Copper-catalyzed C-O bond cleavage and cyclization: synthesis of indazolo[3,2-b]quinazolinones

Article abstract of DOI:10.1039/C6OB02352E

The first example of a copper-catalyzed halogen-free protocol to construct indazolo[3,2-b]quinazolinones was developed through sequential inert C-O bond cleavage followed by intramolecular C-N bond formation. This protocol represents an efficient synthetic tool for accessing a more diverse range of functionalized indazolo[3,2-b]quinazolinones. The structure of the newly synthesized indazolo[3,2-b]quinazolinones was unambiguously confirmed by X-ray crystal diffraction analysis.

Full text of DOI:10.1039/C6OB02352E

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Copper-Catalyzed C-O Bond Cleavage and Cyclization: Synthesis of
Indazolo[3,2-b]quinazolinones
†
3Received 00th January 20xx,
Accepted 00th January 20xx
Rui Qiao,a Leping Ye,b Kun Hu,a Shuling Yu,a Weiguang Yang,a Miaochang Liu,a Jiuxi Chen,*a
Jinchang Dinga and Huayue Wu*a
DOI: 10.1039/x0xx00000x
The first example of copper-catalyzed halogen-free protocol to construct indazolo[3,2-b]quinazolinones was developed
through sequential inert C-O bond cleavage followed by an intramolecular C-N bond formation. This protocol represents
an efficient synthetic tool for accessing a more diverse array of functionalized indazolo[3,2-b]quinazolinones. The structure
of the newly synthesized indazolo[3,2-b]quinazolinones was unambiguously confirmed by X-ray crystal diffraction analysis.
www.rsc.org/
interest.12 On the other hand, palladium catalyst is very expensive
compared with the corresponding copper catalyst. This work forms
part of the continuing efforts in our laboratory toward the
development of new methods for copper-catalyzed chemistry13 and
the synthesis of quinazolinone derivatives.14 we herein report a
novel halogen-free copper-catalyzed intramolecular cross-coupling
reactions of quinazolinone-based aromatic ethers by the cleavage
of inert C−O bond and cyclizaꢀon event to afford indazolo[3,2-
b]quinazolinone derivatives (Scheme 1c). Facile access to such ring
systems which possess diverse functional groups would be of high
value to both synthetic and medicinal chemistry.
Introduction
As an important class of nitrogen-containing heterocycles, fused
quinazolinone polyheterocycles have been shown to be an
important class of alkaloids, such as luotonin A,1 cruciferane,2
circumdatins,3 rutaecarpine,4 vasicinone,5 and tryptanthrin,6 etc.
In particular, the combined molecules of indazole and
quinazolinone skeletons, indazolo[3,2-b]quinazolinones, are
important biological molecules and potent inhibitors of
phosphodiesterase
4
(PDE4).7 Furthermore, indazolo[3,2-
a promising new class of small-molecule
b]quinazoline is
fluorophores.8 Recently, we have demonstrated that indazolo[3,2-
b]quinazolinones could act as anti-tumor agents in hepatocellular
carcinoma cell line, probably through inhibiting the cytoprotective
aspect of the Nrf2/ARE signaling pathway and inducing apoptosis via
inflicting injury to the mitochondria.9 However, the synthesis of
indazolo[3,2-b]quinazolinones are still rarely been investigated. To
the best of our knowledge, only two different types of model
reaction have been developed leading to indazolo[3,2-
b]quinazolinones.7,10-11 First, Pal,7 Wang,10a and our group10b have
independently reported the classic methods for the preparation of
indazolo[3,2-b]quinazolinone derivatives by transition-metal-
catalyzed cross-coupling reactions of halogenated substrates via the
C-X (X = I, Br or Cl) bond cleavage (Scheme 1a). Second, we recently
(a) Synthesis of indazolo[3,2-b]quinazolinones via C-X bond cleavage
O
R
O
R
NH
N
N
[Pd] or [Cu]; X = I, Br, Cl
ref. 7, 10
N
X
R1
R1
R2
N
N
R2
(b) Pd-catalyzed synthesis of indazolo[3,2-b]quinazolinones via C-H amination
R
O
N
O
N
R
NH
N
N
N
[Pd]
H
R1
R1
R2
ref. 11
R2
our prev ious works
(c) Cu-catalyzed synthesis of indazolo[3,2-b]quinazolinones via C-O bond cleavage
reported
palladium-catalyzed
synthesis
of
indazolo[3,2-
O
R
O
N
R
b]quinazolinones involving intramolecular aerobic oxidative C-H
amination of 2-aryl-3-(arylamino)quinazolinones (Scheme 1b).11
In recent years, the use of phenol derivates as aryl C(sp2)−O
electrophiles in cross-coupling reactions have attracted broad
NH
N
N
This work
OMe
N
R1
R1
N
halogen-free
Scheme 1 Strategies for the Synthesis of Indazolo[3,2-b]quinazolinones.
Results and discussion
The study was initiated by examining the conversion of 2-(2-
methoxyphenyl)-3-(phenylamino)quinazolinone (1a) into 5-
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phenylindazolo[3,2-b]quinazolinone (2a) using copper catalysis yield under nitrogen or oxygen atmosphere (Table 1, entries 15-16).
(Table 1).
Trace or no desired product was observed if either copper catalyst
or base was absent (Table 1, entries 17-18).
Table 1 Optimization of the reaction conditionsa
Scheme 2 X-ray crystal structure of 5-phenylindazolo[3,2-b]quinazolinone (2a).
Having the optimized reaction conditions in hand, we next
examined
a
series of 2-(2-methoxyphenyl)-3-(phenylamino)
quinazolinone derivatives containing inert C-O bonds to explore the
scope of the cross-coupling reaction (Table 2).
Table 2 Synthesis of indazolo[3,2-b]quinazolinone derivativesa
O
R
O
R
N
NH
Cu(OAc)2, tBuOK
N
R1
N
R1
o
MS 4A, DMA, 120 oC, 48 h
N
N
MeO
1
2
(1)
(2)
(3)
(4)
Me
Me
O
N
O
O
N
O
Me
N
N
N
N
N
N
N
N
N
N
2a (91%)
2b (85%)
2c (83%)
2d (70%)
(5)
(6)
(7)
(8)
F
CF3
Cl
OMe
a
Unless otherwise noted, the reaction conditions were as follows: 1a (0.2
O
O
O
O
N
N
N
N
N
N
N
N
mmol), Cu catalyst (0.04 mmol), base (0.2 mmol), MS 4 Å (60 mg) and
b
c
solvent (5 mL), air, 120 oC, 48 h. Isolated yield. without MS 4 Å. dUnder
N
N
N
N
O2 atmosphere. eUnder N2 atmosphere.
2f (57%)
2g (61%)
NRb
2e (79%)
(9)
(10)
(11)
(12)
Me
After an initial screen using Cu(OAc)2 as a catalysts with different
bases and solvents, we were delighted to find that the desired
product 5-phenylindazolo[3,2-b]quinazolinone (2a) was isolated in
43% yield when Cu(OAc)2 was used in combination with cesium
carbonate in DMF (Table 1, entry 1). It is noteworthy that the
structure of 2a was unambiguously confirmed by an X-ray single-
crystal diffraction analysis (Scheme 2).15 The yield of 2a was
increased to 60% with 4 Å molecular sieves as an additive.
Encouraged by this promising result, we further evaluated other
reaction parameters in order to obtain more satisfactory results.
First, we evaluated various bases and found a promising result that
the yield of 2a was increased to 79% when employing Cu(OAc)2 and
potassium tert-butanolate as base in DMF (Table 1, entry 4). Other
bases, including Cs2CO3, K2CO3, NaHCO3, DABCO and NaOH, were
less efficient (Table 1, entries 1−5). An investigation of the effect of
solvent (Table 1, entries 6-9) revealed that the use of
dimethylacetamide (DMA) as solvent achieved the best result (91%,
Table 1, entry 7). Among the copper sources evaluated, Cu(OAc)2
exhibited the highest catalytic reactivity with 91% yield (Table 1,
entries 5 and 10-14). In addition, the reaction failed to improve the
Cl
Me
O
O
N
N
Ph
N
Ph
N
O
O
Cl
N
N
N
N
N
N
N
N
2h (59%)
2i (48%)
2j (78%)
2k (76%)
(13)
(14)
(15)
F
(16)
O
O
N
N
Ph
N
O
N
N
Cl
O
Ph
N
Ph
N
Ph
N
N
N
N
Me
N
Me
2l (75%)
2m (45%)
2n (61%)
2o (66%)
(17)
Cl
(18)
(19)
(20)
O2N
O
N
N
O
N
N
O
O
N
N
Ph
N
Ph
N
Ph
N
Ph
N
MeO
N
Cl
N
2p (71%)
2q (24%)
NRb
NRb
a
Unless otherwise noted, the reaction conditions were as follows: 1 (0.2
mmol), Cu(OAc)2 (0.04 mmol), tBuOK (0.2 mmol), MS 4 Å (60 mg), and
DMA (5 mL), air, 120 oC, 48 h. Isolated yield. b NR = no reaction.
First, the influence of substitutions on the N-aryl ring moiety of
the
2-(2-methoxyphenyl)-3-(phenylamino)quinazolinone
was
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investigated. The monosubstituent positions at the N-aryl ring
To elucidate the reaction mechanism of the formation of
moiety were evaluated, and the results demonstrated that steric indazolo[3,2-b]quinazolinones, some control experiments were
effects of substituents had little effects on the reaction. For performed under the standard conditions as shown in Scheme 3.
example, when substrates bearing a para-, meta-, and ortho-methyl The
reaction
of
2-(2-methoxyphenyl)-3-(phenylamino)-2,3-
group were examined, the corresponding desired indazolo[3,2- dihydroquinazolin-4(1H)-one (3) failed to deliver 5-phenyl-12,12a-
b]quinazolinones 2b, 2c and 2d were obtained in 85%, 83% and 70% dihydroindazolo[3,2-b]quinazolin-7(5H)-one (4) along with product
yield respectively (Table 2, entries 2-4). The same phenomena were 2a in 11% yield (Scheme 3a). However, the product 6 could not be
observed using substrates bearing a para-, meta-, and ortho-chloro detected when 2-(2-methoxyphenyl)-1-methyl-3-(phenylamino)-
group (Table 2, entries 7 and 9-10). The electronic properties of the 2,3-dihydroquinazolin-4(1H)-one (5) was used as the substrate
substituents on the N-aryl ring moiety affected the yields to some under the standard conditions; almost 90% of 5 was recovered
extent. In general, the N-aryl ring moiety bearing an electron- (Scheme 3b). The reaction failed to deliver the desired product 2a
donating substituent (e.g., −Me) generally produced a higher yield under the same reaction conditions when 2-phenyl-3-
than those analogues bearing an electron-withdrawing substituent (phenylamino)quinazolin-4(3H)-one (7) was used (Scheme 3c).
(e.g., −F, −Cl, and −CF3) (Table 2, entries 2 and 5-7). However, the
reaction failed to deliver the desired product under the same
reaction
conditions
when
2-(2-methoxyphenyl)-3-((4-
methoxyphenyl)amino)quinazolin-4(3H)-one was used (Table 2,
entry 8).
Next, we turned our attention to study the effect of the various
groups (e.g., R1 = Me, F, Cl, OMe and NO2) of substrates (Table 2,
entries 11-20). First, the steric effects of substituents had an
obvious impact on the efficiency of this transformation. For
example, when substrates bearing a methyl group were examined,
corresponding desired indazolo[3,2-b]quinazolinones 2j, 2k, and 2l
were obtained in 78%, 76% and 75% yield respectively (Table 2,
entries 11-13), while the yield of 2m possessing an ortho-methyl
group was decreased to 45% (Table 2, entry 14). The electronic
properties of groups R1 on the phenyl ring had some effects on the
reaction. Both electron-donating (e.g., −Me) and electron-
withdrawing (e.g., −F and −Cl) subsꢀtuents were tolerated in the
reaction. Generally, substrates with an electron-donating
substituent on the aryl group gave a slightly higher yield of addition
products than those analogues bearing an electron-withdrawing
substituent (Table 2, entries 15-18). The reaction worked well with
the substrates containing the chloro group (commonly used for
cross-coupling reactions) and to afford the corresponding products,
leading to a useful handle for further cross-coupling reactions
(Table 2, entries 7, 9-11 and 16-18). However, the reaction did not
work under the same reaction conditions when substrates bearing
methoxy or nitro group was used (Table 2, entries 19-20).
Scheme
b]quinazolinones.
4
Possible mechanism for the formation of Indazolo[3,2-
On the basis of the above experimental results and relevant
reports in the literature,12,16
a possible mechanism for the
formation of indazolo[3,2-b]quinazolinones is proposed in Scheme 4.
First, the active Cu(I) species can be initially formed through either
the reduction of Cu(II) by the nucleophile or the disproportionation
of Cu(II). Then, the oxidative addition of the 2-(2-methoxyphenyl)-3-
(phenylamino)quinazolinones (1) to the Cu(I) salt would generate
the key C-O insertion Cu(III) intermediate A that can undergo a
“rollover” cyclometalation17 with increasing temperature to afford
six-membered intermediate B by intramolecular ligand exchange
with H-N(Ph)-quinazolinone. Finally, the reductive elimination of
intermediate B along with the C−N bond formaꢀon affords the
indazolo[3,2-b]quinazolinones (2) and regenerates the Cu(I) catalyst.
O
Ph
O
O
N
Ph
Ph
NH
N
Cu(OAc)2, tBuOK
N
N
N
N
(a)
+
o
N
H
MeO
MS 4A, DMA
N
H
However,
a detailed mechanism of the formation of the
3
4
2a
, 11%
, not detected
indazolo[3,2-b]quinazolinones remain unclear at the current stage.
O
N
Ph
O
N
Ph
N
NH
Cu(OAc)2, tBuOK
N
(b)
(c)
N
o
Me
MS 4A, DMA
Conclusions
Me
MeO
5
6
In summary, we have developed an alternative synthetic pathway
to access indazolo[3,2-b]quinazolinones by copper-catalyzed the
inert C-O bond cleavage and intramolecular C-N bond formation
reaction of 2-(2-methoxyphenyl)-3-(arylamino)quinazolinones.
Further efforts to explore the detailed mechanism and extend the
applications of quinazolinone as a directing group are now being
undertaken in our laboratory.
O
Ph
O
Ph
N
NH
Cu(OAc)2, tBuOK
N
N
o
N
MS 4A, DMA
N
7
2a
Scheme 3 Control experiments.
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5-(o-Tolyl)indazolo[3,2-b]quinazolin-7(5H)-one (2d). White
solid, mp 228-229 oC; 1H NMR (500 MHz, CDCl3) δ 8.32-8.29
(m, 2H), 7.91 (d, J = 8.0 Hz, 1H) 7.82-7.79 (m, 1H), 7.63-7.60
(m, 1H), 7.46-7.34 (m, 4H), 7.20 (t, J = 7.0 Hz, 1H), 6.94 (t, J =
8.5 Hz, 2H), 2.47 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 161.4,
157.0, 147.6, 144.0, 134.8, 131.4, 130.5, 129.7, 128.2, 127.8,
127.2, 127.1, 126.9, 124.2, 123.6, 121.8, 121.6, 120.9, 120.1,
110.6, 22.0.
Experimental section
General Methods
All commercial reagents were used without further
purification unless otherwise noted. Melting points are
uncorrected. 1H NMR and 13C NMR spectra were measured on
a 500 MHz spectrometer using DMSO-d6 or CDCl3 as the
solvent with tetramethylsilane (TMS) as an internal standard at
room temperature. Chemical shifts are given in δ relative to
TMS, and the coupling constants J are given in hertz. High-
resolution mass spectrometry (HRMS) was performed with a
TOF MS instrument with an EI or ESI source. 2-(2-
5-(4-Fluorophenyl)indazolo[3,2-b]quinazolin-7(5H)-one (2e).
White solid, mp 194-195 oC; 1H NMR (500 MHz, CDCl3 ) δ 8.32-
8.28 (m, 2H), 7.91 (d, J = 8.0 Hz, 1H), 7.84-7.80 (m, 1H), 7.64 (t,
J = 7.0 Hz, 1H), 7.48-7.42 (m, 2H), 7.38-7.35 (m, 2H), 7.18-7.13
(m, 3H); 13C NMR (125 MHz, DCCl3) δ 156.6, 149.4, 148.8,
148.2, 138.0, 134.2, 133.6, 128.8, 127.2, 126.8, 125.6, 124.6,
123.4, 120.0, 119.0, 116.7, 116.6, 112.5.
Methoxyphenyl)-3-(arylamino)quinazolinones
were
synthesized according to the literature procedures.18 Other
commercially obtained reagents were used without further
purification. Column chromatography was performed using EM
silica gel 60 (300−400 mesh).
5-(4-(Trifluoromethyl)phenyl)indazolo[3,2-b]quinazolin-
7(5H)-one (2f). White solid, mp 215-216 oC; 1H NMR (500 MHz,
DMSO-d6) δ 8.34-8.30 (m, 2H), 7.93 (d, J = 8.0 Hz, 1H), 7.86-
7.83 (m, 1H), 7.75 (d, J = 8.5 Hz, 2H), 7.67-7.64 (m, 1H), 7.52-
7.45 (m, 4H), 7.24 (s, 1H); 13C NMR (125 MHz, DMSO-d6) δ
156.3, 148.2, 147.7, 147.4, 144.9, 134.2, 134.0, 128.0, 127.0,
126.4, 126.0, 125.5, 125.1, 124.3, 124.0, 123.1, 119.4, 118.7,
112.2 .
General procedure for copper-catalyzed synthesis of indazolo[3,2-
b]quinazolinones (2a-2q)
In a 25 mL sealed tube, 2-(2-methoxyphenyl)-3-(phenylamino)-
quinazolinones (0.2 mmol, 1.0 equiv), Cu(OAc)2 (0.04 mmol, 20
mol %), tBuOK (0.2 mmol, 1.0 equiv) and MS 4Å (60 mg), were
dissolved in DMA (5 mL). The reaction mixture was then tightly
capped and stirred for 10 minutes at room temperature for
proper mixing of the reactants, and then heated at 120 °C with
vigorous stirring for 48 hours. The reaction mixture was then
cooled to room temperature, diluted with dichloromethane
and filtered through a small pad of Celite. The filtrate was
concentrated in vacuo and purified by a silica gel packed flash
chromatography column with petroleum ether/ethyl acetate
as the eluent to afford the desired products.
5-(4-Chlorophenyl)indazolo[3,2-b]quinazolin-7(5H)-one (2g)
.
White solid, 233.8-234 oC; 1H NMR (500 MHz, CDCl3) δ 8.33-
8.28 (m, 2H), 7.72 (d, J = 8.5 Hz, 1H), 7.82 (t, J = 7.5 Hz, 1H),
7.64 (t, J = 8.0 Hz, 2H), 7.50-7.44 (m, 4H), 7.31 (d, J = 8.0 Hz,
2H), 7.18 (d, J = 8.5 Hz, 1H); 13C NMR (125 MHz, CDCl3) δ 155.6,
147.9, 147.2, 146.6, 139.2, 133.6, 133.3, 132.6, 128.9, 126.2,
125.8, 125.3, 124.7,123.7, 122.5, 119.0, 118.1, 111.4.
5-(3-Chlorophenyl)indazolo[3,2-b]quinazolin-7(5H)-one (2h).
White solid, mp 249-250 oC; 1H NMR (500 MHz, CDCl3 ) δ 8.34-
8.30 (m, 2H), 7.92 (d, J = 8.5 Hz, 1H), 7.84 (t, J =7.0 Hz, 1H),
7.64 (t, J = 7.5 Hz, 1H), 7.50-7.40 (m, 4H), 7.34 (s, 1H), 7.29 (d, J
= 7.5 Hz, 1H), 7.22 (d, J = 8.5 Hz, 1H); 13C NMR (125 MHz,
CDCl3) δ 155.4, 147.8, 147.7, 147.2, 142.2, 134.3, 133.3, 132.6,
129.6, 128.0, 126.2, 125.8, 124.8, 123.9, 123.8, 122.5, 121.9,
118.8, 118.2, 111.4.
5-Phenylindazolo[3,2-b]quinazolin-7(5H)-one (2a)
.
White
solid, mp 203-204 oC; 1H NMR (500 MHz, CDCl3) δ 8.34-8.28
(m, 2H),7.91 (d, J = 8.0Hz 1H), 7.83-7.80 (m, 1H), 7.64-7.60 (m,
1H), 7.49-7.39 (m, 5H), 7.37-7.35 (m, 2H), 7.21(d, J = 6.0 Hz,
1H); 13C NMR (125 MHz, CDCl3) δ 155.5, 148.2, 147.8, 147.4,
141.0, 133.1, 132.5, 128.6, 127.6, 126.1, 125.8, 124.5, 123.6,
123.4, 122.3, 118.9, 117.9, 111.5.
5-(2-Chlorophenyl)indazolo[3,2-b]quinazolin-7(5H)-one (2i).
o
1
5-(p-Tolyl)indazolo[3,2-b]quinazolin-7(5H)-one (2b)
. White
White solid, mp 203-204 C; H NMR (500 MHz, CDCl3) δ 8.31
(d, J = 8.0 Hz, 2H), 7.91 (d, J = 8.5 Hz, 1H), 7.82-7.80(m, 1H),
7.64(t, J =7.0 Hz, 1H), 7.53 -7.52 (m, 1H), 7.48 -7.40 (m, 5H),
7.07 (d, J = 8.0 Hz, 1H); 13C NMR (125 MHz, CDCl3) δ 155.2,
147.8, 146.6, 137.2, 133.0, 132.6, 131.4, 130.0, 129.6, 127.8,
127.0, 126.2, 125.7, 124.4, 123.2, 122.4, 118.7, 117.9, 110.7,
99.2. IR (KBr): 3435, 3061, 2367, 1678, 1602, 1470 cm-1. HRMS
solid, mp 184-185 oC; 1H NMR (500 MHz, DMSO-d6) δ 8.24 (d, J
= 7.5 Hz, 1H), 8.16 (d, J = 8.0 Hz, 1H), 7.89 (s, 2H), 7.74 (t, J =
7.5 Hz, 1H), 7.54-7.48 (m, 2H), 7.35-7.26 (m, 5H), 3.34 (s, 3H);
13C NMR (125 MHz, CDCl3) δ 156.2, 149.4, 148.4, 147.3, 141.4,
140.4, 132.4, 132.2, 128.6, 127.4, 127.2, 124.4, 124.2, 123.4,
122.4, 118.0, 117.5, 111.5, 22.4; 13C NMR (125 MHz, CDCl3) δ
155.5, 148.4, 147.7, 147.2, 138.3, 137.8, 133.0, 132.4, 129.2,
126.0, 125.8, 124.4, 123.7, 123.2, 122.3, 118.9, 117.8, 111.4,
20.4.
(ESI) calcd for C20H13ClN3O+ [M
346.0744.
+
H]+ 346.0742, found
8-Methyl-5-phenylindazolo[3,2-b]quinazolin-7(5H)-one (2j).
o
1
5-(m-Tolyl)indazolo[3,2-b]quinazolin-7(5H)-one (2c). White
solid, mp 245-246 oC; 1H NMR (500 MHz, CDCl3) δ 8.34-8.28
(m, 2H), 7.91 (d, J = 8.5 Hz, 1H), 7.84-7.80 (m, 1H), 7.64-7.60
(m, 1H), 7.48-7.34 (m, 3H), 7.22-7.14 (m, 4H), 2.38 (s, 3H); 13C
NMR (125 MHz, CDCl3) δ 155.5, 148.4, 147.8, 144.5, 138.8,
137.6, 133.0, 132.4, 128.6, 128.4, 126.1, 125.8, 124.4, 124.1,
123.4, 122.3, 120.8, 119.0, 118.1, 111.6, 20.5.
White solid, mp 210-211 C; H NMR (500 MHz, CDCl3) δ 8.25
(d, J = 8.0 Hz 1H), 7.74 (d, J = 8.0 Hz, 1H), 7.66-7.59 (m, 2H),
7.47 (t, J = 8.0 Hz, 2H), 7.41-7.34 (m, 4H), 7.20 (d, J = 8.5 Hz,
2H), 2.85 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 156.2, 149.4,
148.4, 147.3, 141.4, 140.4, 132.4, 132.2, 128.6, 127.4, 127.2,
124.4, 124.2, 123.4, 122.4, 118.0, 117.5, 111.5, 22.4.
9-Methyl-5-phenylindazolo[3,2-b]quinazolin-7(5H)-one (2k).
o
White solid, mp232-233 C; H NMR (500 MHz, CDCl3 ) δ 8.27
1
4 | J. Name., 2012, 00, 1-3
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(d, J = 8.0 Hz, 1H), 8.11 (s, 1H), 7.81 (d, J = 8.5 Hz, 1H), 7.65-
7.58 (m, 2H), 7.48-7.34 (m, 6H), 7.21 (t, J = 8.0 Hz, 1H), 2.50 (s,
3H); 13C NMR (125 MHz, CDCl3) δ 155.4, 148.2, 146.8, 145.8,
141.2, 134.8, 134.7, 132.2, 128.6, 127.6, 126.0, 125.1, 123.6,
123.4, 122.2, 118.8, 118.2, 111.5, 20.4.
Acknowledgements
We thank Prof. Maolin Hu for X-ray crystallographic analysis.
This work was supported by the Natural Science Foundation of
Zhejiang Province (No. LY14B020009), National Natural Science
Foundation of China (Nos. 21572162, 21472140 and
21272176), Science and Technology Project of Zhejiang
Province (No. 2016C31022) and the Xinmiao Talent Planning
Foundation of Zhejiang Province (Nos. 2015R426061,
2016R426058 and 2016R426059).
10-Methyl-5-phenylindazolo[3,2-b]quinazolin-7(5H)-one (2l).
o
1
White solid, mp 216-217 C; H NMR (500 MHz, CDCl3) δ 8.27
(d, J = 8.0 Hz 1H), 8.20 (d, J = 8.0 Hz, 1H), 7.70 (s, 1H), 7.62-7.59
(m, 1H), 7.47 (t, J = 8.0 Hz, 2H), 7.42-7.34 (m, 4H), 7.29-7.27
(m, 1H), 7.20 (d, J = 8.5 Hz, 1H), 2.56 (s, 3H); 13C NMR (125
MHz, CDCl3) δ 155.5, 148.2, 148.0, 147.4, 144.0, 141.1, 132.4,
128.6, 127.6, 126.3, 125.8, 125.6, 123.6, 123.4, 122.4, 118.1,
116.6, 111.4, 21.1. IR (KBr): 3434, 2359, 1671, 1601, 1460,
1270 cm-1. HRMS (ESI): m/z calcd for C21H16N3O+ [M + H]+
326.1288, found 326.1294.
References
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11-Methyl-5-phenylindazolo[3,2-b]quinazolin-7(5H)-one
(2m). White solid, mp 169.8-170 oC.1H NMR (500 MHz, CDCl3)
δ 8.31 (d, J = 8.0 Hz 1H), 8.18 (d, J = 8.0 Hz, 1H), 7.67-7.58 (m,
2H), 7.48-7.33 (m, 7H), 7.20 (d, J = 8.5 Hz, 1H), 2.80 (s, 3H); 13C
NMR (125 MHz, CDCl3) δ 162.2, 157.2, 146.5, 146.2, 136.8,
136.5, 132.8, 131.3, 130.2, 129.1, 126.8, 124.8, 121.8, 120.8,
117.4, 114.0, 110.7, 100.1, 55.7, 21.4.
2
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7(5H)-one (2n). White solid, mp 239-239.2 oC; 1H NMR (500
MHz, CDCl3 ) δ 8.27 (d, J = 8.0 Hz 1H), 7.95-7.90 (m, 2H), 7.64-
7.61 (m, 1H), 7.57-7.52 (m, 1H), 7.50-7.47 (m, 2H), 7.44-7.40
(m, 2H), 7.36-7.34 (m, 2H), 7.20 (d, J = 8.0 Hz, 1H); 13C NMR
(125 MHz, CDCl3) δ 154.8, 148.2, 146.8, 140.8, 132.6, 128.7,
128.5, 128.4, 127.8, 123.8, 123.6, 122.3, 121.9, 117.8, 112.6,
111.6, 111.3, 110.4. IR (KBr):3439, 2923, 1673, 1624, 1482,
1273 cm-1. HRMS (ESI) calcd for C20H13FN3O+ [M + H]+
330.1037, found 330.1041.
8
, 1287.
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8-Chloro-5-phenylindazolo[3,2-b]quinazolin-7(5H)-one (2o).
o
1
White solid, mp 224-225 C; H NMR (500 MHz, CDCl3) δ 8.24
(d, J = 7.5 Hz, 1H), 7.80-7.78 (m, 1H), 7.65-7.60 (m, 2H), 7.48-
7.35 (m, 7H), 7.18 (d, J = 8.5 Hz, 1H); 13C NMR (125 MHz, CDCl3)
δ 154.8, 151.3, 149.5, 148.8, 141.7, 134.9, 134.2, 133.8, 133.2,
129.8, 129.7, 128.7, 126.4, 124.6, 124.5, 123.4, 119.4, 118.4,
117.0, 112.5. IR (KBr): 3437, 2359, 1683, 1632, 1589, 1461 cm-
1. HRMS (ESI) calcd for C20H13N3OCl+ [M+H]+ 346.0742, found
346.0744.
7
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9-Chloro-5-phenyl-12,12a-dihydroindazolo[3,2-b]quinazolin-
7(5H)-one (2p). White solid, mp 256-257 oC; 1H NMR (500
MHz, CDCl3) δ 8.27 (s, 2H), 7.85 (d, J = 8.5 Hz, 1H), 7.73 (d, J =
8.0 Hz, 1H), 7.63 (s, 1H), 7.48-7.42 (m, 4H), 7.35 (d, J = 6.5 Hz,
2H), 7.21 (d, J = 8.0 Hz, 1H); 13C NMR (125 MHz, CDCl3) δ 154.8,
151.3, 149.5, 148.8, 141.7, 134.9, 134.2, 133.8, 133.2, 129.8,
129.7, 128.7, 126.4, 124.6, 124.5, 123.4, 119.4, 118.4, 117.0,
112.5.
10-Chloro-5-phenylindazolo[3,2-b]quinazolin-7(5H)-one
(2q). Pale-yellow solid, mp 204-205 oC; 1H NMR (500 MHz,
CDCl3) δ 8.28-8.23 (m, 2H), 7.90-7.89 (m, 1H), 7.64 (t, J = 7.5
Hz, 1H), 7.50-7.34 (m, 7H), 7.20 (d, J = 8.0 Hz, 1H); 13C NMR
(125 MHz, DMSO-d6) δ 154.8, 149.3, 148.9, 148.4, 141.3,
138.6, 134.2, 129.3, 128.0, 127.9, 125.8, 125.4, 124.7, 123.9,
123.1, 118.2, 118.0, 112.3.
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15 Crystallographic data for compound 2a has been deposited
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CCDC 1510969.
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