Synthesis of C6-Substituted Isoquinolino[1,2- b]quinazolines via Rh(III)-Catalyzed C-H Annulation with Sulfoxonium Ylides

Article abstract of DOI:10.1021/acs.joc.9b03065

We report the synthesis of C6-substituted isoquinolino[1,2-b]quinazolinones via rhodium(III)-catalyzed C-H annulation with sulfoxonium ylides and evaluation of the cytotoxic activity of the scaffold. This C-H activation approach enables the most straightforward and convergent synthesis of C6-substituted isoquinolino[1,2-b]quinazolines reported to date. This operationally simple method is compatible with a wide variety of the sulfoxonium ylide and arene C-H activation coupling partners, permitting access to diverse isoquinolino[1,2-b]quinazolines. This method shows a high atom economy, generating H₂O and dimethyl sulfoxide (DMSO) as by-products. This method is scalable and operates with exquisite N-lactam cyclization selectivity, thus enabling expedient access to new heterocyclic analogues featuring promising cytotoxic properties.

Full text of DOI:10.1021/acs.joc.9b03065

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Article
Synthesis of C6-Substituted Isoquinolino[1,2-b]quinazolines
via Rh(III)-Catalyzed C–H Annulation with Sulfoxonium Ylides
Jin Zhang, Xiaogang Wang, Di Chen, Yifan Kang, Yangmin Ma, and Michal Szostak
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b03065 • Publication Date (Web): 16 Jan 2020
Downloaded from pubs.acs.org on January 20, 2020
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Synthesis of C6-Substituted Isoquinolino[1,2-b]quinazolines via Rh(III)-Catalyzed C–H
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Annulation with Sulfoxonium Ylides
†,§,
†,§
†,‡
†
†,
†,‖,
Jin Zhang, * Xiaogang Wang, Di Chen, Yifan Kang, Yangmin Ma, * Michal Szostak *
†College of Chemistry and Chemical Engineering, Shaanxi Key Laboratory of Chemical
Additives for Industry, Shaanxi University of Science and Technology, Xi’an 710021, China
‡School of Food and Biological Engineering, Shaanxi University of Science and Technology,
Xi’an 710021, China
‖
Department of Chemistry, Rutgers University, 73 Warren Street, Newark, New Jersey
07102, United States
Corresponding author
zhangjin@sust.edu.cn
mym63@sina.com
michal.szostak@rutgers.edu
ABSTRACT
direct annulation
O
N
O
N
R
[
Cp*RhCl ] (4 mol%)
2 2
AgSbF6 (25 mol%)
H
N
H
O
O
S
N
+
R
R'
CH CN, 160 °C
>30 examples
51-91% yield
R'
3
R''
-arylquinazolines
R''
2
sulfoxonium
ylides
isoquinolino[1,2-b]
quinazolines
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We report the synthesis of C6-substituted isoquinolino[1,2-b]quinazolinones via rhodium(III)-
catalyzed C–H annulation with sulfoxonium ylides and evaluation of the cytotoxic activity of
the scaffold. This C–H activation approach enables the most straightforward and convergent
synthesis of C6-substituted isoquinolino[1,2-b]quinazolines reported to date. This
operationally-simple method is compatible with a wide variety of the sulfoxonium ylide and
arene C–H activation coupling partners, permitting access to diverse isoquinolino[1,2-
0
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b]quinazolines. The method shows high atomy economy generating H O and DMSO as by-
2
products. The method is scalable and operates with exquisite N-lactam cyclization selectivity,
thus enabling expedient access to new heterocyclic analogues featuring promising cytotoxic
properties.
1. INTRODUCTION
Isoquinolino[1,2-b]quinazolinones represent a class of high value, privileged heterocycles
in natural products, drug discovery and advanced organic materials as electroluminescent
dopants for light emitting devices (Figure 1).1–3 However, the efficient synthesis of C6-
substituted isoquinolino[1,2-b]quinazolinones has been severely underdeveloped to date.
The classic way to construct C6-substituted isoquinolino[1,2-b]quinazolinones has relied on
a sequential N-acylation/condensation of 2-aminopyridines with 2-fluorobenzonitriles and
4
derivatives (Scheme 1A). However, this route is limited by the ability to access functionalized
2-aminopyridine condensation partners, and cannot be used for convergent synthesis
required for screening of biological properties.
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Figure 1. Examples of isoquinolino[1,2-b]quinazolines and representative related scaffolds.
Note that C6-substituted isoquinolino[1,2-b]quinazolines are underrepresented due to the
lack of methods for rapid synthesis.
At present, the emergence of powerful cross-coupling and C–H activation reactions has
5
opened up new opportunities to efficiently generate novel heterocycles; however, methods
for the efficient, convergent and waste-minimized synthesis of C6-substituted
isoquinolino[1,2-b]quinazolinones remain unknown.
In the context of the synthetic approaches to isoquinolino[1,2-b]quinazolinones, several
recent reports have described methods based on annulation of 2-arylquinazolin-4(3H)-ones
as a privileged heterocyclic motif.6a A Pd/Cu-co-catalyzed oxidative annulation in the
presence of oxygen delivers C5/C6-dihydrofuran-fused isoquinolino[1,2-b]quinazolinones
(
Scheme 1B).6b A Pd-catalyzed annulation of 2-phenylquinazolin-4(3H)-ones with
diaryliodonium salts furnishes C5/C6-benzene-fused isoquinolino[1,2-b]quinazolinones
(Scheme 1C).6c A Pd-catalyzed direct C–H amination of 2-biphenylquinazolin-4(3H)-ones
provides access to C5/C6-benzene fused isoquinolino[1,2-b]quinazolinones (Scheme 1D).6d
6e
Methods based on Pd- Pd/Ag-co-catalyzed C–H carbonylation, Pd-catalyzed intramolecular
6f
6g
C–H activation, Ru-catalyzed C–H allylation/hydroamination, oxidative Ru(II)-catalyzed
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annulation, Ir-catalyzed C–H alkynylation/electrophilic cyclization and Cu-mediated C–H
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j
amination have accelerated the synthesis of isoquinolino[1,2-b]quinazolinones. However,
none of these approaches allows for the construction of C6-mono-substituted
isoquinolino[1,2-b]quinazolinones, a scaffold which has been essential in the development of
new anticancer therapeutics.
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Scheme 1. Previous studies and this work.
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A: Classical synthesis
R
O
R
CN
F
N
strong base
N
+
H2N
N
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x prefunctionalization not accessible x harsh conditions
x not amenable for complex substrates & diversity synthesis
B: Oxidative Pd/Cu co-catalyzed aerobic annulation
R
O
R
O
O
R
NH
H
Pd, Cu
N
R
+
R
R
N
O2
N

CH activation  convergent annulation x C5/C6-substitution
C: Pd-catalyzed annulation/-extension
O
O
N
NH
H
Pd, Ag
N
+
Ph2IOTf
N

CH activation  convergent annulation x C5/C6-substitution
D: Pd-catalyzed direct CH amination
O
O
N
NH Br
1. Suzuki
2. Pd, Cu
N
+
PhB(OH)2
N

CH activation  convergent coupling x C5/C6-substitution
E: This work: direct CH acylmethylation/C6-substitution
O
O
N
R
NH
H
O
O
S
Rh(III) cat.
N
+
N
R
-DMSO, -H2O

CH acylmethylation  direct cyclization  novel C6-analogues
 broad scope  acid-free  cytotoxic activity
7
8
As a part of our program on the synthesis of heterocycles and C–H activation, herein.
we report the synthesis of C6-substituted isoquinolino[1,2-b]quinazolinones via Rh(III)-
catalyzed C–H activation of 2-arylquinazolin-4(3H)-ones with sulfoxonium ylides and
evaluation of the cytotoxic activity of the scaffold (Scheme 1E). Most crucially, the method
allows for the most straightforward and convergent synthesis of C6-mono-substituted
isoquinolino[1,2-b]quinazolines reported to date, thus enabling expedient access to new
heterocyclic analogues featuring promising cytotoxic properties.
2
. RESULTS AND DISCUSSION
The recent years have witnessed significant progress in the development of new C–H
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activation methods to form C–C(sp ) bonds. Our interest was piqued by the metal-carbene
insertion methods using sulfoxonium ylides.11–13 These carbene precursors offer several
advantages over α-diazo carbonyls, including safe handling, ease of preparation from the
corresponding acyl halides using Corey-Chaykovsky reagent,14 and high reactivity in
acylmethylation.15,16 We hypothesized that following the regioselective C–H acylmethylation,
the pendant acyl moiety could be engaged in dehydrative N to C(O) condensation using the
amide bond nitrogen to rapidly construct the isoquinolino[1,2-b]quinazolinone scaffold. This
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formal 1C homologation/acylative C–C(sp ) bond formation would provide a new route to
C6-mono-substituted isoquinolino[1,2-b]quinazolinones that thus far have been elusive using
other C–H activation methods.1–6
At the outset of our studies, we investigated the reaction between 2-phenylquinazolin-
4
(3H)-one (1a) and sulfoxonium ylide (2a) to optimize the reaction conditions (Table 1). To
our delight, we found that the catalyst formed from the rhodium dimer [Cp*RhCl ] (4 mol%)
2
2
and AgSbF (25 mol%) promoted the coupling of (1a) and (2a) in DCE at 160 °C for 24 h to
6
deliver the desired product (3aa) in promising 11% yield in the absence of any other additives
(
Table, entry 1). With this catalyst system in hand, various solvents were investigated,
including EtOH, n-PrOH, CH CN, n-C H CN (Table 1, entries 2-5), and CH CN gave the best
3
3
7
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results (entry 4). With this solvent, the reaction proceeded efficiently to afford (3aa) in 85%
yield (entry 4). Interestingly, reactions performed with other catalysts, such as Pd(OAc) and
2
[
Ru(p-cym)Cl ] were ineffective (entries 6-7). Other additives to form the cationic Rh(III) also
2
2
resulted in lower reaction efficiency (entries 8-9). Furthermore, high temperature is required
for the efficient reaction (entry 10, 140 °C <10% yield). The use of protic acid additives such
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as PivOH or PhCO H to promote the C–H activation process was unsuccessful (entries 11-12,
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4-25% yield).
Table 1. Optimization of Reaction Conditionsa
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O
O
Ph
NH
O
O
S
N
catalyst, additives
solvent, 160 °C
+
N
Ph
N
1a
2a
3aa
entry
catalyst
additive
solvent
DCE
yield (%)
11
1
2
3
4
5
6
[Cp*RhCl
[Cp*RhCl
[Cp*RhCl
[Cp*RhCl
[Cp*RhCl
]
2 2
]
2 2
]
2 2
]
2 2
]
2 2
AgSbF
AgSbF
AgSbF
AgSbF
AgSbF
AgSbF
AgSbF
6
6
6
6
6
6
6
EtOH
35
n-PrOH
<5
CH
n-C
3
CN
85
3
H
7
CN
72
Pd(OAc)
Ru(p-
cym)Cl
2
CH
CH
3
CN
CN
<5
[
3
<5
7
2 2
]
8
9
[Cp*RhCl
2
]
2
2
AgNTf
2
CH
CH
CH
CH
CH
3
CN
3
CN
3
CN
3
CN
3
CN
65
61
[Cp*RhCl
2
]
AgOTf
1
0b
1c
2d
[Cp*RhCl
[Cp*RhCl
[Cp*RhCl
2
]
2
2
2
AgSbF
AgSbF
AgSbF
6
<10
24
1
2
2
]
]
6
6
1
25
aConditions: 1a (1.0 equiv), 2a (1.2 equiv), catalyst (4 mol%), additive (25 mol%), solvent (0.05
b
c
d
M), 160 °C, 24 h. 140 °C. With 1.0 equiv PivOH. With 1.0 equiv PhCO H.
2
Next, we explored the scope of this heterocycle synthesis using sulfoxonium ylide (2a) as
a representative C–H acylmethylating reagent (Scheme 2). As shown, a variety of
isoquinolino[1,2-b]quinazolinones could be constructed by this method. Crucially, in all cases,
full C6-regioselectivity resulting from a nitrogen-directed C–H acylmethylation was observed,
leading to a synthetically-useful process. Thus, 2-phenylquinazolin-4(3H)-one coupling
partners bearing diverse electron-donating groups (1a-1f), halides (1g-1h), and electron-
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withdrawing substituents (1i-1j) at the para position of the 2-aryl ring worked well and
furnished the corresponding products in good to excellent yields. Further, high selectivity at
the less hindered site was observed using electronically-differentiated meta-substituted
substrates (1k-1m), which resulted in products (3ka-3ma) in 51-83% yields. Importantly, the
method could also enable C–H annulation of five-membered heterocycles, such as thiophene
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(
3na), as well as 6-chloroquinazolinones (3oa) that are known as aldehyde oxidase
17
inhibitors. At the present stage of reaction development C4 substituents OH, NH and NO
2
2
have not been tested. The use of 2-vinylquinazolin-4(3H)-ones as substrates will be the
subject of future studies.
Scheme 2. Scope of 2-Phenylquinazolin-4(3H)-ones.a,b
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O
O
Ph
[
Cp*RhCl2]2 (4 mol%)
AgSbF6 (25 mol%)
NH
O
O
S
N
+
N
Ph
N
R'
R'
CH3CN, 160 °C
1
2a
3
24 h
R''
R''
O
N
O
N
O
N
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1
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0
N
N
N
Me
Et
3
3
3
aa: 85% yield
3ba: 84% yield
3ca: 87% yield
O
N
N
O
N
N
O
N
N
i-Pr
t-Bu
OMe
da: 83% yield
3ea: 81% yield
3fa: 91% yield
O
N
N
O
N
N
O
N
N
F
Br
OCF3
3ia: 62% yield
ga: 82% yield
3ha: 58% yield
O
N
N
O
N
N
O
N
N
CF3
Me
OMe
3
ja: 56% yield
3ka: 81% yield
3la: 83% yieldc
O
N
N
O
N
N
O
N
N
Cl
S
aldehyde oxidase
inhibitor
CF3
3ma: 51% yield
3na: 57% yield
3oa: 73% yield
a
Conditions: 1a (1.0 equiv), 2a (1.2 equiv), [Cp*RhCl ] (4 mol%), AgSbF (25 mol%), CH CN
2
2
6
3
b
c
(
0.05 M), 160 °C, 24 h. Isolated yields. 5.3:1 regioisomers. See Supporting Information (SI)
for details.
We next evaluated the scope of sulfoxonium ylides in this heterocycle synthesis (Scheme
). In general, we found that the method is very broad with respect to the sulfoxonium ylide,
3
3
attesting to the synthetic utility of sulfoxonium carbenes in C–C(sp ) bond forming
reactions.1
1–13
Thus, ylides featuring various electron-donating groups (3ab-3ac), halides
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1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
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5
5
5
5
5
5
5
5
5
5
6
(
3ad-3ae), and electron-withdrawing substituents (3af) enabled regioselective C–H activation
and gave the desired products in high yields (67-85%). Furthermore, substitution at the
sterically-hindered ortho-position was well-tolerated, affording the desired heterocycles in
81-85% yields (3ag-3ah). In addition, meta-substitution is well-compatible (3ai-3ak) as are
other heterocyclic ring systems, such as thiophene and furan (3al-3am), and polyaromatic
rings (3an), affording the desired products in good yields. Finally, we were pleased to find
that the sulfoxonium ylide scope was not limited to aryl substitution, and the reaction also
worked well when alkyl substituted sulfoxonium ylides were used (3ao-3ap). Overall, the
method provides the most straightforward access to the isoquinolino[1,2-b]quinazolinone
scaffold to date.1 Especially noteworthy is broad scope with respect to both coupling
partners and functional group tolerance to sensitive substituents that could be used for
further functionalization by traditional cross-coupling methods.
0
1
2
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5
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8
9
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–3
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Scheme 3. Scope of Sulfoxonium Ylides.a,b
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
O
O
R
[
Cp*RhCl2]2 (4 mol%)
AgSbF6 (25 mol%)
NH
O
O
S
N
+
N
R
N
CH3CN, 160 °C
1a
2
3
24 h
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Me
OMe
Cl
O
O
N
O
N
N
N
N
N
3ab: 80% yield
3ac: 84% yield
3ad: 85% yield
Br
CF3
O
N
N
O
N
N
O
N
N
OMe
3
ae: 67% yield
3af: 78% yield
3ag: 85% yield
Me
Cl
O
N
N
F
O
N
N
O
N
N
3
ah: 81% yield
3ai: 85% yield
3aj: 79% yield
CF3
X
O
N
N
O
N
N
O
N
N
3
ak: 74% yield
3al: 77% yield (X = S)
am: 81% yield (X = O)
3an: 54% yield
3
O
N
O
N
N
N
3ao: 66% yield
3ap: 74% yield
a
Conditions: 1a (1.0 equiv), 2a (1.2 equiv), [Cp*RhCl ] (4 mol%), AgSbF (25 mol%), CH CN
2
2
6
3
b
(0.05 M), 160 °C, 24 h. Isolated yields. See Supporting Information (SI) for details.
The practicality of the method was further evaluated in a gram-scale synthesis (Scheme
4
), which produced the expected isoquinolino[1,2-b]quinazolinone product (3aa) in 73% yield.
Scheme 4. Gram-Scale Synthesis.
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1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
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4
4
4
4
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5
5
5
5
5
5
5
5
5
6
O
N
O
N
Ph
[
Cp*RhCl2]2 (4 mol%)
AgSbF6 (25 mol%)
NH
O
O
S
N
+
Ph
CH3CN, 160 °C
24 h
1
a (4 mmol)
2a (4.80 mmol)
3aa: 0.94 g, 73%
The parent 6-phenyl-8H-isoquinolino[1,2-b]quinazolin-8-one (3aa) was crystalline and
we were able to confirm the amidic N-cyclization mode by X-ray crystallography (Figure 2). It
is interesting to note that the amidic N–C(O) bond (1.421 Å) is only marginally shorter than
the isoquinolino N–C(Ar) bond (1.431 Å). The C6 aromatic ring is practically half-twisted (τ =
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
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7
8
9
0
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0
1
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8
9
0
1
2
3
4
5
6
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8
9
0
4
2.5°) with respect to the isoquinolino[1,2-b]quinazolinone ring. Interestingly, the amide
bond is moderately twisted ( = 14.4°; χ = 5.6°), with the additive Winkler-Dunitz distortion
N
20
parameter (τχ ) of 20.0°.
N
O1
C7
C17
N1
C16
C15
N2
Figure 2. X-ray structure of (3aa). Crystallographic data, CCDC No. 1964235.
Next, we became interested to gain insight into the mechanism of this new method
Scheme 5). Intermolecular competition studies between differently substituted 2-
(
phenylquinazolin-4(3H)-ones revealed that electron-rich arenes are inherently more reactive
than their electron-deficient counterparts (Scheme 5A), consistent with an electrophilic
rhodation pathway. Intermolecular competition studies between differently substituted
sulfoxonium ylides revealed that electron-rich sulfoxonium ylides react preferentially (Scheme
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5
B). Deuterium incorporation revealed that the cyclometallation step is reversible (Scheme
C). Note that deuterium incorporation at other positions of the quinazoline ring was not
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
5
observed. Kinetic isotope effect studies revealed a k /k value of 2.1 (18% conversion),
H
D
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
indicating that the C–H bond cleavage may be involved in the rate-determining step (Scheme
5
D). These studies indicate an electrophilic C–H functionalization pathway.11a,h
A plausible reaction mechanism is shown in Scheme 6. A cationic [Cp*Rh(III)] complex is
generated in the presence of AgSbF . The N-directed C–H bond activation generates a
6
rhodacyclic intermediate 4. Coordination of sulfoxonium ylide and α-elimination of DMSO
leads to the formation of species 5. Migratory insertion of the Rh–carbene gives the six-
membered metallacycle 6. Protonolysis of the Rh–alkyl bond and amide N to CO
condensation regenerates the active catalyst and delivers the condensation product 3aa. We
tentatively propose that the C–H acylmethylation proceeds via amidorhodium species 418
with the electrophilic cyclodehydration facilitated by activation of the carbonyl group by Lewis
19
acidic Rh(III) via the 6-membered intermediate; however, at this stage imine-directed C–H
activation followed by a nitrogen coordination switch cannot be excluded. Note that the
reaction affords the linear fused isomer with exquisite selectivity (vs. angular).5a It is
noteworthy that the reaction proceeds in the absence of additional additives.
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2
2
2
2
3
3
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3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
Scheme 5. Mechanistic Studies.
A: Intermolecular competition: 2-aryl-quinazolin-4(3H)-ones 1
O
O
N
Ph
2
a (1.0 equiv)
[
Cp*RhCl2]2 (4 mol%)
AgSbF6 (25 mol%)
NH
N
N
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
CH3CN, 160 °C, 24 h
X
X
1f:1j (R = MeO:CF3)
1.0 equiv each)
3fa:3ja >20:1
3fa, X = MeO
3ja, X = CF3
(
B: Intermolecular competition: sulfoxonium ylides 2
X
1a (1.0 equiv)
O
O
S
[Cp*RhCl2]2 (4 mol%)
AgSbF6 (25 mol%)
O
N
X
2c:2f
R = MeO:CF3)
1.0 equiv each)
3
CH CN, 160 °C, 24 h
N
(
(
3ac:3af = 2.1:1
3ac, X = MeO
af, X = CF3
3
C: Deuterium incorporation
O
O
[
Cp*RhCl2]2 (4 mol%)
AgSbF6 (25 mol%)
>
95% D
NH
N
NH
D
CH3CN:D2O (10:1)
160 °C, 24 h
N
1a
>
95% D D
1a-d /1a
2
D: Kinetic isotope effect
O
O
Ph
2
a (1.2 equiv)
NH H(D)
[Cp*RhCl2]2 (4 mol%)
AgSbF6 (25 mol%)
N
H(D)
H(D)
H(D)
H(D)
N
N
CH3CN, 160 °C, 4 h
H(D)
H(D)
KIE = 2.1
H(D)
H(D)
1
a + 1a-d5
3aa + 3aa-d4
0.10 mmol + 0.10 mmol
Scheme 6. Proposed Catalytic Cycle.
O
R
[Cp*RhCl2]2
N
AgSbF6
N
3
1
[Cp*RhX2](SbF6)
O
Cp*
O
O
Rh
Cp*
N
R
N Rh
N
N
4
6
O
2
O
Cp*
R
N Rh
N
5
DMSO
Since the present method delivers isoquinolino[1,2-b]quinazolinones that constitute a
class of privileged heterocycles well-known for their anticancer properties, we were keen on
probing the cytotoxic activity of the synthetized compounds (Table 2). The synthesized
products were tested against human lung cancer cells (A549), human breast cancer cells
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(
MDA-MB-231) and human prostate cancer cells (PC3) (see SI for details). It is worth noting
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
that all compounds showed very good solubility in DMSO; even after diluting by 100 times in
water under the highest concentration insoluble residue was not observed. It is likely that the
high solubility of these polyaromatics arises from the presence of polar nitrogen moieties. As
summarized in Table 2, isoquinolino[1,2-b]quinazolinones 3ia, 3af, 3am and 3an showed
promising growth inhibition, and compound 3an shows a strong inhibitory effect on MDA-
MB-231 in the range of cis-platin (3an: IC50 = 29.9 uM). Thus, these results highlight the
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
22
potential of privileged C6-substituted isoquinolino[1,2-b]quinazolines as cytotoxic agents.
Table 2. Cytotoxic Activity of 3aa-3ap.
IC50(μM)
Entry
A549
106.6
156.3
>200
>200
123.0
>200
132.4
>200
58.56
193.3
>200
143.0
>200
>200
161.5
137.2
>200
105.2
108.4
20.1
MDA-MB-231
121.0
>200
>200
>200
> 200
154.1
118.1
>200
78.67
>200
>200
> 200
>200
>200
> 200
172.6
>200
128.7
124.4
57.0
PC3
161.3
>200
>200
>200
> 200
>200
>200
>200
148.7
>200
>200
> 200
>200
>200
153.5
>200
>200
>200
>200
122.6
3aa
ba
ca
da
ea
fa
ga
3ha
ia
3ja
ka
3la
ma
3
3
3
3
3
3
3
3
3
3
na
oa
ab
3
3
3
ac
ad
3ae
af
3
3
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1
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1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
3
ag
3ah
ai
3aj
ak
al
am
>200
>200
>200
129.1
>200
>200
>200
>200
>200
>200
4.969
>200
>200
>200
>200
159.9
>200
>200
89.52
>200
>200
>200
70.40
>200
>200
>200
>200
>200
99.42
29.90
>200
>200
12.15
3
3
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
3
3
3
an
ao
ap
3
3
Cisplatin
3
. CONCLUSION
In summary, we have developed a versatile method for the synthesis of C6-substituted
isoquinolino[1,2-b]quinazolines via rhodium(III)-catalyzed C–H annulation with sulfoxonium
ylides. The reaction enables the most straightforward and convergent route to C6-substituted
isoquinolino[1,2-b]quinazolines reported to date. Further noteworthy features include high
atom economy, with H O and DMSO by-products, high efficiency and broad scope with
2
respect to both coupling components. Crucially, the potential of this approach for the
synthesis of new cytotoxic compounds has been demonstrated. The mono C6-substituted
isoquinolino[1,2-b]quinazolines show promising cytotoxic activity. Further investigation of the
synthesis and biological properties of this class and related quinazolines are underway.
EXPERIMENTAL SECTION
General Information. Unless otherwise noted, all reagents were obtained commercially
and used without further purification. Unless otherwise specified, all other reagents were
purchased from Aldrich, Fisher or Energy and used without further purification. The NMR
1
13
spectra were recorded on a Bruker MERCURY plus-400 (400 MHz, H NMR; 101 MHz, C NMR)
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spectrometer with chemical shifts reported in ppm relative to the residual deuterated solvent
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
1
and the internal standard tetramethylsilane (TMS). Data for H NMR are recorded as follows:
chemical shift (δ, ppm), multiplicity (s = singlet, d = doublet, t = triplet, m = multiplet or
unresolved, br = broad singlet, coupling constant(s) in Hz, integration). Chromatography was
carried out with silica gel (200-300 mesh) or neutral alumina (200-300 mesh) using mixtures
of petroleum ether (b.p. 60-90 °C) and ethyl acetate as eluents. High resolution mass spectra
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
(
HRMS) were measured with a Waters Micromass GCT instrument and accurate masses were
+
reported for the molecular ion [M+H] . The absorbance in each well was measured at 490 nm
using an Epoch microplate reader (BioTek, Winooski, VT, USA). The melting point was
determined by microscopic melting point meter SGW X-4B. 2-Arylquinazolin-4(3H)-ones (1)23
and sulfoxonium ylides (2)11c were prepared using well-established methods. All
Isoquinolino[1,2-b]quinazoline products 3 are new compounds unless stated otherwise.
General Procedure for Synthesis of sulfoxonium ylides (2). To a stirred solution of
KOt-Bu (12.0 mmol) in THF (10 mL) was added trimethylsulfoxonium iodide (9.0 mmol) and
the resulting mixture was refluxed for 3 h. The reaction mixture was then cooled to 0 °C,
followed by addition of acyl chloride (3.0 mmol) in THF (5 mL). The mixture was warm up to
room temperature and stirred for 3 h. Subsequently, the solvent was evaporated under
reduced pressure and the reaction mixture was extracted with EtOAc/H O three times. The
2
organic phase was dried over anhydrous Na SO and concentrated under reduced pressure.
2
4
The residue was pure by column chromatography using EtOAc/MeOH(95:5) to afford the
sulfoxonium ylides 2.
General Procedure for Synthesis of isoquinolino[1,2-b]quinazolinones. A pressure
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2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
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4
4
4
4
4
4
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5
6
tube was charged with 2-phenylquinazolin-4(3H)-one 1 (0.10 mmol, 1.0 equiv), sulfoxonium
ylide 2 (0.12 mmol, 1.2 equiv), [Cp*RhCl ] (0.004 mmol, 4 mol%), AgSbF (0.025 mmol, 25
2 2
6
mol%) and CH CN (0.05 M). The reaction mixture was stirred at 160 °C for 24 h. After cooling
3
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
to room temperature, the reaction mixture was filtered and volatiles were removed under
reduced pressure. The residue was purified by silica gel chromatography using petroleum
ether/ethyl acetate to afford the product.
Representative Procedure for Synthesis of Isoquinolino[1,2-b]quinazolinones. A
pressure tube was charged with 2-phenylquinazolin-4(3H)-one 1a (889.0 mg, 4.0 mmol, 1.0
equiv), sulfoxonium ylide 2a (942.1 mg, 4.8 mmol, 1.2 equiv), [Cp*RhCl ] (98.9 mg, 0.16 mmol,
2
2
4
mol%), AgSbF (343.6 mg, 1.0 mmol, 25 mol%) and CH CN (80 mL, 0.05 M). The reaction
6
3
mixture was stirred at 160 °C for 24 h. After cooling to room temperature, the reaction mixture
was filtered and volatiles were removed under reduced pressure. The residue was purified by
silica gel chromatography using petroleum ether/ethyl acetate to afford the product. Yellow
solid (940 mg). Yield 73%. Characterization data are included in the section below.
Physical Properties and Characterization Data of the Synthesized Compounds. 6-
Phenyl-8H-isoquinolino[1,2-b]quinazolin-8-one (3aa), yellow solid (27.4 mg, 85% yield). New
1
compound. Mp = 197 – 198 °C, H NMR (400 MHz, Chloroform-d) δ 9.09 (d, J = 7.6 Hz, 1H),
8.26 (d, J = 8.0 Hz, 1H), 7.96 (d, J = 7.9 Hz, 1H), 7.91 – 7.83 (m, 1H), 7.75 (t, J = 7.4 Hz, 1H), 7.68
13
(t, J = 7.6 Hz, 1H), 7.62 (d, J = 7.6 Hz, 1H), 7.51 – 7.39 (m, 6H), 6.92 (s, 1H). C{1H} NMR (101
MHz, Chloroform-d) δ 160.8, 147.6, 146.6, 138.3, 138.1, 134.5, 132.4, 132.2, 128.4, 128.0, 127.7
,
127.2, 127.1, 126.8, 126.5, 126.2, 125.7, 119.7, 118.1. HRMS (ESI/Q-TOF) m/z: [M+H]+
+
calculated for C H N O : 323.1179, found : 323.1175.
22 15
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3
-Methyl-6-phenyl-8H-isoquinolino[1,2-b]quinazolin-8-one (3ba), yellow solid (28.2 mg,
1
8
4% yield). New compound. Mp = 192 – 193 °C, H NMR (400 MHz, Chloroform-d) δ 8.87 (d,
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
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3
3
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5
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5
5
5
6
J = 8.2 Hz, 1H), 8.22 (d, J = 7.9 Hz, 1H), 7.93 – 7.74 (m, 2H), 7.51 – 7.31 (m, 8H), 6.79 (s, 1H),
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
13
2.51 (s, 3H). C{1H} NMR (101 MHz, Chloroform-d) δ 160.9, 147.8, 146.9, 143.0, 138.4, 138.1,
134.4, 132.4, 129.9, 128.0, 127.6, 127.2, 127.1, 126.7, 126.5, 126.1, 125.5, 124.9, 119.6, 118.1,
+
+
2
1.7. HRMS (ESI/Q-TOF) m/z: [M+H] calculated for C H N O : 337.1335, found : 337.1332.
23
17
2
3-Ethyl-6-phenyl-8H-isoquinolino[1,2-b]quinazolin-8-one (3ca), yellow solid (30.4 mg,
1
8
7% yield). New compound. Mp = 156 – 157 °C, H NMR (400 MHz, Chloroform-d) δ 8.81 (d,
J = 8.3 Hz, 1H), 8.19 (d, J = 7.9 Hz, 1H), 7.87 – 7.69 (m, 2H), 7.44 – 7.31 (m, 7H), 7.27 (s, 1H),
13
6
.74 (s, 1H), 2.73 (q, J = 7.6 Hz, 2H), 1.28 (t, J = 7.6 Hz, 3H). C{1H} NMR (101 MHz, Chloroform-
d) δ 160.9, 149.0, 147.7, 146.9, 138.5, 138.0, 134.5, 132.5, 128.8, 128.0, 127.7, 127.3, 127.1,
1
26.7, 126.1, 125.4, 125.2, 125.1, 119.6, 118.3, 28.9, 15.2. HRMS (ESI/Q-TOF) m/z: [M+H]+
+
calculated for C H N O : 351.1492, found : 351.1488.
24
19
2
3-Isopropyl-6-phenyl-8H-isoquinolino[1,2-b]quinazolin-8-one (3da), yellow solid (30.2
1
mg, 83% yield). New compound. Mp = 90 – 91 °C, H NMR (400 MHz, Chloroform-d) δ 8.88
(
(
d, J = 8.4 Hz, 1H), 8.21 (d, J = 8.6 Hz, 1H), 7.83 (d, J = 8.0 Hz, 1H), 7.81 – 7.74 (m, 1H), 7.48
dd, J = 8.4, 1.5 Hz, 1H), 7.38 (m, 7H), 6.82 (s, 1H), 3.05 (p, J = 6.9 Hz, 1H), 1.33 (d, J = 6.9 Hz,
13
6
H). C{1H} NMR (101 MHz, Chloroform-d) δ 160.9, 153.7, 147.8, 147.0, 138.5, 138.0, 134.4,
132.6, 128.0, 127.6, 127.5, 127.3, 127.1, 126.8, 126.1, 125.5, 125.3, 123.9, 119.6, 118.4, 34.3,
+
+
2
3.8. HRMS (ESI/Q-TOF) m/z: [M+H] calculated for C H N O : 365.1648, found : 365.1643.
25
21
2
3-(tert-Butyl)-6-phenyl-8H-isoquinolino[1,2-b]quinazolin-8-one(3ea), yellow solid (30.6
1
mg, 81% yield). New compound. Mp = 153 – 154 °C, H NMR (400 MHz, Chloroform-d) δ 8.97
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(
d, J = 8.6 Hz, 1H), 8.28 (d, J = 8.0 Hz, 1H), 8.01 – 7.84 (m, 2H), 7.74 (dd, J = 8.6, 1.5 Hz, 1H),
13
7
.66 – 7.59 (m, 1H), 7.54 – 7.39 (m, 6H), 6.93 (s, 1H), 1.47 (s, 9H). C{1H} NMR (101 MHz,
Chloroform-d) δ 160.9, 156.0, 147.7, 147.0, 138.5, 138.0, 134.4, 132.3, 127.9, 127.6, 127.1, 127.1,
0
1
2
3
4
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6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
126.8, 126.4, 126.1, 125.4, 125.0, 122.8, 119.7, 118.6, 35.2, 31.1. HRMS (ESI/Q-TOF) m/z:
+
+
[
M+H] calculated for C H N O : 379.1805, found : 379.1800.
26
23
2
3-Methoxy-6-phenyl-8H-isoquinolino[1,2-b]quinazolin-8-one (3fa), yellow solid (32.0
1
mg, 91% yield). New compound. Mp = 216 – 217 °C, H NMR (400 MHz, Chloroform-d) δ 8.95
(
d, J = 9.0 Hz, 1H), 8.24 (d, J = 7.8 Hz, 1H), 7.91 – 7.79 (m, 2H), 7.43 (m, 6H), 7.22 (dd, J = 9.0,
2.5 Hz, 1H), 7.00 (d, J = 2.4 Hz, 1H), 6.84 (s, 1H), 3.97 (s, 3H). 13C{1H} NMR (101 MHz,
Chloroform-d) δ 162.8, 160.9, 147.7, 147.1, 138.7, 138.3, 134.5, 134.3, 129.3, 128.0, 127.7, 127.1,
1
26.5, 126.1, 125.2, 120.7, 119.3 118.1, 117.3, 108.1, 55.6. HRMS (ESI/Q-TOF) m/z: [M+H]+
+
calculated for C H N O : 353.1285, found : 353.1280.
23 17
2
2
3-Fluoro-6-phenyl-8H-isoquinolino[1,2-b]quinazolin-8-one (3ga), yellow solid (27.9 mg,
1
82% yield). New compound. Mp = 208 – 209 °C, H NMR (400 MHz, Chloroform-d) δ 9.03 (dd,
J = 8.9, 5.6 Hz, 1H), 8.22 (d, J = 7.8 Hz, 1H), 7.84 (q, J = 8.5 Hz, 2H), 7.43 (m, 4H), 7.40 – 7.36
13
(
(
(
m, 2H), 7.32 (td, J = 8.7, 2.4 Hz, 1H), 7.22 (dd, J = 8.6, 2.4 Hz, 1H), 6.79 (s, 1H). C{1H} NMR
101 MHz, Chloroform-d) δ 166.4, 163.9, 160.7, 146.8 (d, J = 45.5 Hz), 139.5, 137.9, 134.7, 134.5
d, J = 10.0 Hz), 130.4 (d, J = 9.4 Hz), 128.1, 128.0, 127.1, 126.7, 126.1, 125.8, 123.7, 119.6, 117.1
(d, J = 2.9 Hz), 116.8 (d, J = 23.2 Hz), 111.9 (d, J = 22.4 Hz). HRMS (ESI/Q-TOF) m/z: [M+H]+
+
calculated for C H FN O : 341.1085, found : 341.1084.
22
14
2
3-Bromo-6-phenyl-8H-isoquinolino[1,2-b]quinazolin-8-one (3ha), yellow solid (23.2 mg,
1
5
8% yield). New compound. Mp = 271 – 272 °C, H NMR (400 MHz, Chloroform-d) δ 8.90 (d,
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J = 9.1 Hz, 1H), 8.25 (d, J = 7.9 Hz, 1H), 7.88 (q, J = 8.1 Hz, 2H), 7.75 (d, J = 7.7 Hz, 2H), 7.52 –
5
6
7
8
9
1
1
1
1
1
1
1
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1
1
2
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2
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2
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4
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5
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5
5
5
5
5
5
5
5
6
1
3
7
.43 (m, 4H), 7.43 – 7.38 (m, 2H), 6.79 (s, 1H). C{1H} NMR (101 MHz, Chloroform-d) δ 160.7,
1
47.2, 146.5, 146.5, 139.5, 137.8, 134.7, 133.8, 131.6, 129.0, 128.9, 128.1, 128.0, 127.2, 126.8,
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
+
+
126.1, 119.7, 116.6. HRMS (ESI/Q-TOF) m/z: [M+H] calculated for C H BrN O : 401.0284,
22
14
2
found : 401.0282.
6
-Phenyl-3-(trifluoromethoxy)-8H-isoquinolino[1,2-b]quinazolin-8-one (3ia), yellow
1
solid (25.2 mg, 62% yield). New compound. Mp = 203 – 204 °C, H NMR (400 MHz,
Chloroform-d) δ 8.99 (d, J = 8.9 Hz, 1H), 8.20 (d, J = 7.9 Hz, 1H), 7.80 (d, J = 5.8 Hz, 2H), 7.46
13
– 7.34 (m, 8H), 6.77 (s, 1H). C{1H} NMR(101 MHz, Chloroform-d) δ 160.6, 151.9, 146.7, 146.5,
1
1
4
39.7, 137.8, 136.5, 134.7, 134.0, 129.8, 128.1, 128.0, 127.1, 126.9, 126.1, 126.0, 125.6, 124.3,
+
+
20.4 (q, J = 260.0 Hz), 116.9. HRMS (ESI/Q-TOF) m/z: [M+H] calculated for C H F N O :
23
14 3
2
2
07.1002, found : 407.0995.
6
-Phenyl-3-(trifluoromethyl)-8H-isoquinolino[1,2-b]quinazolin-8-one (3ja), yellow solid
1
(21.8 mg, 56% yield). New compound. Mp = 243 – 244 °C, H NMR (400 MHz, Chloroform-d)
δ 9.11 (d, J = 8.3 Hz, 1H), 8.23 (d, J = 7.9 Hz, 1H), 7.92 – 7.79 (m, 4H), 7.52 – 7.36 (m, 6H), 6.87
13
(
(
(
s, 1H). C{1H} NMR (101 MHz, Chloroform-d) δ 160.6, 146.6, 146.3, 139.6, 137.7, 134.8, 133.7
q, J = 33.0 Hz), 132.4, 129.9, 128.2, 128.1, 127.2, 127.0, 126.5, 126.1, 124.4 (q, J = 3.3 Hz), 123.6
q, J = 273.8 Hz), 123.6 (q, J = 3.9 Hz), 120.0, 118.5, 117.0. HRMS (ESI/Q-TOF) m/z: [M+H]+
+
calculated for C H F N O : 391.1053, found : 391.1050.
23
14 3
2
2
-Methyl-6-phenyl-8H-isoquinolino[1,2-b]quinazolin-8-one (3ka), yellow solid (27.2 mg,
1
8
1% yield). New compound. Mp = 196 – 197 °C, H NMR (400 MHz, Chloroform-d) δ 8.82 (s,
1
H), 8.27 (d, J = 8.8 Hz, 1H), 7.90 (d, J = 8.1 Hz, 1H), 7.88 – 7.81 (m, 1H), 7.55 – 7.40 (m, 8H),
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2
2
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3
3
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3
3
3
3
3
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4
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5
5
5
5
5
5
5
6
1
3
6
.86 (d, J = 2.8 Hz, 1H), 2.60 (s, 3H). C{1H} NMR (101 MHz, Chloroform-d) δ 160.9, 147.7,
1
46.8, 138.7, 138.4, 137.1, 134.5, 133.6, 130.1, 128.0, 127.6, 127.1, 127.1, 126.9, 126.7, 126.5,
+
+
1
26.1, 125.7, 119.7, 118.1, 21.8. HRMS (ESI/Q-TOF) m/z: [M+H] calculated for C H N O :
23
17
2
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
337.1335, found : 337.1332.
2
-Methoxy-6-phenyl-8H-isoquinolino[1,2-b]quinazolin-8-one (3la) and 4-methoxy-6-
phenyl-8H-isoquinolino[1,2-b]quinazolin-8-one (3la’). 5.3:1 mixture of regioisomers. Yellow
1
solid (28.9 mg, 82% yield). Major isomer 3la: New compound. Mp = 203 – 204 °C, H NMR
(
400 MHz, Chloroform-d) δ 8.48 (d, J = 2.4 Hz, 1H), 8.29 (d, J = 7.7 Hz, 1H), 7.93 (d, J = 8.1 Hz,
1H), 7.89 – 7.83 (m, 1H), 7.54 (d, J = 8.6 Hz, 1H), 7.46 (m, 6H), 7.35 (d, J = 2.6 Hz, 1H), 6.88 (s,
13
1
H), 4.09 (s, 3H). C{1H} NMR (101 MHz, Chloroform-d) δ 161.0, 159.8, 147.4, 146.7, 138.5,
1
35.9, 134.4, 128.8, 128.1, 128.0, 127.5, 127.1, 126.8, 126.4, 126.2, 126.1, 125.7, 122.1, 119.7,
+
+
1
17.9, 108.1, 55.8. HRMS (ESI/Q-TOF) m/z: [M+H] calculated for C H N O : 353.1285,
23 17
2
2
found : 353.1284.
6-Phenyl-2-(trifluoromethyl)-8H-isoquinolino[1,2-b]quinazolin-8-one (3ma), yellow
1
solid (19.9 mg, 51% yield). New compound. Mp = 245 – 246 °C, H NMR (400 MHz,
Chloroform-d) δ 9.28 (s, 1H), 8.23 (d, J = 7.8 Hz, 1H), 7.88 (m, 3H), 7.67 (d, J = 8.1 Hz, 1H), 7.51
13
–
7.36 (m, 6H), 6.86 (s, 1H). C{1H} NMR(101 MHz, Chloroform-d) δ 160.6, 146.7, 146.3, 140.4,
1
37.7, 134.9, 134.8, 130.2 (q, J = 33.2 Hz), 128.3 (q, J = 3.5 Hz), 128.2, 128.1, 127.5, 127.1, 127.0,
126.4, 126.1, 124.8 (q, J = 4.2 Hz), 123.8 (q, J = 273.6 Hz), 119.9, 116.8. HRMS (ESI/Q-TOF) m/z:
+
+
[
M+H] calculated for C H F N O : 391.1053, found : 391.1049.
23
14 3
2
5
-Phenyl-7H-thieno[3',2':3,4]pyrido[2,1-b]quinazolin-7-one (3na), yellow solid (18.7 mg,
1
5
7% yield). New compound. Mp = 202 – 203 °C, H NMR (400 MHz, Chloroform-d) δ 8.24 (d,
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J = 8.2 Hz, 1H), 7.80 (m, 3H), 7.49 – 7.37 (m, 6H), 7.33 (d, J = 5.1 Hz, 1H), 7.03 (s, 1H). C{1H}
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
NMR (101 MHz, Chloroform-d) δ 160.8, 147.3, 145.5, 139.9, 139.7, 138.4, 134.7, 133.6, 133.0,
28.0, 127.8, 127.3, 126.4, 126.1, 125.0, 124.7, 118.8, 114.2. HRMS (ESI/Q-TOF) m/z: [M+H]+
1
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
+
calculated for C H N OS : 329.0743, found : 329.0742.
20
13
2
10-Chloro-6-phenyl-8H-isoquinolino[1,2-b]quinazolin-8-one (3oa), yellow solid (26.0
1
mg, 73% yield). New compound. Mp = 248 – 249 °C, H NMR (400 MHz, Chloroform-d) δ 9.03
(
d, J = 8.0 Hz, 1H), 8.23 (d, J = 2.4 Hz, 1H), 7.86 (d, J = 8.7 Hz, 1H), 7.81 – 7.74 (m, 2H), 7.72 –
13
7
.66 (m, 1H), 7.64 (d, J = 7.7 Hz, 1H), 7.50 – 7.40 (m, 5H), 6.94 (s, 1H). C{1H} NMR (101 MHz,
Chloroform-d) δ 159.9, 147.9, 145.3, 138.0, 134.9, 132.4, 131.2, 128.5, 128.5, 128.0, 127.8, 127.2,
+
+
1
26.6, 126.3, 126.1, 120.6, 118.4. HRMS (ESI/Q-TOF) m/z: [M+H] calculated for C H ClN O
22
14
2
:
357.0789, found : 357.0787.
6-(p-Tolyl)-8H-isoquinolino[1,2-b]quinazolin-8-one (3ab), yellow solid (26.9 mg, 80%
1
yield). New compound. Mp = 189 – 190 °C, H NMR (400 MHz, Chloroform-d) δ 9.02 (d, J =
8.0 Hz, 1H), 8.28 (d, J = 8.1 Hz, 1H), 7.90 (d, J = 8.1 Hz, 1H), 7.85 (dd, J = 8.2, 6.9 Hz, 1H), 7.70
(
dt, J = 7.6, 1.9 Hz, 1H), 7.67 – 7.61 (m, 1H), 7.58 (dd, J = 7.6, 2.8 Hz, 1H), 7.47 (t, J = 7.4 Hz,
H), 7.34 – 7.25 (m, 4H), 6.87 (d, J = 2.1 Hz, 1H), 2.46 (s, 3H). 13C{1H} NMR (101 MHz,
1
Chloroform-d) δ 161.0, 147.7, 146.8, 138.1, 137.5, 135.4, 134.5, 132.5, 132.2, 128.8, 128.3, 127.3,
27.2, 127.1, 126.8, 126.5, 126.0, 125.7, 119.8, 117.8, 21.4. HRMS (ESI/Q-TOF) m/z: [M+H]+
1
+
calculated for C H N O : 337.1335, found : 337.1334.
23
17
2
6-(4-Methoxyphenyl)-8H-isoquinolino[1,2-b]quinazolin-8-one (3ac), yellow solid (29.5
1
mg, 84% yield). New compound. Mp = 218 – 219 °C, H NMR (400 MHz, Chloroform-d) δ 9.03
(
d, J = 8.0 Hz, 1H), 8.27 (d, J = 7.8 Hz, 1H), 7.91 (d, J = 8.1 Hz, 1H), 7.85 (t, J = 7.6 Hz, 1H), 7.72
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(
(
t, J = 7.4 Hz, 1H), 7.64 (t, J = 7.5 Hz, 1H), 7.59 (d, J = 7.7 Hz, 1H), 7.47 (t, J = 7.7 Hz, 1H), 7.35
13
d, J = 8.6 Hz, 2H), 6.98 (d, J = 8.7 Hz, 2H), 6.86 (s, 1H), 3.89 (s, 3H). C{1H} NMR (101 MHz,
Chloroform-d) δ 161.0, 159.1, 147.8, 146.7, 137.8, 134.5, 132.5, 132.2, 130.7, 128.2, 127.3, 127.2,
0
1
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1
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3
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7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
+
127.1, 126.8, 126.4, 125.7, 119.8, 117.6, 113.5, 55.2. HRMS (ESI/Q-TOF) m/z: [M+H] calculated
+
for C H N O : 353.1285, found : 353.1285.
23
17
2
2
6-(4-Chlorophenyl)-8H-isoquinolino[1,2-b]quinazolin-8-one (3ad), yellow solid (30.3 mg,
1
8
5% yield). New compound. Mp = 224 – 225 °C, H NMR (400 MHz, Chloroform-d) δ 9.04 (d,
J = 8.0 Hz, 1H), 8.26 (d, J = 8.8 Hz, 1H), 7.92 (d, J = 7.8 Hz, 1H), 7.90 – 7.84 (m, 1H), 7.75 (td, J
= 7.5, 1.2 Hz, 1H), 7.71 – 7.65 (m, 1H), 7.62 (d, J = 7.7 Hz, 1H), 7.52 – 7.46 (m, 1H), 7.44 – 7.39
13
(
m, 2H), 7.37 – 7.32 (m, 2H), 6.87 (s, 1H). C{1H} NMR(101 MHz, Chloroform-d) δ 160.8, 147.5,
1
46.7, 136.8, 136.8, 134.7, 133.5, 132.4, 132.1, 128.7, 128.3, 127.4, 127.3, 127.1, 126.9, 126.6,
+
+
1
26.0, 119.6, 118.4. HRMS (ESI/Q-TOF) m/z: [M+H] calculated for C H ClN O : 357.0789,
22 14
2
found : 357.0789.
6-(4-Bromophenyl)-8H-isoquinolino[1,2-b]quinazolin-8-one (3ae), yellow solid (26.8 mg,
1
6
7% yield). New compound. Mp = 224 – 225 °C, H NMR (400 MHz, Chloroform-d) δ 9.01 (d,
J = 8.0 Hz, 1H), 8.25 (d, J = 8.0 Hz, 1H), 7.92 – 7.83 (m, 2H), 7.73 (t, J = 7.4 Hz, 1H), 7.66 (t, J =
13
7
.5 Hz, 1H), 7.62 – 7.54 (m, 3H), 7.51 – 7.45 (m, 1H), 7.31 – 7.25 (m, 2H), 6.85 (s, 1H). C{1H}
NMR (101 MHz, Chloroform-d) δ 160.8, 147.4, 146.7, 137.3, 136.8, 134.7, 132.3, 132.1, 131.2,
128.7, 127.7, 127.4, 127.2, 127.0, 126.9, 126.6, 125.9, 121.6, 119.5, 118.3. HRMS (ESI/Q-TOF)
+
+
m/z: [M+H] calculated for C H BrN O : 401.0284, found : 401.0281.
22
14
2
6-(4-(Trifluoromethyl)phenyl)-8H-isoquinolino[1,2-b]quinazolin-8-one (3af), yellow solid
1
(
30.4 mg, 78% yield). New compound. Mp = 215 – 216 °C, H NMR (400 MHz, Chloroform-d)
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δ 9.02 (d, J = 8.0 Hz, 1H), 8.22 (d, J = 8.0 Hz, 1H), 7.86 (m, 2H), 7.74 – 7.63 (m, 4H), 7.58 (d, J =
5
6
7
8
9
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1
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5
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5
6
1
3
7
.5 Hz, 1H), 7.47 (m, 3H), 6.85 (s, 1H). C{1H} NMR (101 MHz, Chloroform-d) δ 160.7, 147.3,
1
46.8, 141.9, 136.6, 134.7, 132.3, 131.9, 129.5 (q, J = 32.8 Hz), 128.9, 128.7, 127.6, 127.3, 127.0,
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
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6
7
8
9
0
1
2
3
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7
8
9
0
1
2
3
4
5
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7
8
9
0
1
2
3
4
5
6
7
8
9
0
126.7, 126.4, 126.0, 125.0 (q, J = 3.6 Hz), 124.1 (q, J = 273.1 Hz), 119.5, 118.8. HRMS (ESI/Q-
+
+
TOF) m/z: [M+H] calculated for C H F N O : 391.1053, found : 391.1055.
23
14 3
2
6
-(2-Methoxyphenyl)-8H-isoquinolino[1,2-b]quinazolin-8-one (3ag), yellow solid (29.9
1
mg, 85% yield). New compound. Mp = 200 – 201 °C, H NMR (400 MHz, Chloroform-d) δ 9.06
(
d, J = 7.9 Hz, 1H), 8.27 (d, J = 8.8 Hz, 1H), 7.90 (d, J = 8.0 Hz, 1H), 7.88 – 7.81 (m, 1H), 7.72 (t,
J = 7.3 Hz, 1H), 7.66 (t, J = 7.0 Hz, 1H), 7.63 – 7.55 (m, 2H), 7.49 – 7.41 (m, 2H), 7.15 (t, J = 7.4
1
3
Hz, 1H), 6.95 – 6.86 (m, 2H), 3.57 (s, 3H). C{1H} NMR (101 MHz, Chloroform-d) δ 160.6, 155.8,
1
47.3, 146.8, 136.0, 134.2, 132.6, 132.0, 129.3, 128.3, 127.9, 127.6, 127.6, 127.2, 126.9, 126.8,
+
1
26.4, 125.5, 120.6, 119.5, 117.7, 109.7, 55.3. HRMS (ESI/Q-TOF) m/z: [M+H] calculated for
+
C H N O : 353.1285, found : 353.1285.
23
17
2
2
6-(2-Fluorophenyl)-8H-isoquinolino[1,2-b]quinazolin-8-one (3ah), yellow solid (27.5 mg,
1
8
1% yield). New compound. Mp = 174 – 175 °C, H NMR (400 MHz, Chloroform-d) δ 9.07 (d,
J = 7.9 Hz, 1H), 8.30 (d, J = 8.0 Hz, 1H), 7.91 (d, J = 8.1 Hz, 1H), 7.88 – 7.82 (m, 1H), 7.73 (t, J =
7
.3 Hz, 1H), 7.68 (t, J = 7.6 Hz, 1H), 7.63 – 7.54 (m, 2H), 7.45 (m, 2H), 7.32 (d, J = 7.5 Hz, 1H),
13
7
.14 – 7.07 (m, 1H), 6.91 (s, 1H). C{1H} NMR (101 MHz, Chloroform-d) δ 160.7, 160.0, 157.5,
146.8 (d, J = 31.5 Hz), 134.6, 132.8, 132.2, 132.0, 129.6 (d, J = 8.2 Hz), 128.8, 128.1 (d, J = 3.2
Hz), 127.7, 127.4, 127.2, 126.9, 126.8, 126.5, 125.9, 124.0 (d, J = 3.4 Hz), 119.2, 118.8, 114.7 (d,
+
+
J = 21.3 Hz). HRMS (ESI/Q-TOF) m/z: [M+H] calculated for C H FN O : 341.1085, found :
22
14
2
341.1082.
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6
-(m-Tolyl)-8H-isoquinolino[1,2-b]quinazolin-8-one (3ai), yellow solid (28.5 mg, 85%
1
yield). New compound. Mp = 168 – 169 °C, H NMR (400 MHz, Chloroform-d) δ 9.02 (dd, J =
7
.7, 4.0 Hz, 1H), 8.28 (d, J = 7.4 Hz, 1H), 7.90 (d, J = 8.2 Hz, 1H), 7.85 (dt, J = 8.2, 4.1 Hz, 1H),
0
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2
3
4
5
6
7
8
9
0
1
2
3
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6
7
8
9
0
1
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8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
7.70 (t, J = 7.0 Hz, 1H), 7.68 – 7.62 (m, 1H), 7.58 (t, J = 7.1 Hz, 1H), 7.47 (t, J = 7.4 Hz, 1H), 7.36
(
d, J = 7.6 Hz, 1H), 7.31 – 7.23 (m, 2H), 7.19 (d, J = 7.5 Hz, 1H), 6.88 (d, J = 5.1 Hz, 1H), 2.46 (s,
13
3
H). C{1H} NMR (101 MHz, Chloroform-d) δ 160.9, 147.7, 146.8, 138.3, 138.2, 137.7, 134.5,
1
32.4, 132.2, 128.6, 128.3, 127.9, 127.3, 127.2, 127.1, 126.8, 126.7, 126.5, 125.7, 123.3, 119.8,
+
+
1
17.9, 21.6. HRMS (ESI/Q-TOF) m/z: [M+H] calculated for C H N O : 337.1335, found :
23
17
2
337.1335.
6-(3-Chlorophenyl)-8H-isoquinolino[1,2-b]quinazolin-8-one (3aj), yellow solid (28.1 mg,
1
7
9% yield). New compound. Mp = 200 – 201 °C, H NMR (400 MHz, Chloroform-d) δ 9.03 (d,
J = 8.0 Hz, 1H), 8.26 (d, J = 8.0 Hz, 1H), 7.93 – 7.84 (m, 2H), 7.77 – 7.70 (m, 1H), 7.71 – 7.64 (m,
H), 7.61 (d, J = 7.6 Hz, 1H), 7.52 – 7.46 (m, 1H), 7.44 (s, 1H), 7.37 (q, J = 7.9 Hz, 2H), 7.29 –
1
13
7.23 (m, 1H), 6.88 (s, 1H). C{1H} NMR (101 MHz, Chloroform-d) δ 160.7, 147.4, 146.7, 140.0,
1
1
3
36.5, 134.7, 134.0, 132.4, 132.0, 129.2, 128.8, 127.7, 127.4, 127.3, 127.1, 126.9, 126.6, 126.1,
+
+
26.0, 124.5, 119.6, 118.5. HRMS (ESI/Q-TOF) m/z: [M+H] calculated for C H ClN O :
22
14
2
57.0789, found : 357.0790.
6-(3-(Trifluoromethyl)phenyl)-8H-isoquinolino[1,2-b]quinazolin-8-one (3ak), yellow
1
solid (28.1 mg, 79% yield). New compound. Mp = 194 – 195 °C, H NMR (400 MHz,
Chloroform-d) δ 9.04 (d, J = 8.0 Hz, 1H), 8.24 (d, J = 8.0 Hz, 1H), 7.89 (m, 2H), 7.77 – 7.65 (m,
13
4
H), 7.62 (d, J = 7.6 Hz, 1H), 7.55 (d, J = 6.0 Hz, 2H), 7.49 (t, J = 7.3 Hz, 1H), 6.89 (s, 1H). C{1H}
NMR (101 MHz, Chloroform-d) δ 160.7, 147.3, 146.7, 139.1, 136.4, 134.7, 132.4, 132.0, 130.5
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(
q. J = 32.5 Hz), 129.5, 128.9, 128.3, 127.5, 127.3, 127.0, 127.0, 126.7, 126.0, 124.3 (q, J = 3.7
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
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5
5
5
5
5
5
5
5
6
Hz), 124.0 (q, J = 273.6 Hz), 122.8 (q, J = 3.7 Hz), 119.5, 118.8. HRMS (ESI/Q-TOF) m/z: [M+H]+
+
calculated for C H F N O : 391.1053, found : 391.1055.
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0
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8
9
0
6-(Thiophen-3-yl)-8H-isoquinolino[1,2-b]quinazolin-8-one (3al), yellow solid (25.2 mg,
1
7
7% yield). New compound. Mp = 188 – 189 °C, H NMR (400 MHz, Chloroform-d) δ 8.99 (d,
J = 8.0 Hz, 1H), 8.29 (d, J = 7.9 Hz, 1H), 7.92 – 7.80 (m, 2H), 7.74 – 7.67 (m, 1H), 7.64 (t, J = 7.6
Hz, 1H), 7.57 (d, J = 7.6 Hz, 1H), 7.48 (t, J = 7.3 Hz, 1H), 7.42 (d, J = 4.9 Hz, 1H), 7.16 – 7.08 (m,
13
2
H), 7.03 (s, 1H). C{1H} NMR (101 MHz, Chloroform-d) δ 160.7, 147.4, 146.5, 139.7, 134.5,
132.2, 132.0, 131.1, 128.7, 127.3, 127.6, 127.1, 126.8, 126.6, 126.6, 125.9, 125.5, 125.3, 119.9,
+
+
1
19.2. HRMS (ESI/Q-TOF) m/z: [M+H] calculated for C H N OS : 329.0743, found :
20
13
2
329.0741.
6-(Furan-3-yl)-8H-isoquinolino[1,2-b]quinazolin-8-one (3am), yellow solid (25.3 mg, 81%
1
yield). New compound. Mp = 166 – 167 °C, H NMR (400 MHz, Chloroform-d) δ 9.03 (d, J =
7.9 Hz, 1H), 8.34 (d, J = 8.0 Hz, 1H), 7.93 – 7.82 (m, 2H), 7.73 (t, J = 7.2 Hz, 1H), 7.67 (t, J = 7.3
Hz, 1H), 7.61 (d, J = 7.6 Hz, 1H), 7.55 (s, 1H), 7.49 (t, J = 7.4 Hz, 1H), 7.09 (s, 1H), 6.65 (d, J =
13
3
.3 Hz, 1H), 6.57 (dd, J = 3.0, 1.9 Hz, 1H). C{1H} NMR (101 MHz, Chloroform-d) δ 160.5, 150.6,
147.1, 146.6, 142.5, 134.6, 132.2, 131.9, 128.9, 128.0, 127.5, 127.4, 127.2, 126.9, 126.7, 125.9,
+
+
1
19.6, 118.3, 111.0, 107.4. HRMS (ESI/Q-TOF) m/z: [M+H] calculated for C H N O
:
20
13
2
2
313.0972, found : 313.0970.
6-(Naphthalen-2-yl)-8H-isoquinolino[1,2-b]quinazolin-8-one (3an), yellow solid (20.0
1
mg, 54% yield). New compound. Mp = 216 – 217 °C, H NMR (400 MHz, Chloroform-d) δ 9.11
(
d, J = 7.7 Hz, 1H), 8.25 (d, J = 8.8 Hz, 1H), 7.98 (d, J = 13.1 Hz, 2H), 7.94 – 7.84 (m, 4H), 7.79 –
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2
2
2
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7
.73 (m, 1H), 7.72 – 7.67 (m, 1H), 7.64 (d, J = 7.6 Hz, 1H), 7.57 – 7.52 (m, 2H), 7.48 (t, J = 7.5
13
Hz, 1H), 7.42 (dd, J = 8.5, 1.7 Hz, 1H), 7.02 (s, 1H). C{1H} NMR (101 MHz, Chloroform-d) δ
60.8, 147.7, 138.0, 136.0, 134.7, 133.1, 132.7, 132.5, 132.5, 128.6, 128.2, 127.8, 127.4, 127.3,
127.2, 126.7, 126.6, 126.4, 126.2, 125.9, 124.8, 124.2, 119.6, 118.6. HRMS (ESI/Q-TOF) m/z:
1
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
+
+
[
M+H] calculated for C H N O : 373.1335, found : 373.1335.
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6-Cyclohexyl-8H-isoquinolino[1,2-b]quinazolin-8-one (3ao), yellow solid (22.3 mg, 68%
1
yield). New compound. Mp = 159 – 160 °C, H NMR (400 MHz, Chloroform-d) δ 8.90 (d, J =
8.0 Hz, 1H), 8.37 (d, J = 8.0 Hz, 1H), 7.92 – 7.74 (m, 2H), 7.69 – 7.61 (m, 1H), 7.59 – 7.45 (m,
3H), 6.84 (d, J = 2.8 Hz, 1H), 4.01 (tt, J = 11.3, 2.7 Hz, 1H), 2.15 (d, J = 12.0 Hz, 2H), 1.93 – 1.76
13
(
m, 3H), 1.61 – 1.45 (m, 2H), 1.39 – 1.23 (m, 3H). C{1H} NMR (101 MHz, Chloroform-d) δ
1
1
62.7, 148.0, 146.5, 146.1, 134.3, 132.7, 131.9, 127.6, 127.1, 126.8, 126.9, 126.6, 125.8, 125.5,
+
+
20.2, 112.1, 39.5, 33.8, 26.7, 26.4. HRMS (ESI/Q-TOF) m/z: [M+H] calculated for C H N O
22 21
2
:
329.1648, found : 329.1650.
6-Benzyl-8H-isoquinolino[1,2-b]quinazolin-8-one (3ap), yellow solid (24.9 mg, 74%
1
yield). New compound. Mp = 127 – 128 °C, H NMR (400 MHz, Chloroform-d) δ 8.96 (d, J =
8.0 Hz, 1H), 8.28 (d, J = 8.0 Hz, 1H), 7.80 (d, J = 5.8 Hz, 2H), 7.72 – 7.63 (m, 1H), 7.59 (t, J = 7.0
13
Hz, 1H), 7.53 – 7.40 (m, 2H), 7.30 – 7.17 (m, 5H), 6.69 (s, 1H), 4.78 (s, 2H). C{1H} NMR (101
MHz, Chloroform-d) δ 162.1, 147.8, 146.4, 139.1, 138.5, 134.3, 132.4, 132.0, 129.0, 128.4, 128.0,
127.3, 127.3, 126.9, 126.7, 126.5, 125.8, 125.6, 120.0, 116.7, 41.3. HRMS (ESI/Q-TOF) m/z:
+
+
[
M+H] calculated for C H N O : 337.1335, found : 337.1335.
23
17
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ASSOCIATED CONTENT
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1H and 13 C NMR spectra. MTT assay and mechanistic studies. This material is available
free of charge via the Internet at http://pubs.acs.org.
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AUTHOR INFORMATION
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Corresponding Author
zhangjin@sust.edu.cn
mym63@sina.com
michal.szostak@rutgers.edu
Author Contributions
§These authors contributed equally to this work.
ACKNOWLEDGMENT
J.Z. thanks the China Scholarship Council (No. 201808610096). Financial support was
provided by the Foundation for Young Scholars of Shaanxi University of Science and
Technology (No. BJ12-26). M.S. thanks Rutgers University and the NSF (CAREER CHE-
1650766).
REFERENCES
(
1) (a) Mhaske, S. B.; Argade, N. P. The Chemistry of Recently Isolated Naturally Occurring
Quinazolinone Alkaloids. Tetrahedron 2006, 62, 9787-9826. (b) Khan, I.; Ibrar, A.; Abbas, N.;
Saeed, A. Recent Advances in the Structural Library of Functionalized Quinazoline and
Quinazolinone Scaffolds. Synthetic Approaches and Multifarious Applications. Eur. J. Med.
Chem. 2014, 76, 193-244. (c) Kshirsagar, U. A. Recent Developments in the Chemistry of
Quinazolinone Alkaloids. Org. Biomol. Chem. 2015, 13, 9336-9352.
(
2) (a) Rakesh, K. P.; Kumara, H. K.; Manukumar, H. M.; Gowda, D. C. Anticancer and DNA
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