Efficient access to 8H-isoquinolino[1,2-b]quinazolin-8-ones and phthalazino[2,3-a]cinnoline-8,13-diones through cyclic amide-directed Ru(II)/Ir(III)-catalyzed C-H bond activation, has been developed. Consecutive C-H bond activation, carbene insertion, and condensation annulation processes were realized, affording 8H-isoquinolino[1,2-b]quinazolin-8-one and phthalazino[2,3-a]cinnoline-8,13-dione derivatives in good-to-excellent yields under mild conditions, with H2O and N2 being generated as the only byproducts.
Efficient access to 8H-isoquinolino[1,2-b]quinazolin-8-ones and phthalazino[2,3-a]cinnoline-8,13-diones through cyclic amide-directed Ru(II)/Ir(III)-catalyzed C-H bond activation, has been developed. Consecutive C-H bond activation, carbene insertion, and condensation annulation processes were realized, affording 8H-isoquinolino[1,2-b]quinazolin-8-one and phthalazino[2,3-a]cinnoline-8,13-dione derivatives in good-to-excellent yields under mild conditions, with H2O and N2 being generated as the only byproducts.
As poly cyclic nitrogen-containing
heterocycles, 8H-isoquinolino[1,2-b]quinazolin-8-ones and phthalazino[2,3-a]cinnoline-8,13-diones
are ubiquitous in many bioactive
synthetic compounds as well as natural products (Scheme ). For example, compounds A and B as shown in Scheme were proved to have efficient antitumor
activities.[1,2] Poly cyclic nitrogen-containing heterocycles
were also commonly applied in anticonvulsant,[3−5] anti-inflammatory,[6] antiallergy,[7,8] antimicrobial,[9] cardiotonic,[10] and
cell imaging[11,12] research. Scaffold of 11H-pyrido[2,1-b]quinazolin-11-one H was found in many natural products[13] (Scheme ). Traditional
synthesis of such polycyclic compounds suffered from multiple steps
and harsh reaction conditions. Thus, developing general and efficient
approaches for the construction of 8H-isoquinolino[1,2-b]quinazolin-8-one and phthalazino[2,3-a]cinnoline-8,13-dione derivatives attracted a lot of efforts. For
example, Peng and Cui developed ruthenium and palladium catalyzed
directed C–H bond activation of 2-phenylquinazolin-4(3H)-ones and alkyne insertion annulations for the synthesis
of 8H-isoquinolino[1,2-b]quinazolin-8-ones,
respectively (Scheme ).[14,15] Synthesis of phthalazino[2,3-a]cinnoline-8,13-diones was independently reported by Gandhi and Perumal
via ruthenium and rhodium catalyzed alkyne insertion reactions with
2-phenyl-2,3-dihydrophthalazine-1,4-diones.[16,17]
Scheme 1
Representative Bioactive Molecules
Scheme 2
Transition-Metal Catalyzed C–H Activation Reactions
of 2-Phenylquinazolin-4(3H)-ones and 2-Phenyl-2,3-dihydrophthalazine-1,4-diones
Transition-metal catalyzed
C–H bond activation reactions
have been a long-term research interest of organic chemists for the
construction of new C–C and C–X (X = N, O, S et al.)
bonds because of the environmental benignity and simple operation.
As a C1 building block, carbene has attracted much attention based
on its high and diverse reaction reactivities.[18−21] 1,3-Diketone-2-diazo compounds
can not only react as a C1 synthon but also be used as an equivalent
of alkynes, undergoing formal C2 insertion reaction with cyclic compounds
being constructed.[22] However, compared
with alkynes, 1,3-diketone-2-diazo compounds have their unique characteristics.
For instance, no additional oxidants, to which lots of substrates
cannot tolerate, were needed. Additionally, cyclic 1,3-diketone-2-diazo
compounds have their priorities because of the instability of cyclicalkynes.[23] Herein, we report facile access
to 8H-isoquinolino[1,2-b]quinazolin-8-ones
and phthalazino[2,3-a]cinnoline-8,13-diones via ruthenium
and iridium catalyzed C–H bond activation/annulation reaction
of cyclic amide derivatives. In these reactions, both cyclic and acyclic
1,3-diketone-2-diazo compounds could be transformed to corresponding
products smoothly in good to excellent yields with H2O
and N2 as the only byproducts.
Results and Discussion
The reaction was initiated with 2-(p-tolyl)quinazolin-4(3H)-one (1a) and 2-diazo-5-methylcyclohexane-1,3-dione
(2a) as model substrates with the catalysis of (RhCp*Cl2)2/AgNTf2 at 90 °C (Table , entry 1). To our delight,
the desired product 2,6-dimethyl-2,3-dihydro-4H-quinazolino[3,2-f]phenanthridine-4,14(1H)-dione (3a) was obtained in 58% yield. Screening of catalysts revealed
that 3 mol % of [(p-cymene)RuCl2]2 gave the best result (entries 2–5). Further investigation
of additives and solvents showed lower efficacy (entries 6–11).
In addition, no better results were found at lower or higher reaction
temperatures (80 and 100 °C).
Table 1
Optimization of Reaction
Conditionsa
entry
catalyst (mol %)
additive (30 mol %)
solvent
temp. (°C)
time (min)
yield (%)b
1
(RhCp*Cl2)2 (3)
AgNTf2
t-BuOH
90
40
58
2
(IrCp*Cl2)2 (3)
AgNTf2
t-BuOH
90
40
47
3
[(p-cymene)RuCl2]2 (3)
AgNTf2
t-BuOH
90
40
73
4
[(p-cymene)RuCl2]2 (1)
AgNTf2
t-BuOH
90
40
49
5
[(p-cymene)RuCl2]2 (5)
AgNTf2
t-BuOH
90
40
66
6
[(p-cymene)RuCl2]2 (3)
AgSbF6
t-BuOH
90
40
51
7
[(p-cymene)RuCl2]2 (3)
CsOAc
t-BuOH
90
40
40
8
[(p-cymene)RuCl2]2 (3)
AgNTf2
DMF
90
40
58
9
[(p-cymene)RuCl2]2 (3)
AgNTf2
DCE
90
40
40
10
[(p-cymene)RuCl2]2 (3)
AgNTf2
toluene
90
40
31
11
[(p-cymene)RuCl2]2 (3)
AgNTf2
t-AmOH
90
40
66
12
[(p-cymene)RuCl2]2 (3)
AgNTf2
t-BuOH
80
40
41
13
[(p-cymene)RuCl2]2 (3)
AgNTf2
t-BuOH
100
40
29
Reaction conditions: 1a (0.50 mmol), 2a (0.5 mmol) in the presence
of catalyst/additive
in 5 mL of solvent under air.
Isolated yields.
Reaction conditions: 1a (0.50 mmol), 2a (0.5 mmol) in the presence
of catalyst/additive
in 5 mL of solvent under air.Isolated yields.With the
optimized conditions in hand, the substrate scope of 2-phenylquinazolin-4(3H)-one derivatives were investigated first (Scheme ). Substituents such as OMe,
OBn, Br, Bu, Cl, and OH on the aromatic
rings were well tolerated under the optimal conditions, generating
the corresponding products in moderate-to-good yields (3a–3i). It is worthy to note that the substrate
with the hydroxyl group which is intolerable under many reaction conditions
could be transformed to product 3i in an acceptable 50%
yield. When phenyl, dimethyl, or nonsubstituted cyclic diazo compounds
worked as the reactants, products 3j–3l were obtained in moderate yields. Meanwhile, heterocyclic C–H
bond activation was realized to generate 3m in 68% yield.
However, acyclic 1,3-diketone-2-diazo compounds failed to suffer the
reaction conditions.
Scheme 3
Scope of the Reaction with 2-Phenylquinazolin-4(3H)-ones
Reaction conditions: 1 (0.50 mmol), 2 (0.5 mmol), [(p-cymene)RuCl2]2 (3 mol %), AgNTf2 (30 mol %), 5 mL
of BuOH, 90 °C. Isolated yields.
Scope of the Reaction with 2-Phenylquinazolin-4(3H)-ones
Reaction conditions: 1 (0.50 mmol), 2 (0.5 mmol), [(p-cymene)RuCl2]2 (3 mol %), AgNTf2 (30 mol %), 5 mL
of BuOH, 90 °C. Isolated yields.Other types of cyclic amide-directed C–H
bond activations
were further investigated with easily accessible 2-phenyl-2,3-dihydrophthalazine-1,4-dione
(4a) and 2-diazo-5,5-dimethylcyclohexane-1,3-dione (2b) as model substrates. With the above optimized catalytic
system at a higher temperature of 100 °C, 2,2-dimethyl-2,3-dihydrobenzo[c]phthalazino[2,3-a]cinnoline-4,10,15(1H)-trione (5a) was generated in 60% yield (Table , entry 1). After
optimization of the reaction conditions, the yield of 5a was increased to 93% under the condition of (IrCp*Cl2)2/AgSbF6 as catalyst in DCE at 100 °C
(entry 3).
Table 2
Optimization of Reaction Conditions
for Synthesis of 5aa
entry
catalyst (mol %)
additive (mol %)
solvent
temp. (°C)
time (h)
yield (%)b
1
[(p-cymene)RuCl2]2 (3)
AgNTf2 (30)
t-BuOH
100
14
60
2
(IrCp*Cl2)2 (1.5)
AgSbF6 (20)
DCE
100
14
67
3
(IrCp*Cl2)2 (2)
AgSbF6 (20)
DCE
100
14
93
4
(IrCp*Cl2)2 (2.5)
AgSbF6 (20)
DCE
100
14
70
5
(IrCp*Cl2)2 (2)
AgSbF6 (10)
DCE
100
14
68
6
(IrCp*Cl2)2 (2)
AgSbF6 (30)
DCE
100
14
56
7
(IrCp*Cl2)2 (2.5)
AgSbF6 (20)
acetone
100
14
32
8
(RhCp*Cl2)2 (2)
AgSbF6 (30)
THF
100
14
10
Reaction conditions: 1a (0.50 mmol), 4a (0.5 mmol), catalyst/additive (as indicated
in the table), 5 mL solvent, 14 h, nitrogen atmosphere.
Isolated yields.
Reaction conditions: 1a (0.50 mmol), 4a (0.5 mmol), catalyst/additive (as indicated
in the table), 5 mL solvent, 14 h, nitrogen atmosphere.Isolated yields.Next, the scope of the reaction
was investigated under the optimized
conditions (Scheme ). Substrates with Me, Bu, F, Cl, and
Br underwent the reaction efficiently with 2-diazo-5,5-dimethylcyclohexane-1,3-dione
(2b), generating the corresponding products in good to
excellent yields (5a–5i). Steric
hindered ortho-substituted substrates could tolerate the reaction
conditions, generating 5g and 5h in 81 and
82% yields, respectively. Diverse poly cyclic heterocycles were obtained
in good yields when using monomethyl, phenyl, and nonsubstituted cyclicdiazo compounds as the reaction partners (5j–5r). It is worthy to note that five-membered-cyclic and acyclic
1,3-carbonyl-2-diazo compounds tolerated the reaction conditions,
generating the corresponding products 5s–5x in excellent yields.
Scheme 4
Scope of the Reaction with 2-Phenyl-2,3-dihydrophthalazine-1,4-diones
Reaction conditions: 4 (0.5 mmol), 2 (0.5 mmol), (IrCp*Cl2)2 (2 mol %), AgSbF6 (20 mol %), 5 mL of DCE, 100
°C. Isolated yields.
Scope of the Reaction with 2-Phenyl-2,3-dihydrophthalazine-1,4-diones
Reaction conditions: 4 (0.5 mmol), 2 (0.5 mmol), (IrCp*Cl2)2 (2 mol %), AgSbF6 (20 mol %), 5 mL of DCE, 100
°C. Isolated yields.On the basis of
the reported transition-metal-catalyzed C–H
bond activation/carbene insertion reactions[22,23,24] and the experiment results, a possible mechanism
was proposed in Scheme . An active catalytic species I was generated by ligand
exchange, which catalyzed C–H bond activation to form intermediate II. Carbene coordination and migratory insertion to intermediate II generated alkyl-ruthenium intermediate IV,
which was then protonated to intermediate V. The catalyst I was released to complete the catalytic cycle. An isomerization/intramolecular
condensation process of V took place spontaneously, affording
the compound 3.
Scheme 5
Proposed Reaction Mechanism
Conclusion
In
conclusion, we have developed an efficient and practical method
for the synthesis of 8H-isoquinolino[1,2-b]quinazolin-8-one and phthalazino[2,3-a]cinnoline-8,13-dione derivatives via ruthenium and iridium catalyzed
C–H bond activation reactions. Diverse nitrogen-containing
poly cyclic compounds were synthesized effectively under mild conditions.
The reaction proceeds through consecutive C–H bond activation,
carbene insertion, and annulation reaction with water and N2 as the only byproducts, revealing the environmental benignity of
this reaction.
Experimental Section
General Comments
Unless otherwise specified, all reagents
and starting materials were purchased from commercial sources and
used as received and the solvents were purified and dried using standard
procedures. The chromatography solvents were of technical grade and
distilled prior to use. Flash chromatography was performed using 200–300
mesh silica gel with the indicated solvent system according to standard
techniques. The 1H and 13C NMR data were recorded
on 300/500 and 75/125 MHz NMR spectrometers, unless otherwise specified.
Chemical shifts (δ) in parts per million are reported relative
to the residual signals of chloroform (7.26 ppm for 1H
and 77.16 ppm for 13C), and all 13C NMR were
recorded with proton broadband decoupling and indicated as 13C{1H} NMR. Multiplicities are described as s (singlet),
d (doublet), t (triplet), q (quartet), or m (multiplet), and the coupling
constants (J) are reported in hertz. HRMS analysis
with a quadrupole time-of-flight mass spectrometer yielded ion mass/charge
(m/z) ratios in atomic mass units.
IR spectra were measured as dry films (KBr), and the peaks are reported
in terms of wave number (cm–1).
Procedure A:
The Synthesis of 8H-Isoquinolino[1,2-b]quinazolin-8-one Derivatives 3
To
a solution of 2-(p-tolyl)quinazolin-4(3H)-one (0.5 mmol) and [(p-cymene)RuCl2]2 (3 mol %)/AgNTf2 (30 mol %) in t-BuOH (2 mL) at 90 °C was added portion wise a solution of 2-diazo-5-methylcyclohexane-1,3-dione
(0.5 mmol). After being stirred for another 40 min, the mixture was
cooled to room temperature. The reaction was quenched with water,
and the mixture was extracted with DCM three times. The combined organic
layers were dried over anhydrous Na2SO4, filtered
and concentrated in vacuo. The residue was purified by flash column
chromatography on silica gel to afford 2,6-dimethyl-2,3-dihydro-4H-quinazolino[3,2-f] phenanthridine-4,14(1H)-dione 3.
Procedure B: The Synthesis
of Phthalazino[2,3-a]cinnoline-8,13-dione Derivatives 5
A mixture
of cyclic 2-diazo-1,3-diketones 2 (0.5 mmol), 2-phenyl-2,3-dihydrophthalazine-1,4-dione 4 (0.5 mmol), [Cp*IrCl2]2 (2 mol %),
and AgSbF6 (20 mol %) in DCE (2 mL) was heated in an oil
bath at 100 °C for 14 h. Upon completion of the reaction, the
mixture was cooled to room temperature. The residue was purified by
flash column chromatography on silica gel (200–300 mesh) with
ethyl acetate and petroleum ether (1:6–1:8, v/v) as the elution
solvent to give the desired products 5.
Authors: Alan Ford; Hugues Miel; Aoife Ring; Catherine N Slattery; Anita R Maguire; M Anthony McKervey Journal: Chem Rev Date: 2015-08-18 Impact factor: 60.622
Authors: J Bartroli; E Turmo; M Algueró; E Boncompte; M L Vericat; L Conte; J Ramis; M Merlos; J García-Rafanell; J Forn Journal: J Med Chem Date: 1998-05-21 Impact factor: 7.446
Scheme 1
Scheme 2
Scheme 3
Scheme 4
Scheme 5