Copper-catalyzed tandem Ullmann type C-N coupling and dehydrative cyclization: Synthesis of imidazo[1,2-c]quinazolines

Article abstract of DOI:10.1039/c5ob02469b

A simple and efficient one-pot protocol has been demonstrated for the synthesis of imidazo[1,2-c]quinazoline derivatives through a copper catalyzed tandem reaction between substituted 2-(2-bromophenyl)-1H-imidazoles and formamide. The synthetic protocol involves initial Ullmann-type C-N coupling followed by intramolecular dehydrative cyclization. The method uses readily available 2-(2-bromophenyl)-1H-imidazoles as the starting materials to afford imidazo[1,2-c]quinazolines in moderate to good yields and provided 610 mg (71%) yield of 3a from a gram scale reaction.

Full text of DOI:10.1039/c5ob02469b

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Copper-catalyzed Tandem Ullmann type C–N Coupling and
Dehydrative Cyclization: Synthesis of Imidazo[1,2-c]quinazolines
Received 00th January 20xx,
Accepted 00th January 20xx
Nitesh K. Nandwana, Shiv Dhiman, Ganesh M. Shelke and Anil Kumar
A simple and efficient one-pot protocol has been demonstrated for the synthesis of imidazo[1,2-c]quinazoline derivatives
through copper catalyzed tandem reaction between substituted 2-(2-bromophenyl)-1H-imidazoles and formamide. The
synthetic protocol involves initial Ullmann-type C−N coupling followed by intramolecular dehydrative cyclization. The
method uses readily available 2-(2-bromophenyl)-1H-imidazoles as the starting materials to afford imidazo[1,2-
c]quinazolines in moderate to good yields and provided 610 mg (71%) yield of 3a from a gram scale reaction.
DOI: 10.1039/x0xx00000x
www.rsc.org/
Copper-catalyzed tandem reactions have emerged as powerful
tools for the synthesis of polyheterocycles,15-24 and some
quinazoline fused heterocycles have been synthesized via copper-
Introduction
Nitrogen containing polyheterocyclic compounds have received
much attention from synthetic as well as medicinal chemists,
because of the diverse range of their pharmacological properties.
Among them quinazoline fused molecules such as indolo-, imidazo-
and benzimidazo-quinazolines are found to exhibit a wide range of
therapeutic activities such as PI3-kinase inhibition,1 tumor necrosis
factor alpha (TNF-α) production inhibitors,2 antimicrobial agents
(BMCL)3 etc. (Figure 1). The hybrid structures of benzimidazole and
quinazoline derivatives also show interesting properties in organic
light–emitting devices (OLEDs). Dihydrobenzo[4,5]imidazo[1,2-
c]quinazoline derivatives have been reported to behave as selective
ratiometric fluorescent chemosensor for iron and aluminum ions
catalyzed tandem reactions.25-29 Fu and co–workers synthesized
benzo[4,5]imidazo[1,2-c]quinazolineand indolo[1,2-c]quinazoline
derivatives using copper-catalyzed cascade reaction of amidines or
amino acids with 2-(2-bromophenyl)-1H-benzo[d]imidazolesand 2-
26
(2-halophenyl)indoles, respectively (Scheme 1).25,
Wang et. al
have demonstrated a copper-catalyzed cascade approach of fused
quinazoline from N-(2-benzimidazolyl)-2-aminobenzamide and 2-
halobenzaldehyde via C–N coupling.27 Indolo[1,2-c]quinazolines
have been synthesized from 2-(2-halophenyl)-1H-indoles and
(aryl)methanamines by copper-catalyzed sequential Ullmann N-
arylation and aerobic oxidative C–H amination.28 Synthesis of
benzimidazo[1,2-c]quinazolines was reported through copper-
5
(Figure 1).4, Despite high importance of these molecules in
catalyzed
cross-coupling
reactions
of
2-(2-halophenyl)-
pharmaceuticals and materials science, synthetic methods for the
preparation of quinazoline fused heterocyclic frameworks are
limited.6-9 Moreover, these methods generally require multistep
synthesis, strict reaction conditions and inaccessible starting
materials. Therefore, alternative synthetic approaches for
quinazoline fused heterocyclic frameworks are desired.
benzoimidazoles with aldehydes using sodium azide as nitrogen
source.29 We reported synthesis of azole-fused quinazolines via
copper catalyzed one-pot, sequential Ullmann–type coupling and
Pd/Cu co-catalyzed intramolecular dehydrative C–N bonding.30 In
the pursuit of our continuous efforts for the synthesis of fused
heterocycles,31-37 herein we report a convenient and efficient ligand
free copper-catalyzed synthesis of imidazo[1,2-c]quinazoline
derivatives via sequential Ullmann type C–N coupling and
dehydrative cyclization between 2-(2-bromophenyl)-1H-imidazoles
and formamide (Scheme 1).
N
imidazole
N
N
N
N
OCH3
OCH3
N
N
NH
O
N
N
N
NH
N
Ar
S
quinazoline
imidazo[1,2-c]quinazoline
Ratiometric fluorescent
chemosensor
PI3-K inhibitor
TNF-α inhibitor
N
X
Previous work
Figure 1: Structure of some important quinazoline fused heterocyclic compounds
+
R
NH2
N
H
Br
Cu(OAc)2, K2CO3
24 h
R = Aryl
In recent years, copper salts have been proven to be highly
efficient catalysts in cross coupling reactions including Ullmann-
type couplings reactions due to their less toxicity and high
functional group tolerance and economical attractiveness.10-14
X
X
X
N
Cu powder, L-proline
CuI, K3PO4, DMSO
60 °C, N2, 16 h
N
H
+
N
H
Br
Br
CsCO3, DMSO, 80 o
R = Aryl
C
+
N
HN
NH2
NaN3 RCHO
R = Alkyl, Aryl
X = CH, N
R
R
Present work
N
N
CuI, CH3ONa
DMF, 150 °C, 10 h
O
N
H
N
N
H
NH2
Br
Scheme 1.Copper-catalyzedsynthesis of quinazolinefused heterocycles.
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presence of CuI as catalyst (Table 1, entries 10-13). Among these
bases, use of CH3ONa gave highest yield of 3a (Table 1, entries 13).
Variation of solvents for the model reaction revealed that polar
aprotic solvents such as DMF, DMA and DMSO were suitable for
this transformation (Table 1, entries 13-15). Formation of 3a was
not observed when non-polar aprotic solvents such as toluene and
1,4-dioxane were used (Table 1, entries 16, 17). It is also important
to mention that use of different additive such as zinc iodide,
potassium per sulphate, pivolic acid and ligands such as 1,10-
phenonthroline, and L-proline did not improve the yield of 3a.
After having the optimized reaction conditions in hand (Table 1,
entry 4), the generality of the tandem process was investigated by
employing various substituted 2-(2-bromophenyl)-1H-imidazoles
(Table 2). Reactions of 2-(2-bromophenyl)-4,5-diaryl-1H-imidazoles
having substituted aryl rings at C4- and C5-positions of imidazole
with formamide gave corresponding imidazo[1,2-c]quinazolines (3a-
f) in 35-70% yields. Similarly, reaction of 2-(2-bromophenyl)-1H-
imidazoles with different substituents such as fluoro, methyl,
methoxy on both aryl rings at C4- and C5-positions as well as on C2-
position of imidazole with formamide gave corresponding
imidazo[1,2-c]quinazolines(3g-q) in 45-58% yields. Structure of all
the synthesized imidazo[1,2-c]quinazolines was elucidated by NMR
and HRMS data (Supporting information).
Results and discussion
Our initial study commenced with the model reaction of 2-(2-
bromophenyl)-4,5-diphenyl-1H-imidazole (1a) with formamide (2a)
in the presence of CuCl2 (10 mol %), K2CO3 (2.0 equiv) in
dimethylformamide (DMF) at 150 °C under air atmosphere for 10 h.
To our delight 2,3-diphenylimidazo[1,2-c]quinazoline (3a) was
isolated in 30% yield (Table 1, entry 1).
Table 1: Optimization of reaction conditions for the synthesis of 3a.a
Entry
1
Catalyst (mol %)
CuCl2 (10)
Base
Solvent
DMF
% Yieldb
30
K2CO3
2
CuBr (10)
Cu(OAc)2 (10)
Cu(OTf)2 (10)
CuI (10)
K2CO3
K2CO3
DMF
DMF
34
39
3
4
K2CO3
DMF
33
5
K2CO3
DMF
45
6
CuI (20)
K2CO3
DMF
52
7
CuI (30)
K2CO3
DMF
60
8
CuI (40)
K2CO3
DMF
61
NRc
_
9
K2CO3
DMF
10
11
12
13
14
15
16
17
18
19
20
21
22
23
CuI(30)
CuI(30)
CuI(30)
CuI (30)
CuI(30)
CuI(30)
CuI(30)
CuI(30)
CuI (30)
CuI (30)
CuI (30)
CuI (30)
CuI (30)
CuI (30)
K3PO4
DMF
45
Table 2: Substrate scope for synthesis of imidazo[1,2-c]quinazoline (3)a
KOH
DMF
56
t-BuOK
CH3ONa
CH3ONa
CH3ONa
CH3ONa
CH3ONa
CH3ONa
CH3ONa
CH3ONa
CH3ONa
CH3ONa
CH3ONa
DMF
48
DMF
DMA
DMSO
Toluene
Dioxane
DMF
70
62
60
NR
NR
traced
62e
58f
63g
65h
63i
Sr. No.
1
R
R’
Product
3b
3c
Yieldb
70
35
42
61
55
55
58
48
51
51
46
57
52
45
53
31
56
C6H5
H
2
4-CH3C6H4
3-OCH3C6H4
4-OCH3C6H4
4-FC6H4
CH3
H
DMF
3
H
3d
3e
3f
DMF
4
H
H
DMF
5
DMF
6
H
3a
DMF
7
CH3
5-F
3g
aReaction conditions: 1a (1.0 mmol), 2a (10 mmol), catalyst (0.3 mmol), base
(2.0 mmol), solvent (2.0 mL), 150 °C, 10 h. bIsolated yields. cNR = No
reaction. dUnder N2 atm. eZinc iodide (30 mol %) used as additive.
fPotassium per sulphate (50 mol %) used as additive. gPivolic acid (30 mol %)
8
C6H5
4-CH3
5-F
3h
3i
9
C6H5
10
11
12
13
14
15
16
17
C6H5
5-OCH3
5-F
3j
4-CH3C6H4
C6H5
3k
used as additive. h1,10-phenonthroline (40 mol %) used as ligand. L-proline
i
4,5-(OCH3)2
4,5-(OCH3)2
4,5-(OCH3)2
4,5-(OCH3)2
5-F
3l
(40 mol %) used as ligand.
4-CH3C6H4
4-OCH3C6H4
4-FC6H4
4-FC6H4
4-OCH3C6H4
3m
3n
3o
3p
3q
Encouraged by the results of model reaction, task of reaction
optimization for improved yield of 3a was undertaken by varying
bases, catalysts and solvents. The results for various optimization
experiments are summarized in table 1. Screening of various copper
catalyst such as CuCl2, CuBr, Cu(OAc)2, Cu(OTf)2 and CuI revealed
that among all the screened copper salt, CuI was found to give
highest yield (45%) of 3a using 10 mol % catalyst loading (Table 1,
entries 1-5). Subsequently, effect of catalyst loading was
investigated. Initially significant increment in the yield of 3a was
observed by increasing loading of CuI from 10 mol % to 30 mol %,
however, further increase in loading of CuI did not improve yield of
3a (Table 1, entries 4-8). Formation of 3a was not observed in the
absence of the catalysts even after keeping the reaction for longer
time (Table 1, entry 9). Next, we evaluated effect of different bases
such as K3PO4, KOH, KOtBu, and CH3ONa on the yield of 3a in the
5-F
aReaction conditions: 1a (1.0 mmol), 2a (10.0 mmol), catalyst (0.3 mmol), base
(2.0 mmol), solvent (2.0 mL), 150 °C, 10 h. bIsolated yields.
Reaction of 2-(2-bromophenyl)-4,5-diphenyl-1H-imidazole (1a)
with acetamide (2b) and benzamide (2c) under the optimized
reaction condition gave C-N coupled product N-(2-(4,5-diphenyl-1H-
imidazol-2-yl)phenyl)acetamide (4b) and N-(2-(4,5-diphenyl-1H-
imidazol-2-yl)phenyl)benzamide (4c) in 65% and 60% yields,
respectively (Scheme 2). The expected imidazo[1,2-c]quinazolines
were not observed from these reactions even after longer reaction
time. This might be due to relatively low electrophilicity of amide
carbonyl group in these amides as compared to formamide.
2 | J. Name., 2012, 00, 1-3
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However, on treating 4b and 4c with BF3.OEt2 in DMF at 150 °C for 5 from the reaction of 1 g of 1a under the optimized reaction
corresponding imidazo[1,2-c]quinazolines 5b and 5c were condition.
h
obtained in 57% and 43%, respectively.
Conclusions
In summary, we have successfully developed a novel and efficient
copper catalyzed one-pot tandem approach for the synthesis of
imidazo[1,2-c]quinazolines from 2-(2-bromoaryl)-1H-imidazoles and
formamide. The protocol involves sequential copper-catalyzed
Ullmann type coupling of formamide followed by dehydrative
Scheme 2. Reaction of 1a with acetamide (2b) and benzamide (2c).
cyclization to give target compounds in moderate to good yields
.
To investigate the possible reaction pathway for this tandem
approach, we performed some control experiment (Scheme 3).
Temperature dependent study was performed for the reaction of
1a with 2a in the presence of CuI, CH3ONa in DMF. No product
formation was observed up to 50 °C, but when reaction mixture
was heated at 100 °C for 24 h along with expected imidazo[1,2-
c]quinazoline (3a), C-N coupled product, N-(2-(4,5-diphenyl-1H-
imidazol-2-yl)phenyl)formamide (4a) was also observed in 63%
yield. Further, imidazo[1,2-c]quinazoline (3a) was obtained in 71%
yield when isolated 4a was allowed to react under optimized
reaction condition.
Experimental Section
General information
Melting points were determined in open capillary tubes on a EZ-
Melt Automated melting point apparatus and are uncorrected.
Reactions were monitored by using thin layer chromatography (TLC)
on 0.2 mm silica gel F254 plates (Merck). The chemical structures of
final products were determined by their NMR spectra (1H and 13C
NMR) using Bruker AV 400 MHz spectrometer. 13C NMR spectra are
fully decoupled. High resolution mass spectra (HRMS) were carried
out using a quadrupole time of-flight (Q-TOF) mass spectrometer
(Applied Biosystem). 2-(2-Bromoaryl)-1H-imidazoles (1a-q) were
synthesized throughone-pot, three-component condensation of
benzils, 2-bromoarylaldehydes and ammonium acetate using
Yb(OTf)3 as catalyst.41All other chemicals were obtained from the
commercial suppliers and used without further purification.
Scheme 3: Control experiments
On the basis of literature reports38-40 and our own results, a plausible
mechanism for the synthesis of imidazo[1,2-c]quinazolines is
outlined in scheme 4. It is believed that oxidative addition of CuI
with 2-(2-bromophenyl)-4,5-diphenyl-1H-imidazole leads to
formation of copper(III) intermediate I. This step is assisted by the
presence of internal directing group from imidazole which also acts
as ligand for this reaction. Further, substitution of iodide from I by
formamide in the presence of CH3ONa affords intermediate II which
then undergoes reductive elimination to give N-arylated amide 4.
Representative procedure for 2,3-
diphenylimidazo[1,2-c]quinazoline derivatives
A clean oven dried 10 mL round bottom flask was charged with
1a (1.0 mmol), 2a (10 mmol), CH3ONa (2 mmol), CuI (0.25 mmol) in
DMF (2.0 mL) was stirred at 150 °C for 10 h. Reaction progress was
monitored by TLC. After completion, the reaction mass was allowed
to cool to ambient temperature, diluted with water (10 mL) and
Finally, copper catalyst assisted intramolecular dehydrative extracted with EtOAc (2 × 10 mL). The combined organic layer was
cyclization of 4 via intermediate III results in the formation of fused
quinazoline derivative 3. Formation of imidazo[1,2-c]quinazolines
5b and 5c by adding Lewis acid BF3-OEt2 to 4b and 4c is also in
agreement with involvement of intermediate III via nucleophilic
addition to amidic carbonyl group.
dried with anhydrous Na2SO4 and evaporated under reduced
pressure. The crude material was purified by column
chromatography to get the desired imidazo[1,2-c]quinazoline3a in
70% yield (90 mg).
2,3-Diphenylimidazo[1,2-c]quinazoline (3a). Brown solid (90 mg,
70%), mp 175-177 °C; 1H NMR (400 MHz, CDCl3) δ 8.71 (s, 1H), 8.69
– 8.66 (m, 1H), 7.97 (d, J = 8.0 Hz, 1H), 7.77 – 7.69 (m, 4H), 7.61 –
7.52 (m, 5H), 7.36 – 7.30 (m, 3H); 13C NMR (100 MHz, CDCl3) δ
142.4, 141.8, 141.1, 135.6, 133.4, 130.7, 130.0, 129.7, 129.4, 128.6,
128.5, 128.4, 128.3, 128.1, 127.9, 123.0, 121.5, 119.4; HRMS (ESI)
calcd for C22H16N3[M+H]+ 322.1339 found 322.1344.
2,3-Di-p-tolylimidazo[1,2-c]quinazoline (3b). Off-white solid (46
1
mg, 35%), mp 188-190 °C; H NMR (400 MHz, CDCl3) δ 8.70 (s, 1H),
8.69 – 8.68 (m, 1H), 7.97 – 7.95 (m, 1H), 7.72 – 7.69 (m, 2H), 7.65
(d, J = 8.2 Hz, 2H), 7.43 – 7.37 (m, 4H), 7.16 (d, J = 8.0 Hz, 2H), 2.50
(s, 3H), 2.37 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 142.2, 141.7,
141.1, 139.4, 137.6, 135.7, 130.6, 130.6, 130.4, 129.9, 129.1, 128.5,
Scheme 4: Probable reaction mechanism
Finally, to evaluate the scalability of the protocol, model reaction
was performed at gram scale and 3a was isolated in 610 mg (71%)
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128.3, 127.9, 125.5, 122.9, 121.2, 119.4, 21.5, 21.3; HRMS (ESI) (m, 3H); 13C NMR (100 MHz, CDCl3) δ 162.0 (d, J = 249.7 Hz), 141.7
calcd for C24H20N3 [M+H]+ 350.1652 found 350.1655.
(d, J = 4.4 Hz), 137.74 (d, J = 1.9 Hz), 134.87 (d, J = 2.5 Hz) 133.2,
130.8 (d, J = 9.2 Hz), 130.7, 129.7, 129.6, 128.6, 128.5, 128.3,
128.11, 127.99, 127.9, 121.8, 120.8, 120.7, 118.6 (d, J = 24.3 Hz),
108.1 (d, J = 24.6 Hz); HRMS (ESI) calcd for C22H15FN3 [M+H]+
340.1245 found 340.1248.
2,3-Bis(3-methoxyphenyl)imidazo[1,2-c]quinazoline (3c). Off-
white solid (55 mg, 42%), mp 160-162 °C; 1H NMR (400 MHz, DMSO)
δ 8.75 (s, 1H), 8.54 (m, 1H), 7.95 (d, J = 7.2 Hz, 1H), 7.79 – 7.76 (m,
2H), 7.56 – 7.52 (m, 1H), 7.27 – 7.17 (m, 4H), 7.19 – 7.15 (m, 2H),
6.88 (s, 1H), 3.81 (s, 3H), 3.67 (s, 3H); 13C NMR (100 MHz, DMSO) δ
9-Methoxy-2,3-diphenylimidazo[1,2-c]quinazoline (3j). Off white
160.4, 159.6, 141.6, 141.1, 140.4, 137.0, 135.1, 131.2, 130.8, 130.0, solid (66 mg, 51%), mp 220-222 °C; 1H NMR (400 MHz, CDCl3) δ 8.63
129.8, 129.2, 128.6, 123.5, 122.8, 122.2, 120.3, 119.1, 116.5, 115.8, (s, 1H), 8.03 (d, J = 2.7 Hz, 1H), 7.87 (d, J = 9.0 Hz, 1H), 7.76 – 7.70
113.9, 113.3, 55.8, 55.3; HRMS (ESI) calcd for C24H20N3O2[M+H]+ (m, 2H), 7.61 – 7.53 (m, 5H), 7.37 – 7.29 (m, 4H), 4.05 (s, 3H); 13C
382.1550 found 382.1543.
NMR (100 MHz, CDCl3) δ 159.7, 142.3, 141.7, 135.8, 133.5, 133.4,
130.7, 130.0, 129.7, 129.4, 128.58, 128.5, 128.2, 127.8, 121.5,
120.6, 120.4, 102.7, 56.0; HRMS (ESI) calcd for C23H18N3O [M+H]+
352.1444 found 352.1420.
2,3-Bis(4-methoxyphenyl)imidazo[1,2-c]quinazoline (3d). Off-
white solid (81 mg, 61%), mp 195-196 °C; 1H NMR (400 MHz, CDCl3)
δ 8.69 (s, 1H), 8.67 – 8.66 (m, 1H), 7.96 – 7.94 (m, 1H), 7.72 – 7.66
(m, 4H), 7.45 (d, J = 8.7 Hz, 2H), 7.10 (d, J = 8.7 Hz, 2H), 6.88 (d, J =
9-Fluoro-2,3-di-p-tolylimidazo[1,2-c]quinazoline (3k). Brown
8.8 Hz, 2H), 3.93 (s, 3H), 3.83 (s, 3H); 13C NMR (101 MHz, CDCl3) δ solid (60 mg, 46%), mp 235-240 °C; 1H NMR (400 MHz, CDCl3) δ 8.66
160.3, 159.3, 142.0, 141.4, 141.1, 135.7, 132.1, 129.9, 129.2, 128.5, (s, 1H), 8.31 (dd, J = 8.6, 2.6 Hz, 1H), 7.96 (dd, J = 8.9, 5.1 Hz, 1H),
128.3, 126.1, 122.9, 120.5, 120.4, 119.3, 115.2, 113.9, 55.4, 55.3; 7.63 (d, 2H), 7.46 – 7.36 (m, J = 8.1 Hz, 5H), 7.16 (d, J = 7.9 Hz, 2H),
HRMS (ESI) calcd for C24H20N3O2[M+H+] 382.1550 found 382.1556.
2.51 (s, 3H), 2.37 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 161.9 (d, J =
249.4 Hz), 141.5 (d, J = 4.2 Hz), 139.6, 137.8, 137.7, 135, 135.0,
130.7 (d, J = 9.1 Hz), 130.5, 130.4, 129.2, 127.9, 125.3, 121.5, 120.7
(d, J = 10.5 Hz), 118.5 (d, J = 24.3 Hz), 108.1 (d, J = 24.6 Hz), 21.5,
21.3; HRMS (ESI) calcd for C24H19FN3 [M+H]+ 368.1558 found
368.1561.
2,3-Bis(4-fluorophenyl)imidazo[1,2-c]quinazoline (3e). Off white
1
solid (72 mg, 55%), mp 230 °C; H NMR (400 MHz, CDCl3) δ 8.68 (s,
1H), 8.66 – 8.64 (m, 1H), 7.98 – 7.96 (m, 1H), 7.76 – 7.67 (m, 4H),
7.54 – 7.50 (m, 2H), 7.33 – 7.28 (m, 2H), 7.04 (t, J = 8.7 Hz, 2H); 13
C
NMR (101 MHz, CDCl3) δ 163.3 (d, J = 250.8 Hz), 162.6 (d, J = 247.8
Hz), 142.4, 141.1, 135.2, 132.7 (d, J = 8.4 Hz), 130.3, 129.8 (d, J = 8.1
8,9-Dimethoxy-2,3-diphenylimidazo[1,2-c]quinazoline (3l). Off-
Hz), 129.4 (d, J = 3.2 Hz), 128.7, 128.4, 124.3 (d, J = 3.5 Hz), 122.9, white solid (75 mg, 57%), mp 207-210 °C; 1H NMR (400 MHz, CDCl3)
120.1, 119.2, 117.1 (d, J = 21.8 Hz), 115.5 (d, J = 21.5 Hz); HRMS δ 8.65 (s, 1H), 8.00 (s, 1H), 7.73 – 7.71 (m, 2H), 7.60 – 7.52 (m, 5H),
(ESI) calcd for C22H14F2N3 [M+H+] 358.1150 found 358.1153.
7.38 – 7.29 (m, 4H), 4.13 (s, 3H), 4.05 (s, 3H); 13C NMR (101 MHz,
CDCl3) δ 151.7, 150.5, 142.5, 141.7, 136.8, 134.1, 133.6, 130.7,
129.6, 129.3, 128.7, 128.5, 128.2, 127.8, 120.9, 113.3, 108.9, 102.5,
56.6, 56.2; HRMS (ESI) calcd for C24H20N3O2[M+H]+ 382.1550 found
381.1553.
2,3-Dimethylimidazo[1,2-c]quinazoline (3f). Off-white solid (65
mg, 55%), mp 180-182 °C; 1H NMR (400 MHz, CDCl3) δ 8.67 (s, 1H),
8.52 (m, 1H), 7.96 – 7.93 (m, 1H), 7.69 – 7.62 (m, 2H), 2.53 (s, 3H),
2.47 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 141.4, 140.5, 138.7, 135.1,
129.5, 128.4, 128.2, 122.3, 119.0, 116.1, 13, 8.1; HRMS (ESI) calcd
for C12H12N3 [M+H]+ 198.1026 found 198.1032.
8,9-Dimethoxy-2,3-di-p-tolylimidazo[1,2-c]quinazoline
(3m).
Greyish solid(69 mg,52%), mp 190-192 °C; 1H NMR (400 MHz, CDCl3)
δ 8.62 (s, 1H), 7.99 (s, 1H), 7.66 – 7.62 (m, 2H), 7.40 – 7.37 (m, 5H),
7.15 – 7.11 (m, 2H), 4.14 (s, 3H), 4.04 (s, 3H), 2.49 (s, 3H), 2.35 (s,
3H); 13C NMR (101 MHz, CDCl3) δ 151.6, 150.4, 142.3, 141.5, 139.2,
137.5, 136.7, 134.2, 130.8, 130.6, 130.3, 129.1, 127.0, 125.8, 120.5,
113.3, 108.9, 102.5, 56.6, 56.2, 21.5, 21.3; HRMS (ESI) calcd for
C26H24N3O2 [M+H]+ 410.1863 found 410.1867.
9-Fluoro-2,3-dimethylimidazo[1,2-c]quinazoline (3g). Brown
1
solid (70 mg, 58%), mp 190 °C; H NMR (400 MHz, CDCl3) δ 8.61 (s,
1H), 8.10 (dd, J = 8.8, 2.8 Hz, 1H), 7.92 (dd, J = 9.0, 5.1 Hz, 1H), 7.36
(td, J = 8.6, 2.9 Hz, 1H), 2.52 (s, 3H), 2.45 (s, 3H); 13C NMR (101 MHz,
CDCl3) 13C NMR (101 MHz, CDCl3) δ 161.83 (d, J = 249.2 Hz), 140.75
(d, J = 4.4 Hz), 139.08, 137.12, 134.37 (d, J = 2.5 Hz), 130.67 (d, J =
9.2 Hz), 120.34 (d, J = 10.5 Hz), 118.03 (d, J = 24.4 Hz), 116.55,
8,9-Dimethoxy-2,3-bis(4-methoxyphenyl)imidazo[1,2-
107.32 (d,
12H11FN3[M+H+] 216.0932 found 216.0926.
8-Methyl-2,3-diphenylimidazo[1,2-c]quinazoline(3h).
J =
24.6 Hz), 12.96, 8.13; HRMS (ESI) calcd for c]quinazoline (3n). Brown solid (60 mg, 45%), mp 170– 175 °C; 1H
C
NMR (400 MHz, CDCl3) δ 8.59 (s, 1H), 7.99 (s, 1H), 7.67 (d, J = 8.3 Hz,
2H), 7.44 (d, J = 7.9 Hz, 3H), 7.37 (s, 1H), 7.10 (d, J = 8.1 Hz, 1H), 6.88
(d, J = 8.6 Hz, 2H), 4.12 (s, 3H), 4.04 (s, 3H), 3.93 (s, 3H), 3.82 (s, 3H);
13C NMR (100 MHz, CDCl3) δ 160.2, 159.2, 158.9, 151.6, 150.4,
136.7, 134.2, 132.1, 129.3, 129.1, 126.3, 120.8, 119.8, 115.1, 114.0,
113.2, 109.0, 102.4, 56.5, 56.2, 55.4, 55.3; HRMS (ESI) calcd for
C26H24N3O4 [M+H]+ 442.1761 found 442.1765
Brown
1
solid (62 mg, 48%), mp 210 °C; H NMR (400 MHz, CDCl3) δ 8.69 (s,
1H), 8.58 (d, J = 8.1 Hz, 1H), 7.77 – 7.73 (m, 3H), 7.58 – 7.53 (m, 5H),
7.36 – 7.28 (m, 4H), 2.59 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 142.6,
141.6, 141.3, 140.6, 135.61, 133.5, 130.7, 130.2, 129.6, 129.4,
128.6, 128.4, 128.1, 128.1, 127.8, 122.7, 121.2, 116.9, 21.6; HRMS
(ESI) calcd for C23H18N3 [M+H]+ 336.1495 found 336.1499.
2,3-Bis(4-fluorophenyl)-8,9-dimethoxyimidazo[1,2-c]quinazoline
1
(3o). Light brown solid (60 mg, 53%): mp 255-257 °C; H NMR (400
9-Fluoro-2,3-diphenylimidazo[1,2-c]quinazoline (3i). Brown solid
1
MHz, CDCl3) δ 8.58 (s, 1H), 7.96 (s, 1H), 7.67 (s, 2H), 7.50 (s, 2H),
7.37 (s, 1H), 7.28 (s, 2H), 7.03 (s, 2H), 4.13 (s, 3H), 4.05 (s, 3H), 13C
NMR (101 MHz, CDCl3) δ 163.2 (d, J = 250.6 Hz), 162.6 (d, J = 248.0
Hz), 151.9, 150.6, 142.5, 141.01, 136.83, 133.78, 132.7 (d, J = 8.3
(66 mg, 51%): mp 230 °C; H NMR (400 MHz, CDCl3) δ 8.67 (s, 1H),
8.32 (dd, J = 8.7, 2.8 Hz, 1H), 7.97 (dd, J = 9.0, 5.1 Hz, 1H), 7.74 –
7.72 (m, 2H), 7.60 – 7.53 (m, 5H), 7.46 – 7.41 (m, 1H), 7.36 – 7.31
4 | J. Name., 2012, 00, 1-3
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Hz), 129.8 (d, J = 8.1 Hz), 129.6, 124.5, 119.4, 117.1 (d, J = 21.8 Hz), 3H); 13C NMR (100 MHz, CDCl3) δ 146.7, 143.5, 142.1, 140.5, 133.7,
115.5 (d, J = 21.5 Hz), 113.1, 108.9, 102.4, 56.5, 56.2; HRMS (ESI) 132.5, 131.9, 130.0, 129.63, 128.7, 128.3, 127.9, 127.7, 127.5,
calcd for C24H18F2N3O2 [M+H]+ 418.1362 found 418.1365.
127.2, 122.9, 122.7, 118.8, 24.4; HRMS (ESI) calcd for C23H18N3
336.1495 found 336.1492 [M+H+].
8-Fluoro-2,3-bis(4-fluorophenyl)imidazo[1,2-c]quinazoline (3p).
White off solid (41 mg, 31%), mp 261-263 °C; 1H NMR (400 MHz,
2,3,5-Triphenylimidazo[1,2-c]quinazoline (5c): White solid (68
1
CDCl3) δ 8.61 (s, 1H), 8.29 (dd, J = 8.6, 2.8 Hz, 1H), 7.97 (dd, J = 9.0, mg, 43%), mp 230-232 °C; H NMR (400 MHz, CDCl3) δ 8.80 (dd, J =
5.1 Hz, 1H), 7.70 – 7.65 (m, 2H), 7.51– 7.49 (m, 2H), 7.47 – 7.42 (m, 7.7, 1.5 Hz, 1H), 8.0 (dd, J = 7.7, 1.5 Hz, 1H), 7.77 – 7.73 (m, 2H),
1H), 7.33 – 7.28 (m, 2H), 7.07 – 7.03 (m, 2H); 13C NMR (101 MHz, 7.57 – 7.52 (m, 2H), 7.29 – 7.24 (m, 5H), 7.18 (t, J = 7.5 Hz, 1H), 7.11
CDCl3) δ 163.4 (d, J = 251.0 Hz), 162.6 (d, J = 248.1 Hz), 162.0 (d, J = (t, J = 7.4 Hz, 1H), 7.08 – 6.99 (m, 4H), 6.97 – 6.93 (m, 2H); 13C NMR
250.1 Hz), 141.8 (d, J = 4.4 Hz), 141.3, 137.7, 134.5 (d, J = 2.5 Hz), (100 MHz, CDCl3) δ 147.64, 144.42, 142.72, 140.60, 133.89, 133.82,
132.7 (d, J = 8.4 Hz), 130.8 (d, J = 9.2 Hz), 129.8 (d, J = 8.2 Hz), 129.1 131.26, 130.48, 130.13, 129.33, 128.72, 128.71, 128.22, 128.20,
(d, J = 3.3 Hz), 124.0 (d, J = 3.6 Hz), 120.5 (d, J = 10.5 Hz) , 120.3, 128.04, 127.78, 127.60, 127.56, 123.35, 122.99, 118.68; HRMS (ESI)
118.8 (d, J = 24.4 Hz), 117.2 (d, J = 21.9 Hz), 115.6 (d, J = 21.6 Hz), calcd for C28H20N3 398.1652 found 398.1657 [M+H+].
108.1 (d, J = 24.6 Hz); HRMS (ESI) calcd for C22H13F3N3 [M+H]+
376.1056 found 376.1062.
Acknowledgements
9-Fluoro-2,3-bis(4-methoxyphenyl)imidazo[1,2-c]quinazoline
(3q). Off white solid (74 mg, 56%), mp 218-220 °C; 1H NMR (400
Authors sincerely acknowledge Council of Scientific and
Industrial Research (CSIR), New Delhi [02(0115)/13/EMR-II]
and Department of Science and Technology, New Delhi [CSI-
174/2008] for the financial support. SD is thankful to Ranbaxy
Laboratories Pvt. Ltd. (India) and GS is thankful to CSIR, New
Delhi for senior research fellowship.
MHz, CDCl3) δ 8.63 (s, 1H), 8.30 (dd, J = 8.7, 2.8 Hz, 1H), 7.95 (dd, J =
9.0, 5.1 Hz, 1H), 7.70 – 7.60 (m, 2H), 7.46 – 7.30 (m, 3H), 7.13 – 7.09
(m, 2H), 6.91 – 6.87 (m, 2H), 3.94 (s, 3H), 3.84 (s, 1H); 13C NMR (101
MHz, CDCl3) δ 161.9 (d, J = 249.3 Hz), 160.4, 159.4, 141.7, 141.4 (d, J
= 3.9 Hz), 137.7 (d, J = 1.8 Hz), 135.0 (d, J = 2.5 Hz), 132.1, 130.7 (d, J
= 9.2 Hz), 129.2, 125.9, 120.7, 120.7 (d, J = 10.3 Hz), 118.4 (d, J =
24.3 Hz), 120.3, 115.2, 113.9, 108.0 (d, J = 24.5 Hz), 55.4, 55.3;
HRMS (ESI) calcd for C24H19 FN3O2 [M+H]+ 400.1456 found 400.1461.
Notes and references
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N-(2-(4,5-diphenyl-1H-imidazol-2-yl)phenyl)formamide
(3a).
White solid (88 mg, 63%), mp 218-220 °C; 1H NMR (400 MHz,
DMSO) δ 12.99 (s, 1H), 12.66 (s, 1H), 8.65 (d, J = 5.8 Hz, 1H), 8.11 (d,
J = 7.6 Hz, 1H), 7.60 – 7.52 (m, 4H), 7.51 – 7.31 (m, 7H), 7.27 – 7.21
(M 2H); 13C NMR (101 MHz, DMSO) δ 162.88, 160.81, 145.19,
136.46, 136.17, 134.50, 130.86, 129.93, 129.59, 129.34, 129.23,
128.90, 128.78, 127.45, 126.85, 123.69, 120.99, 116.39; HRMS (ESI)
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δ 13.00 – 12.99 (m, 2H), 8.63 (d, J = 8.2 Hz, 1H), 8.11 (d, J = 7.0 Hz,
1H), 7.58 – 7.54 (m, 4H), 7.51 – 7.43 (m, 3H), 7.39 – 7.32 (m, 3H),
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MHz, DMSO) δ 168.7, 145.5, 137.5, 135.7, 134.6, 130.8, 129.6,
129.4, 129.2, 128.9, 128.8, 128.4, 127.4, 127.1, 126.5, 123.0, 119.9,
115.8, 25.7; HRMS (ESI) calcd for C23H20N3O [M+H]+ 354.1601found
354.1604.
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1
white solid (100 mg, 60%), mp 242-245 °C; H NMR (400 MHz,
DMSO) δ 13.68 (s, 1H), 13.05 (s, 1H), 8.88 (d, J = 8.4 Hz, 1H), 8.21 (d,
J = 7.7 Hz, 1H), 8.09 (d, J = 7.5 Hz, 2H), 7.64 – 7.58 (m, 1H), 7.57 –
7.34 (m, 13H), 7.25 (t, J = 7.1 Hz, 1H); 13C NMR (101 MHz, DMSO) δ
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128.9, 128.7, 128.5, 128.01, 127.9, 127.6, 126.7, 123.5, 120.4,
116.6; HRMS (ESI) calcd for C28H22N3O [M+H]+ 416.1757 found
416.1761.
5-Methyl-2,3-diphenylimidazo[1,2-c]quinazoline (5b): White
solid (77 mg, 57%), mp 138-142 °C; 1H NMR (400 MHz, CDCl3) δ 8.70
(d, J = 7.2 Hz, 1H), 7.85 (d, J = 7.8 Hz, 1H), 7.77 – 7.65 (m, 2H), 7.63
(d, J = 6.7 Hz, 2H), 7.60 – 7.47 (m, 5H), 7.35-7.24 (m, 3H), 2.32 (s,
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