Synthesis of novel azole-fused quinazolines via one-pot, sequential Ullmann-type coupling and intramolecular dehydrogenative C-N bonding

Article abstract of DOI:10.1039/c4ob02375g

An efficient one-pot sequential procedure is described for the synthesis of novel azole-fused quinazolines through Pd/Cu co-catalyzed, Ullmann-type coupling followed by cross dehydrogenative coupling of various azoles such as 1H-imidazole, 1H-benzimidazole and 1H-1,2,4-triazole with 2-(2-bromophenyl)-1H-imidazole/benzimidazoles. The developed strategy has offered good yields (52-81%) of diverse N-fused tetra-, penta- and hexa-cyclic frameworks in a single step.

Full text of DOI:10.1039/c4ob02375g

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Communication
Synthesis of Novel Azole FusedꢀQuinazolines via Oneꢀpot Sequential
Ullmann type Coupling and Intramolecular Dehydrogenative C−N
Bonding
Nitesh K. Nandwana, Kasiviswanadharaju Pericherla, Pinku Kaswan and Anil Kumar*
5
Received (in XXX, XXX) Xth XXXXXXXXX 20XX, Accepted Xth XXXXXXXXX 20XX
DOI: 10.1039/b000000x
45 (OLEDs).7 Despite their importance in medicinal chemistry and
An efficient oneꢀpot sequential procedure has been described
material science, very few synthetic methods are available to
access these fused frameworks which might be due to the
unavailability of starting materials and complex multistep
procedures.
for the synthesis of novel azole fused quinazolines through
Pd/Cu coꢀcatalyzed Ullmann type coupling followed by cross
10 dehydrogenative coupling of various azoles such as 1Hꢀ
imidazole, 1Hꢀbenzimidazole and 1Hꢀ1,2,4ꢀtriazole with 2ꢀ(2ꢀ
bromophenyl)ꢀ1Hꢀimidazole/benzimidazoles. The developed
strategy has offered good yields (52ꢀ81%) of diverse Nꢀfused
tetraꢀ, pentaꢀ and hexaꢀcyclic frameworks in a single step.
15 Synthesis of nitrogen containing heterocycles is an everlasting
demand in organic chemistry as they are in the core of many
natural products and pharmacologically potent molecules.1
Construction of C−N bond by Ullmannꢀtype reaction or
Buchwald coupling is more common procedure to access
20 functionalized azaheterocycles.2 In recent years, transition metal
catalyzed cross dehydrogenative couplings or oxidative
cyclizations are emerged as efficient and straightforward methods
for the synthesis of these functionalized azaheterocycles from
simple and commercially available nonꢀprefunctionalized starting
25 materials.3 These protocols have received great attention in recent
years due to their advantageous features such as atomꢀeconomy
and reduced byꢀproduct generation.4
Quinazolines and their analogues are found to have
considerable interest because of their wide range of biological
30 properties such as antibacterial, antimalarial, anticonvulsant,
antitumor, diuretic and antihypertensive.5 In addition,
quinazolines are the core structures in several pharmacologically
potent molecules such as erlotinib, a tyrosine kinase inhibitor
used for the treatment of pancreatic cancer (Figure 1). As a
35 consequence several synthetic methods have been developed to
fabricate these compounds.6 Also there are several azole
containing drug molecules. For example, omeprazole, a proton
pump inhibitor is a benzimidazole derivative (Figure 1). It is
believed that fusion of two or more bioactive heterocycles may
40 lead to new hybrid motif with interesting properties. Fused
azaheterocycles structures have shown enhanced antimicrobial,
antitumor and antipsychotic activities (Figure 1).8 Also, fused
polycyclic structures derived from fusion of quinazolines with
azoles have been studied as organic lightꢀemitting devices
50
Fig. 1 Pharmacologically active azaheterocycles
Recently, Lv and colleagues reported synthesis of azole fused
quinazolines via copper catalyzed domino addition followed by
double cyclization (Scheme 1).7a In continuation to our interest in
55 the assembly of nitrogen containing polyheterocyclic compounds
by employing C−H functionalizations,9 herein we wish to report
our recent results for the synthesis of azole fused quinazolines
through a sequential Ullmann type C−N coupling and palladium
catalyzed cross dehydrogenative coupling (Scheme 3). The key
60 precursors used for these studies were synthesized by means of
well established and economically attractive procedures.10
2ꢀ(2ꢀBromophenyl)ꢀ4,5ꢀdiphenylꢀ1Hꢀimidazole (1a) and 1Hꢀ
imidazole (2a) were selected as model substrates for the
preliminary investigations. On the basis of Mori and Schreiber
65 reports,11 we envisaged that catalytic amount of copper will
enable the dual C−N bonding, Ullmann type coupling and
oxidative C−N bonding, between 1a and 2a to furnish the
targeted fused quinazoline, 2,3ꢀdiaryldiimidazo[1,2ꢀa:1',2'ꢀ
c]quinazoline (5a).
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40 DMF and N,Nꢀdimethylacetamide (DMA) are suitable solvents
for the sequential process while other solvents, like 1,4ꢀdioxane,
toluene and acetonitrile offered low yields of 5a (entries 11ꢀ14,
Table 1). Attempts to replace Cu(OAc)2 with other oxidants such
as PhI(OAc)2, Ag2CO3 CuCl2, Cu2O and CuSO4 were
45 unsuccessful (entries 15ꢀ19, Table 1). Only traces of 5a were
detected when the sequential process was carried out in the
absence of palladium catalyst (entry 20, Table 1). When isolated
3a was allowed to react under optimized conditions of the second
step, 5a was formed in 70% yield. It is also worth to mention that
50 oneꢀstep reaction of 1a and 2a in the presence of Pd(OAc)2 (5
mol %) and Cu(OAc)2 gave fused quinazolines 5a in 58% yield
along with dehalogenated byꢀproduct, 2,4,5ꢀtriphenylꢀ1Hꢀ
imidazole (6), in 14% yield ( (Scheme 3c).
Scheme 1 Retrosynthesis for the novel azole fused quinazolines
Copper catalyzed Ullmann type coupling of 1a with imidazole 2a
in the presence of CuI (20 mol %) and K2CO3 (2 equiv.) in N,Nꢀ
dimethylformamide after 1 h at 150 °C resulted in formation of 2ꢀ
(2ꢀ(1Hꢀimidazolꢀ1ꢀyl)phenyl)ꢀ4,5ꢀdiphenylꢀ1Hꢀimidazole (3a) in
81% yield (Scheme 2a). The reaction was clean and no side
product was formed in this reaction. Reaction of 1a was
performed in the absence of 2a under these conditions to examine
5
10 the selectivity of the reaction (Scheme 2b). Interestingly,
formation of 2,3,10,11ꢀtetraphenyldibenzo[c,g]diimidazo[1,2ꢀ
a:1',2'ꢀe][1,5]diazocine (4) was not observed even after longer
reaction time and 1a was recovered in almost quantitative yield.
55
Scheme 3 One-pot sequential synthesis of azole fused quinazolines
Table 1 Optimization of reaction conditionsa
15
Scheme 2 Copper catalyzed Ullmann type coupling of 1a
Entry
1
Catalyst
PdCl2
Oxidant
Cu(OAc)2 K2CO3
Base
Solvent
DMF
Yieldb (%)
65
Next to synthesize azole fused quinazolines 5a under copper
catalyzed oxidative C–N coupling reaction; the above reaction
was continued for 24 h at 150 °C. As expected, targeted molecule
5a was detected in the reaction mass albeit in 8% yield (Scheme
2
Pd(PPh3)4 Cu(OAc)2 K2CO3
Pd(PPh3)2Cl2 Cu(OAc)2 K2CO3
Pd(OAc)2 Cu(OAc)2 K2CO3
Pd(OAc)2 Cu(OAc)2 K2CO3
Pd(OAc)2 Cu(OAc)2 K2CO3
Pd(OAc)2 Cu(OAc)2 Cs2CO3
Pd(OAc)2 Cu(OAc)2 K3PO4
Pd(OAc)2 Cu(OAc)2 Na2CO3
Pd(OAc)2 Cu(OAc)2 tꢀBuOK
Pd(OAc)2 Cu(OAc)2 K2CO3
Pd(OAc)2 Cu(OAc)2 K2CO3
Pd(OAc)2 Cu(OAc)2 K2CO3
Pd(OAc)2 Cu(OAc)2 K2CO3
Pd(OAc)2 PhI(OAc)2 K2CO3
DMF
38
3
DMF
45
4
DMF
DMF
71
5
67c
63d
52
20 3a). The major product isolated from this experiment was
Ullmann coupled product, 2ꢀ(2ꢀ(1Hꢀimidazolꢀ1ꢀyl)phenyl)ꢀ4,5ꢀ
diphenylꢀ1Hꢀimidꢀazole (3a, 68%). This might be due to less
reactivity of azole N−H toward the oxidative cyclizations. To
improve the efficiency of dehydrogenative C−N coupling,
25 catalytic amount of PdCl2 (5 mol %) together with the Cu(OAc)2
(2.0 equiv) was added post Ullmann coupling (Scheme 3b).9b,12
To our delight Pd/Cu system effectively promoted the oxidative
C−N bonding through C−H activation/functionalization to deliver
fused quinazoline 5a in 65% yield (entry 1, Table 1) in a shorter
30 reaction time.
We then screened various palladium catalysts, oxidants, bases,
and solvents to obtain the optimum condition for the sequential
oneꢀpot two step reaction (Table 1). Among different palladium
catalyst such as Pd(OAc)2, Pd(PPh3)2Cl2 and Pd(PPh3)4 screened
35 for the oxidative C–N coupling, Pd(OAc)2 offered highest yield
of 5a (entries 2ꢀ4, Table 1). Diminished yields of 5a were
obtained when K2CO3 was replaced with other bases such as
Cs2CO3, K3PO4, Na2CO3 and tꢀBuOK (entries 7ꢀ10, Table 1).
Simultaneously, various solvents were screened and realized that
6
DMF
7
DMF
8
DMF
48
9
DMF
28
10
11
12
13
14
15
16
17
18
19
20
DMF
21
DMA
1,4ꢀdioxane
toluene
CH3CN
DMF
65
ꢀe
20
52
42
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
ꢀf
Ag2CO3 K2CO3
DMF
38
CuCl2
Cu2O
K2CO3
K2CO3
K2CO3
DMF
64
ꢀe
DMF
CuSO4
DMF
61
Cu(OAc)2 K2CO3
DMF
traces
aReaction conditions: 1a (1.0 mmol), 2a (1.2 mmol), CuI (20 mol %),
base (2.0 mmol), solvent (4 ml), 150 °C, 1 h followed by palladium
b
c
60 catalyst (5 mol %), oxidant (2.0 mmol), 150 °C, 2 h. Isolated yield. 1.2
mmol of Cu(OAc)2 were used. 1.2 mmol of K2CO3 were used. eOnly 3a
d
was formed. fReaction was performed in the absence of palladium
catalyst.
2
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With the established conditions in hand (entry 4, Table 1), we
then focussed our attention on evaluating substrate scope for the
sequential process and the results were summarized in Table 2.
Besides 1Hꢀimidazole, 1Hꢀbenzimidazole and 1Hꢀ1,2,4ꢀtriazole
also expediently gave moderate to good yields of Nꢀfused
structures under these conditions. Diversely substituted 2ꢀ(2ꢀ
bromophenyl)ꢀ4,5ꢀdiphenylꢀ1Hꢀimidazoles smoothly participated
in oneꢀpot reaction and delivered the corresponding fused
5
10 structures in good yields (5aꢀl, Table 2). Imidazoles with electron
withdrawing group such as fluoro on aryl rings at C4 and C5
positions furnished higher yields of fused quinazolines when
compared to aryl groups of electron rich groups like methyl and
methoxy. Similarly, 2ꢀ(2ꢀbromophenyl)ꢀ1Hꢀbenzo[d]imidazole
15 also underwent smooth Ullmann type coupling followed by
oxidative cyclization and offered polycyclic Nꢀfused structures in
good yields (5mꢀo, Table 2).
Scheme 4 Plausible mechanism for the formation of 5.
Table 2 Substrate scope for the sequential dual C−N bondinga, b
Conclusions
35 An expedient and straightforward method has been disclosed to
access diversely substituted Nꢀfused polycyclic structures by
employing C−H functionalization. The designed strategy
necessitates simple and easily accessible precursors and builds
fused structures with high complexity in a single step. Further
40 applications and mechanism of the reported reaction is under
progress in our laboratory.
5a, 71%
5d, 52%
5b, 62%
5e, 81%
5c, 58%
F
Acknowledgements
N
N
N
Authors sincerely acknowledge Council of Scientific and
Industrial Research (CSIR), New Delhi [02(0115)/13/EMRꢀII]
45 and Department of Science and Technology, New Delhi [DSTꢀ
FIST, CSIꢀ174/2008] for the financial support. KP is thankful to
UGC, New Delhi and PK is thankful to CSIR, New Delhi for
research fellowship.
N
F
5f, 65%
5g, 79%
5h, 56%
5i, 61%
Notes and references
50 a Department of Chemistry, Birla Institute of Technology and Science,
Pilani, Pilani 333031, India.Fax: 91 1596 244183; Tel: 91 1596 515514
†Electronic Supplementary Information (ESI) available: [General
experimental details, copies of 1H and 13C NMR of the synthesized
compounds 3a and 5aꢀo are available]. See DOI: 10.1039/b000000x/
55
5j, 56%
5k, 52%
5n, 68%
5l, 58%
5o, 61%
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