
Hz, 1H), 2.54 (s, 3H), 13C NMR (100 MHz, CDCl3): d 166.05, (100 MHz, CDCl3): d 161.06, 152.69, 149.18, 134.30, 132.69,
163.54, 159.72, 149.77, 141.49, 132.84, 130.03, 129.90, 129.82, 131.04, 129.42, 128.47, 127.95, 127.11, 125.80, 121.04, 120.13,
129.57, 128.27, 125.87, 121.08, 120.06, 116.03, 115.82, 114.72, 114.54, 105.23, 34.17, 23.85; HRMS (ESI, m/z): calcd for
104.96, 21.70; HRMS (ESI, m/z): calcd for C23H16FN3 (M + H+)
C
25H21N3 (M + H+) 363.1735, found: 363.1736.
353.1328, found: 353.1330.
4.3.14. 2-(2-Chloro-6-fluorophenyl)-4-phenylbenzo[4,5]imidazo-
4.3.8. 2-(4-Bromophenyl)-4-p-tolylbenzo[4,5]imidazo[1,2-a]- [1,2-a]-pyrimidine. Yield 75%; yellow solid; Mp: 248–250 1C; 1H NMR
1
pyrimidine. Yield 84%; yellow solid; Mp: 240–242 1C; H NMR (400 MHz, CDCl3): d 8.02 (d, J = 7.3, 1H), 7.64–7.71 (m, 5H), 7.47
(400 MHz, CDCl3): d 8.09 (d, J = 8.4 Hz, 2H), 7.92 (s, 1H), 7.57 (t, J = 7.3, 1H), 7.34–7.40 (m, 1H), 7.31 (d, J = 8.1 Hz, 1H), 7.13
(d, J = 8.1 Hz, 2H), 7.52 (d, J = 8.1 Hz, 2H), 7.45 (d, J = 7.7 Hz, 2H), (t, J = 8.1 Hz, 1H), 7.06 (t, J = 8.4 Hz, 1H), 6.88 (s, 1H), 6.78 (d, J =
7.40 (t, J = 6.4 Hz, 1H), 7.12 (s, 1H), 7.00 (t, J = 7.3 Hz, 1H), 6.75 8.4 Hz, 1H), 13C NMR (100 MHz, CDCl3): d 161.77, 159.26,
(d, J = 8.4 Hz, 1H), 2.55 (s, 3H), 13C NMR (100 MHz, CDCl3): d 157.27, 151.50, 149.23, 145.43, 133.96, 132.08, 131.26, 131.17,
159.66, 149.94, 141.57, 135.55, 132.11, 130.09, 129.23, 128.30, 129.45, 128.40, 126.23, 125.90, 121.61, 120.67, 114.91, 114.83,
126.00, 121.25, 120.15, 114.80, 104.92, 21.75; HRMS (ESI, m/z): 114.61, 110.11; HRMS (ESI, m/z): calcd for C22H13ClFN3
calcd for C23H16BrN3 (M + H+) 413.0527, found: 413.0526.
(M + H+) 373.0782, found: 373.0784.
4.3.9. 2-(4-Chlorophenyl)-4-p-tolylbenzo[4,5]imidazo[1,2-a]-
4.3.15. 2-(3-Methylphenyl)-4-phenylbenzo[4,5]imidazo[1,2-a]-
pyrimidine. Yield 81%; yellow solid; Mp: 206–208 1C; H NMR pyrimidine. Yield 82%; yellow solid; Mp: 248–250 1C; 1H NMR
(400 MHz, CDCl3): d 8.17 (d, J = 7.0 Hz, 2H), 7.91 (d, J = 7.0 Hz, (400 MHz, CDCl3): d 8.16 (s, 1H), 8.03 (d, J = 7.7, 1H), 7.94 (d, J =
1H), 7.41–7.51 (m, 8H), 7.12 (s, 1H), 7.00 (t, J = 7.3 Hz, 1H), 6.74 8.1, 1H), 7.62–7.72 (m, 5H), 7.42 (t, J = 7.7 Hz, 1H), 7.37 (t, J =
(d, J = 7.3 Hz, 1H), 2.55 (s, 3H), 13C NMR (100 MHz, CDCl3): d 7.7 Hz, 1H), 7.30 (d, J = 7.7 Hz, 1H), 7.22 (s, 1H), 6.99 (t, J = 7.7 Hz,
159.63, 149.89, 141.56, 137.52, 130.09, 129.15, 129.03, 128.29, 1H), 6.66 (d, J = 8.4 Hz, 1H), 2.44 (s, 3H), 13C NMR (100 MHz,
125.99, 121.22, 120.18, 114.77, 104.97, 21.75; HRMS (ESI, m/z): CDCl3): d 161.21, 149.27, 145.60, 138.73, 136.61, 132.67, 132.14,
1
calcd for C23H16ClN3 (M + H+) 369.1032, found: 369.1031.
131.09, 129.44, 128.83, 128.57, 128.47, 125.88, 124.97, 121.13,
4.3.10. 2-(4-Fluorophenyl)-4-phenylbenzo[4,5]imidazo[1,2-a]- 120.23, 114.59, 105.42, 21.57; HRMS (ESI, m/z): calcd for
1
pyrimidine. Yield 80%; yellow solid; Mp: 197–199 1C; H NMR C23H17N3 (M + H+) 335.1422, found: 335.1421.
(400 MHz, CDCl3): d 8.21–8.24 (m, 2H), 7.89 (d, J = 8.1 Hz, 1H),
4.3.16. 2-(2,5-Dimethylphenyl)-4-phenylbenzo[4,5]imidazo-
7.64–7.71 (m, 5H), 7.39 (t, J = 7.5 Hz, 1H), 7.11 (t, J = 8.4 Hz, 3H), [1,2-a]-pyrimidine. Yield 79%; yellow solid; Mp: 156–158 1C;
6.97 (t, J = 7.7 Hz, 1H), 6.62 (d, J = 8.4 Hz, 1H), 13C NMR (100 MHz, 1H NMR (400 MHz, CDCl3): d 7.98 (d, J = 8.1, 1H), 7.62–7.72
CDCl3): d 159.73, 151.96, 149.47, 145.47, 136.93, 132.47, 131.13, (m, 5H), 7.49 (s, 1H), 7.45 (t, J = 8.2 Hz, 1H), 7.21 (d, J = 8.1 Hz,
129.93, 129.83, 129.41, 128.40, 127.38, 125.91, 121.20, 120.12, 1H), 7.18 (d, J = 7.7 Hz, 1H), 7.03 (t, J = 8.4 Hz, 1H), 6.97 (s, 1H),
116.05, 115.83, 114.56, 104.90; HRMS (ESI, m/z): calcd for 6.72 (d, J = 8.4 Hz, 1H), 2.60 (s, 3H), 2.37 (s, 3H), 13C NMR
C22H14FN3 (M + H+) 339.1171, found: 339.1172.
(100 MHz, CDCl3): d 164.87, 151.87, 148.76, 145.44, 137.72,
4.3.11. 2-(2,6-Dimethylphenyl)-4-phenylbenzo[4,5]imidazo- 135.67, 134.01, 132.54, 131.56, 131.13, 130.65, 130.54, 129.48,
[1,2-a]-pyrimidine. Yield 76%; yellow solid; Mp: 190–192 1C; 128.96, 128.45, 127.42, 125.93, 121.19, 120.39, 114.68, 109.24,
1H NMR (400 MHz, CDCl3): d 8.02 (d, J = 8.4, 1H), 7.63–7.70 21.02, 20.67; HRMS (ESI, m/z): calcd for C24H19N3 (M + H+)
(m, 5H), 7.47 (t, J = 7.3 Hz, 1H), 7.22 (d, J = 7.3 Hz, 1H), 7.12 349.1579, found: 349.1579.
(d, J = 7.7 Hz, 2H), 7.06 (t, J = 8.1 Hz, 1H), 6.80 (d, J = 8.1 Hz, 1H),
4.3.17. 2-(3,4,5-Trimethoxyphenyl)-4-phenylbenzo[4,5]imidazo-
6.74 (s, 1H), 2.25 (s, 6H), 13C NMR (100 MHz, CDCl3): d 162.98, [1,2-a]-pyrimidine. Yield 84%; yellow solid; Mp: 230–232 1C;
154.59, 147.80, 138.65, 135.43, 132.24, 131.22, 129.44, 128.79, 1H NMR (400 MHz, CDCl3): d 7.88 (d, J = 8.4 Hz, 1H), 7.67–7.71
128.39, 127.92, 126.03, 121.33, 120.47, 114.82, 109.92, 20.42; HRMS (m, 5H), 7.53 (s, 2H), 7.39 (t, J = 7.3 Hz, 1H), 7.16 (s, 1H), 6.97
(ESI, m/z): calcd for C24H19N3 (M + H+) 349.1579, found: 349.1580. (t, J = 7.7 Hz, 1H), 6.62 (d, J = 8.4 Hz, 1H), 3.95 (s, 6H), 3.93
4.3.12. 2-(2,4-Difluorophenyl)-4-phenylbenzo[4,5]imidazo- (s, 3H), 13C NMR (100 MHz, CDCl3): d; 160.15, 153.40, 149.08,
[1,2-a]-pyrimidine. Yield 74%; yellow solid; Mp: 252–254 1C; 145.33, 140.98, 132.45, 131.75, 129.34, 128.70, 128.40, 127.38,
1H NMR (400 MHz, CDCl3): d 8.49–8.55 (m, 1H), 8.96 (d, J = 125.80, 121.08, 119.89, 114.42, 104.92, 60.94, 56.33; HRMS (ESI, m/z):
8.1 Hz, 1H), 7.62–7.73 (m, 5H), 7.45 (t, J = 8.1 Hz, 1H), 7.34 calcd for C25H21N3O3 (M + H+) 411.1582, found: 411.1581.
(s, 1H), 7.08 (t, J = 8.4 Hz, 1H), 7.03 (t, J = 8.5 Hz, 1H), 6.90–6.95
4.3.18. 2-(4-Ethoxyphenyl)-4-phenylbenzo[4,5]imidazo[1,2-a]-
(m, 1H), 6.71 (d, J = 8.4, 1H), 13C NMR (100 MHz, CDCl3): d pyrimidine. Yield 82%; yellow solid; Mp: 202–204 1C; 1H NMR
160.46, 156.92, 151.67, 149.24, 145.41, 133.23, 133.13, 132.42, (400 MHz, CDCl3): d 8.18 (d, J = 7.7, 2H), 7.90 (s, 1H), 7.61–7.65
131.16, 129.44, 128.43, 126.12, 121.35, 120.27, 114.73, 112.48, (m, 5H), 7.37 (s, 1H), 7.10 (s, 1H), 6.89–6.96 (m, 3H), 6.61 (d, J =
108.52, 108.39, 104.66; HRMS (ESI, m/z): calcd for C22H13F2N3 7.7 Hz, 1H), 4.0 (q, J = 7.0 Hz, 2H), 1.39 (t, J = 7.0 Hz, 3H), 13C NMR
(M + H+) 357.1077, found: 357.1075.
(100 MHz, CDCl3): d 161.71, 160.49, 148.90, 145.44, 132.63,
4.3.13. 2-(4-Isopropylphenyl)-4-phenylbenzo[4,5]imidazo[1,2-a]- 130.93, 129.42, 129.31, 128.78, 128.42, 125.59, 120.78, 119.87,
1
pyrimidine. Yield 81%; yellow solid; Mp: 166–168 1C; H NMR 114.61, 114.41, 104.84, 63.61, 14.74; HRMS (ESI, m/z): calcd for
(400 MHz, CDCl3): d 8.21 (d, J = 8.4 Hz, 2H), 7.93 (d, J = 7.7, Hz, C24H19N3O (M + H+) 365.1528, found: 365.1529.
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4.3.19. 2-(2-Nitrophenyl)-4-phenylbenzo[4,5]imidazo[1,2-a]- (400 MHz, CDCl3): d 8.17 (d, J = 8.4 Hz, 2H), 7.93 (d, J = 8.4 Hz,
1
pyrimidine. Yield 71%; yellow solid; Mp: 218–220 1C; H NMR 1H), 7.61–7.66 (m, 3H), 7.38–7.41 (m, 1H), 7.33 (d, J = 8.1 Hz, 1H),
(400 MHz, CDCl3): d 7.95 (d, J = 7.7, 2H), 7.19 (d, J = 6.2 Hz, 1H), 7.27 (d, J = 8.1 Hz, 2H), 7.19 (s, 1H), 7.16 (d, J = 8.1 Hz, 1H), 6.98
7.61–7.68 (m, 4H), 7.55 (t, J = 7.3 Hz, 1H), 7.45 (t, J = 6.6 Hz, 2H), (t, J = 7.7 Hz, 1H), 6.64 (d, J = 8.4 Hz, 1H), 2.39 (s, 3H), 13C NMR
7.05 (t, J = 7.7 Hz, 2H), 6.79 (s, 1H), 6.75 (d, J = 7.7 Hz, 1H), 13
C
(100 MHz, CDCl3): d 161.09, 152.29, 149.19, 145.52, 141.88,
NMR (100 MHz, CDCl3): d 160.59, 149.57, 148.42, 145.24, 133.92, 132.69, 131.06, 129.71, 128.42, 128.99, 128.47, 127.80,
133.62, 133.24, 131.89, 131.56, 131.37, 130.68, 129.48, 128.36, 127.53, 126.67, 125.84, 121.06, 120.14, 114.53, 105.23, 21.55;
126.32, 124.74, 121.83, 120.38, 114.93, 107.89; HRMS (ESI, m/z): HRMS (ESI, m/z): calcd for C23H17N3 (M + H+) 335.1422, found:
calcd for C22H14N4O2 (M + H+) 366.1116, found: 366.1117.
335.1421.
4.3.26. 2-(4-Bromophenyl)-4-phenylbenzo[4,5]imidazo[1,2-a]-
4.3.20. 2-(2-Methoxyphenyl)-4-phenylbenzo[4,5]imidazo[1,2-a]-
1
pyrimidine. Yield 79%; yellow solid; Mp: 160–162 1C; H NMR pyrimidine. Yield 84%; yellow solid; Mp: 210–212 1C; 1H NMR
(400 MHz, CDCl3): d 8.27 (d, J = 8.1, 1H), 7.95 (d, J = 8.4 Hz, 1H), (400 MHz, CDCl3): d 8.12 (d, J = 6.6 Hz, 2H), 7.96 (s, 1H), 7.65–7.72
7.62–7.70 (m, 5H), 7.50 (s, 1H), 7.40–7.45 (m, 2H), 7.12 (t, J = (m, 5H), 7.59 (d, J = 7.3 Hz, 2H), 7.42 (s, 1H), 7.17 (s, 1H), 7.00
7.7 Hz, 1H), 6.98 (d, J = 8.4 Hz, 2H), 6.68 (d, J = 8.4 Hz, 1H), 3.87 (t, J = 7.7 Hz, 1H), 3.69 (d, J = 7.0 Hz, 1H), 13C NMR (100 MHz,
(s, 3H), 13C NMR (100 MHz, CDCl3): d 161.26, 158.07, 152.28, CDCl3): d 160.61, 152.40, 151.45, 138.47, 136.25, 135.58, 133.78,
147.64, 145.37, 132.88, 132.20, 131.98, 130.85, 129.32, 128.53, 132.25, 129.68, 128.18, 127.88, 125.71, 122.62, 116.54, 114.68,
127.41, 126.62, 125.68, 121.33, 120.87, 120.12, 114.59, 111.54, 103.02; HRMS (ESI, m/z): calcd for C22H14BrN3 (M + H+) 399.0371,
110.10, 55.71; HRMS (ESI, m/z): calcd for C23H17N3O (M + H+) found: 399.0372.
351.13716, found: 351.13716.
4.3.27. 2-Isopropyl-4-phenylbenzo[4,5]imidazo[1,2-a]pyr-
4.3.21. 2-(4-Chlorophenyl)-4-phenylbenzo[4,5]imidazo[1,2-a]- imidine. Yield 52%; yellow solid; Mp: 193–195 1C; 1H NMR
pyrimidine. Yield 85%; yellow solid; Mp: 198–200 1C; 1H NMR (400 MHz, CDCl3): d 7.98 (br, 1H), 7.66–7.60 (m, 5H), 7.43
(400 MHz, CDCl3): d 8.16 (d, J = 8.8 Hz, 2H), 7.90 (d, J = 8.1 Hz, (s, 1H), 7.02 (t, J = 7.6 Hz, 1H), 6.69 (s, 2H), 3.23 (m, 1H), 1.43
1H), 7.63–7.73 (m, 5H), 7.42 (d, J = 8.8 Hz, 3H), 7.14 (s, 1H), 6.98 (d, J = 6.2 Hz, 6H), 13C NMR (100 MHz, CDCl3): d 173.49,
(t, J = 8.1 Hz, 1H), 6.64 (d, J = 8.4 Hz, 1H), 13C NMR (100 MHz, 148.88, 132.67, 130.89, 129.26, 128.81, 128.13, 127.78, 125.46,
CDCl3): d 159.66, 151.93, 149.62, 145.57, 137.61, 135.07, 132.49, 120.67, 120.09, 114.39, 106.88, 37.13, 21.52; HRMS (ESI, m/z):
131.20, 129.48, 129.18, 129.06, 128.44, 127.44, 126.05, 121.35, calcd for C19H17N3 (M + H+) 287.1422, found: 287.1424.
120.25, 114.63, 104.92; HRMS (ESI, m/z): calcd for C22H14ClN3
(M + H+) 355.0876, found: 355.0877.
4.3.22. 2-(2-Fluoro,5-bromophenyl)-4-phenylbenzo[4,5]-
imidazo[1,2-a]-pyrimidine. Yield 81%; yellow solid; Mp:
References
195–197 1C; 1H NMR (400 MHz, CDCl3): d 8.64 (d, J = 6.6,
1H), 7.97 (d, J = 6.6, 1H), 7.64–7.72 (m, 5H), 7.54–7.57 (m, 1H),
7.46 (t, J = 7.3, 1H), 7.36 (s, 1H), 7.02–7.09 (m, 2H), 6.73 (d, J =
7.7 Hz, 1H), 13C NMR (100 MHz, CDCl3): d 161.71, 156.25, 149.49,
145.56, 135.42, 134.25, 131.27, 129.52, 128.46, 126.30, 121.59,
118.52, 118.26, 114.86, 108.59, 108.45; HRMS (ESI, m/z): calcd for
C22H13BrFN3 (M + H+) 417.0276, found: 417.0278.
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pyrimidine. Yield 80%; yellow solid; Mp: 188–190 1C; 1H NMR
(400 MHz, CDCl3): d 7.98 (s, 1H), 7.83 (d, J = 7.3 Hz, 1H), 7.61–7.65
(m, 6H), 7.43 (t, J = 7.0 Hz, 2H), 7.28 (t, J = 7.7 Hz, 1H), 7.17 (s, 1H),
7.01 (t, J = 7.3 Hz, 1H), 6.75 (d, J = 7.7 Hz, 1H), 13C NMR (100 MHz,
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129.39, 128.33, 127.84, 125.95, 121.42, 121.37, 114.85, 109.83; HRMS
(ESI, m/z): calcd for C22H14BrN3 (M + H+) 399.0371, found: 399.0373.
4.3.24. 2-(2-Fluorophenyl)-4-phenylbenzo[4,5]imidazo[1,2-a]-
1
pyrimidine. Yield 78%; yellow solid; Mp: 172–174 1C; H NMR
(400 MHz, CDCl3): d 8.47 (s, 1H), 8.00 (s, 1H), 7.63–7.69 (m, 5H),
7.45–7.50 (m, 2H), 7.39 (s, 1H), 7.33 (t, J = 7.7 Hz, 1H), 7.14–7.19
(m, 1H), 7.01 (t, J = 7.7 Hz, 1H), 6.76 (s, 1H), 13C NMR (100 MHz,
CDCl3): d 160.05, 157.68, 149.23, 147.32, 145.79, 132.69, 132.60,
131.52, 131.01, 129.28, 128.31, 125.80, 124.79, 121.26, 116.48,
116.25, 108.95, 108.82; HRMS (ESI, m/z): calcd for C22H14FN3
(M + H+) 339.1171, found: 339.1172.
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pyrimidine. Yield 83%; yellow solid; Mp: 190–192 1C; 1H NMR
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