Palladium-Catalyzed Cascade Reaction of 2-Amino-N′-arylbenzohydrazides with Triethyl Orthobenzoates To Construct Indazolo[3,2-b]quinazolinones

Article abstract of DOI:10.1021/jo5024848

A palladium-catalyzed sequential cyclization/C-H activation cascade reaction of 2-amino-N′-arylbenzohydrazides with triethyl orthobenzoates has been developed, providing indazolo[3,2-b]quinazolinones in good to high yields. Two key intermediates of the re

Full text of DOI:10.1021/jo5024848

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Article
Palladium-Catalyzed Cascade Reaction of 2-Amino-N'-arylbenzohydrazides
with Triethyl Orthobenzoates to Construct Indazolo[3,2-b]quinazolinones
Weiguang Yang, Rui Qiao, Jiuxi Chen, Xiaobo Huang,
Miaochang Liu, Wenxia Gao, Jinchang Ding, and Huayue Wu
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/jo5024848 • Publication Date (Web): 01 Dec 2014
Downloaded from http://pubs.acs.org on December 10, 2014
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Palladium-Catalyzed Cascade Reaction of 2-Amino-N'-arylbenzohydrazides with
Triethyl Orthobenzoates to Construct Indazolo[3,2-b]quinazolinones
Weiguang Yang, Rui Qiao, Jiuxi Chen,* Xiaobo Huang, Miaochang Liu, Wenxia Gao, Jinchang
Ding, and Huayue Wu*
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College of Chemistry and Materials Engineering, Wenzhou University, Wenzhou 325035, China
Fax: 86-577-8836-8280. E-mail: jiuxichen@wzu.edu.cn or huayuewu@wuz.edu.cn
ABSTRACT: A palladium-catalyzed sequential cyclization/C-H activation cascade
reaction of 2-amino-N'-arylbenzohydrazides with triethyl orthobenzoates has been
developed, providing indazolo[3,2-b]quinazolinones in good to high yields. Two key
intermediates of the reaction, 2-phenyl-3-(phenylamino)quinazolinone and C-H
insertion palladacycle, were isolated, and their structures were unambiguously
confirmed by X-ray crystallography. This method represents an unprecedented
example for a halogen-free protocol to access indazolo[3,2-b]quinazolinones.
Moreover, this chemistry also provides a useful tool for the discovery of fluorescent
materials.
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INTRODUCTION
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Quinazolinone-based fused poly-N-heterocycles have shown to be important class
of alkaloids in the past few years because they are widely found in natural
products such as luotonin A,1 cruciferane,2 circumdatins,3 rutaecarpine,4
vasicinone,5 and tryptanthrin,6 etc. The combined molecules of indazole and
quinazolinone frameworks, indazoloquinazolinone derivatives, are important
biological molecules and some of them are potent inhibitors of phosphodiesterase
4 (PDE4).7a However, the efficient synthetic method has been under-developed.
Pal,7a Wang,7b and our group7c have independently reported the methods for the
preparation of indazoloquinazolinone derivatives, but the use of halogenated
substrates put a limitation on the reported method. For example, halogenated
compounds themselves and halide byproducts are generally environmental
pollutants. In addition, halogenated compounds are not always easily available and
their preparation often involves tedious steps, harsh reaction conditions, and
production of waste. As a consequence, the development of new synthetic
strategies to access unique quinazolinone-based fused poly-N-heterocycles for new
leads in drug discovery is still highly desirable. From a synthetic standpoint,
developing cascade processes involving transition-metal-catalyzed C-H bond
amination represents one of the most versatile and practical approaches for
installation nitrogen-containing molecules.8 Recently, we reported palladium-
catalyzed intramolecular aerobic oxidative C−H amination of 2-aryl-3-
(arylamino)quinazolinones for the synthesis of indazolo[3,2-b]quinazolinones.9
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This work stands for part of the ongoing program in our laboratory toward the
development of new metal-catalyzed C-H activation10 for the synthesis of
quinazolinone derivatives.11 Herein, we report a new protocol to construct
indazolo[3,2-b]quinazolinones (3) from 2-amino-N'-arylbenzohydrazides (1) with
triethyl orthobenzoates (2) in one-pot formation of triple C-N bonds via palladium-
catalyzed sequential cyclization/C-H activation cascade process (Scheme 1).
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Scheme 1. Synthesis of indazolo[3,2-b]quinazolinones
RESULTS AND DISCUSSION
Our preliminary studies were focused on the reaction between 2-amino-N'-
phenylbenzohydrazide (1a) and triethyl orthobenzoate (2a) to obtain 2,3-diphenyl-
3H-benzo[e][1,2,4] triazepin-5(4H)-one (5a)12 by condensation /intramolecular
cyclization reaction (Scheme 2). Through the screening process, no target product
5a was detected under a variety of conditions. We were surprised to find that a
trace amount of unexpected 5-phenylindazolo[3,2-b]quinazolinone (3a) and 2-
phenyl-3-(phenylamino)quinazolinone (4a) were observed by GC/MS (EI)
analysis using benzoquinone13 as an oxidant in the presence of Pd(OAc)2. When
oxone was used as the oxidant, compounds 3a and 4a were obtained in 17% and
39% isolated yields, respectively. Their structures were unambiguously confirmed
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by X-ray crystallography (Figure 1).14 The formation of the unexpected product 3a
may undergo cyclization reaction of 1a and 2a followed by intramolecular C-H
amination of the key intermediate 4a.
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Scheme 2. Reaction of 1a with 2a
Figure 1. X-ray crystal structure of compound 3a and 4a. Thermal ellipsoids are
drawn at 50% probability, and H atoms have been omitted for clarity.
This finding inspired us to explore the more challenging cascade reactions for
the synthesis of 3a. We next investigated the model reaction using silver salts as
the oxidant. Silver salts such as Ag2O, Ag2SO4 and Ag(TFA) could promote the
reaction, leading to 3a in 53%, 45% and 79% yields, respectively (Table 1, entries
2-4). Other oxidants exhibited lower efficiencies (see entries 1–13 of Table S1 in
the Supporting Information). We were delighted to find that the yield of 3a was
improved to 88% yield when the combination of Pd(OAc)2 and AgOAc was
employed in HOAc (Table 1, entry 5). Replacement of Pd(OAc)2 with other Pd
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sources resulted in lower yields (see Table 1, entries 6-8, and entries 14-19 of
Table S1 in the Supporting Information). In addition, adjusting other reaction
parameters, including solvents, temperatures, and molar ratios, failed to increase
the yields of 3a (see entries 20-29 of Table S1 in the Supporting Information).
Catalytic activity was also observed under O2 or N2 atmosphere, albeit in slightly
low yields of 79% and 81%, respectively (Table 1, entries 9-10). In the absence of
the palladium catalyst or silver salt, no or only a trace amount of the desired 3a
was detected (Table 1, entries 11-12).
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Table 1. Screening of Reaction Conditionsa
a Unless otherwise noted, all reactions were carried out as follows: 1a (0.2 mmol), 2a (0.8 mmol),
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b
c
Pd source (10 mol%), oxidant (4 equiv) and AcOH (6 mL), air, 120 C, 48 h. Isolated yield.
Under O2 atmosphere. d Under N2 atmosphere.
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Having the optimial reaction conditions, we further expanded the substrate
scope containing different functional groups (Table 2). First, the variation of the
R2 group of 2-amino-N'-arylbenzohydrazides 1 was investigated by testing the
reaction between various 2-amino-N'-arylbenzohydrazides and triethyl
orthobenzoate (2a) under the standard conditions. The results showed that both
electron-donating and electron-withdrawing substituents were well-tolerated and
provided the corresponding products in moderate to good yields. For example,
substrates bearing methyl group afforded the cyclized products 3b and 3c in 87%
and 82% yield, respectively (Table 2, entries 2 and 3). To our satisfaction, it was
found that ortho-methyl group is also well-tolerated, affording the desired product
3d in 69% yield (Table 2, entry 4). It is noteworthy that only trace yield of 3d was
detected in our previous protocol.9 The electron-withdrawing fluoro, chloro, and
trifluoromethyl groups allowed formation of the cyclized products 3e, 3f and 3g in
83−91% yields (Table 2, entries 5-7). However, 3-(benzylamino)-2-
phenylquinazolinone (3h') was isolated in 16% yield and confirmed by NMR when
2-amino-N'-benzylbenzohydrazide was used as substrate (Table 2, entry 8).
We next examined the substitution effect on the aromatic ring of 2-amino-N'-
arylbenzohydrazides 1. Substrates bearing a para-, and ortho-methyl substituent
with respect to the amino group were evaluated, affording 3i (83% yield) and 3j
(64% yield) respectively (Table 2, entries 9 and 10). The lower yield of 3i may
arise from the steric hindrance. The electronic property of the substituents is not
critical for this transformation. In general, the substrates bearing an electron-
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Table 2. Palladium-catalyzed synthesis of indazolo[3,2-b]quinazolinonesa
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a
Unless otherwise noted, all reactions were carried out as follows: 1 (0.2 mmol), 2 (0.8 mmol),
o
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Pd(OAc)2 (10 mol%), AgOAc (4 equiv) and AcOH (6 mL), air, 120 C, 48 h. Isolated yield are
provided in parentheses.
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donating substituent (e.g., –OMe) provided a slightly higher yield than those
bearing an electron-withdrawing substituent (e.g., –F or –Cl) (Table 2, entries 11-
14). Finally we tested the reaction scope of triethyl orthobenzoates. The results
showed that electron-donating groups had more favorable effects than electron-
withdrawing groups. For example, treatment of 2-amino-N'-phenyl
benzohydrazide (1a) with p-methyl triethyl orthobenzoate afforded 3o in 85%
yield, while the yield of 3p was decreased to 76% with p-chloro triethyl
orthobenzoate (Table 2, entries 15 and 16).
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It is noteworthy that the ability to incorporate the whole range of halogen
substituents makes this method particularly appealing, since the successful
synthesis of halogen-substituted products, such as 3e, 3f, 3l, 3m, 3n, and 3p
(Table 2, entries 5, 6, 12-14 and 16) enabled further access to more complex
compounds in combination with cross-coupling transformations.
To elucidate the mechanism of the formation of indazolo[3,2-b]quinazolinones,
some control experiments were performed under the standard conditions as shown
in Scheme 3. It was found that 2-phenyl-3-(phenylamino)quinazolinone (4a) was
obtained in 83% yield when the reaction of 2-amino-N'-phenylbenzohydrazide (1a)
and triethyl orthobenzoate (2a) was performed in the absence of palladium catalyst
(Scheme 3a). The desired product 3a was isolated in 89% yield when 4a was used
(Scheme 3b). However, the product 7 could not be detected when N-methyl-2-
phenyl-3-(phenylamino)-2,3-dihydroquinazolin-4(1H)-one (6) was used as
substrate under the standard conditions, almost 90% of 6 was recovered (Scheme
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3c). The reaction of 2-phenyl-3-(phenylamino)-2,3-dihydroquinazolin-4(1H)-one
(8) failed to deliver 5-phenyl-12,12a-dihydroindazolo[3,2-b]quinazolin-7(5H)-one
(9) along with product 3a in 12% yield (Scheme 3d). These results above revealed
that 2-phenyl-3-(phenylamino)quinazolinone (4a) is the key intermediate for the
transformation.
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Scheme 3. Control Experiments
On the other hand, although we could not observe the formation of six-
membered palladacycle complex15 (Figure 2, mode I), we were able to obtain the
key intermediate five-membered palladacycle complex 10 (Figure 2, mode II) and
its structure was confirmed by X-ray crystallography,9 by the treatment of 2-
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phenyl-3-(phenylamino)quinazolinone (4a) with a stoichiometric equivalent of
Pd(OAc)2 in dichloromethane (Scheme 4a). It was found palladacycle complex 10
can be smoothly converted to 3a in the presence of AgOAc in AcOH at 120 °C
(Scheme 4b). This implies that the cascade reaction of 2-amino-N'-
arylbenzohydrazides with triethyl orthobenzoates could proceed via palladacycle
complex 10.
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Figure 2. Coordination Mode
Scheme 4. Control Experiments
On the basis of these results and relevant reports in the literature,16 a possible
mechanism for this cascade reaction was proposed in Scheme 5. The first step may
involve the formation of 2-phenyl-3-(phenylamino)quinazolinone (4a) by
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condensation/cyclization reaction of 2-amino-N'-phenyl benzohydrazide (1a) with
triethyl orthobenzoate (2a). Next, C−H activation of 4a generates five-membered
complex 10, which undergoes “rollover” cyclometalation17 in the presence of
AgOAc and AcOH with the increasing of temperature to afford six-membered
palladacycle complex 11 by intramolecular ligand exchange with H-
N(Ph)quinazolinone. Finally, the reductive elimination of complex 11 along with
the C-N bond formation affords the desired product 3a and Pd(0). AgOAc as an
oxidant reoxidizes Pd(0) to Pd(II) to close the catalytic cycle. However, the
mechanism of the reaction through a Pd(II)/Pd(IV) pathway cannot be ruled out.18
A detailed mechanism need to be addressed with further studies.
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Scheme 5. Plausible Mechanism for the Formation of Indazolo[3,2-
b]quinazolinones through Pd-catalyzed C-H Activation
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1.0
0.8
3a
3b
3c
3d
3e
3g
3i
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0.6
absorbance
3j
3k
3l
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3m
3n
3o
3p
Normalized
0.2
0.0
250
300
350
400
Wavelength (nm)
Figure 3. UV-vis Absorption Spectra of Indazolo[3,2-b]quinazolinones 3 in
CHCl3 (1×10-5 mol/L).
1.0
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3b
3c
3d
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3e
3g
3i
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3j
3k
3l
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3m
3n
Normalized Emission
3o
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3p
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400
450
500
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Wavelength (nm)
Figure 4. Fluorescence Spectra of Indazolo[3,2-b]quinazolinones 3 in CHCl3
(1×10-5 mol/L). EX Slit: 5.0 nm; EM Slit: 5.0 nm; Voltage: 700 V.
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Considering that nitrogen-containing heterocycles often showed excellent
photophysical properties and were widely used in the field of organic
fluorescent materials,19 the UV-vis absorption and fluorescence spectra of
indazolo[3,2-b]quinazolinones were measured in CHCl3 (Figure 3, Figure 4 and
Table 3).
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Table 3. Photophysical Properties of Indazolo[3,2-b]quinazolinones in CHCl3
Compd
3a
λabs (nm)
λem (λex, nm)
427 (360)
429 (352)
430 (357)
402, 422 (356)
426 (350)
424 (349)
429 (352)
430 (352)
434 (354)
424 (354)
426 (351)
426 (353)
424 (350)
428 (354)
Stokes shift (nm)
ФPL
241, 266, 288, 348
241, 266, 288, 350
241, 266, 288, 351
241, 271, 354
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0.07
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0.20
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0.27
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0.09
0.04
0.11
3b
3c
3d
3e
241, 264, 288, 350
241, 263, 287, 350
241, 267, 290, 351
243, 262, 291, 354
242, 269, 293, 353
240, 268, 358
3g
3i
3j
3k
3l
3m
3n
3o
240, 265, 287, 353
243, 274, 357
240, 267, 287, 348
241, 265, 289, 354
3p
Indazolo[3,2-b]quinazolinones showed well-resolved absorption peaks between
241 nm and 357 nm, and emited blue fluorescence light in the range of 403–430
nm. It was found that indazolo[3,2-b]quinazolinones with electron-donating (e.g.,
–Me and –OMe) and electron-withdrawing groups (e.g., –F, –Cl and –CF3)
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exhibited slight influence. The novel dyes showed outstanding Stokes shifts
between 68 nm and 81 nm, which is an attractive property for the detection of
emission wavelength by avoiding the interference from the excitation
wavelength.20 In addition, the fluorescence efficiency (ФF) of indazolo[3,2-
b]quinazolinones was determined to be in the range of 0.02–0.2, using quinine
sulfate solution (ФF = 0.55 in 0.5 mol/L H2SO4) as the fluorescence reference.21
Thus, the potential utility of indazolo[3,2-b]quinazolinones has been demonstrated
as a new class of blue fluorophores in the field of organic fluorescent materials.
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CONCLUSIONS
In summary, we have developed a new strategy for synthesis indazolo[3,2-
b]quinazolinone derivatives in moderate to excellent yields from the palladium-
catalyzed cascade reaction of 2-amino-N'-arylbenzohydrazides with triethyl
orthobenzoates. X-ray structure of the C−H insertion intermediate has provided
valuable insight into the coordination mode of quinazolinones and the possible
origin of their power in directing C−H activation. Further efforts to explore the
detailed mechanism and extend the applications of the transformation are currently
underway in our laboratories. Additionally, the resulting indazolo[3,2-
b]quinazolinones represent a new class of nitrogen-containing heterocyclic
fluorophores with large Stokes shifts and moderate fluorescence efficiency.
EXPERIMENTAL SECTION
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General Information. Melting points are uncorrected. H 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 n δ relative to TMS, and the coupling constants J are given
in hertz. High-resolution mass spectra (HRMS) were recorded on a TOF MS
instrument with an EI or ESI source. 2-Amino-N'-arylbenzohydrazides were
synthesized according to the method described in the literature.22 Other commercially
obtained reagents were used without further purification. All reactions under nitrogen
atmosphere were conducted using standard Schlenk techniques. Column
chromatography was performed using EM silica gel 60 (300−400 mesh).
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General Procedure for the Preparation of 2-Amino-N'-arylbenzohydrazides.
To a 50 mL round bottom flask a suspension of isatoic anhydrides (10 mmol) in THF
(20 mL) was treated by slow addition of 1.2 equiv. of hydrazines (12 mmol). The
reaction mixture was refluxed for overnight. The mixture was cooled to room
temperature and concentrated in vacuo. 2-Amino-N'-arylbenzohydrazides 1 was
obtained as white solid after crystallized from ethanol.
General Procedure for the Palladium-Catalyzed Synthesis of Indazolo[3,2-
b]quinazolinones. In a 25 mL sealed tube, 2-amino-N'-arylbenzohydrazides 1 (0.2
mmol), Pd(OAc)2 (0.02 mmol, 10 mol %), AgOAc (0.8 mmol), were dissolved in
HOAc (6 mL) under air, then triethyl orthobenzoates 2 (0.8 mmol) was added to the
reaction mixture. 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
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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 washed with saturated NaHCO3 and then brine. After the
aqueous layer was extracted with ethyl acetate, the combined organic layers were
dried over anhydrous Na2SO4 and evaporated under a vacuum. The residue was
purified by a silica gel packed flash chromatography column (hexane/ethyl acetate) to
afford the desired products 3.
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Preparation of Compounds 6 and 8. To a solution of an isatoic anhydride (2
mmol) in MeCN (3 mL) was added a phenylhydrazine (2 mmol) and the reaction
mixture was stirred under reflux (progress of the reaction was monitored by TLC).
After the reaction was finished, benzaldehyde (2 mmol) and TsOH (15 mol%) were
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added, and the reaction mixture was stirred at 80 C with vigorous stirring overnight.
The reaction mixture was cooled to room temperature and concentrated in vacuo. The
resulting residue was purified by a silica gel packed flash chromatography column
(hexane/ethyl acetate) to afford compounds 6 and 8 in 63% and 72% yield,
respectively.
Intramolecular Amination of Palladium Complex 10. In a 25 mL sealed tube,
complex 10 (47.8 mg, 0.05 mmol, 1.0 equiv.), AgOAc (33.4 mg, 0.2 mmol 4.0 equiv.).
The reaction mixture was then tightly capped and stirred for 10 minutes at room
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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.
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The filtrate was concentrated in vacuo and purified by a silica gel packed flash
chromatography column (hexane/ethyl acetate). The product 3a was obtained as a
white solid amorphous solid (17.4 mg, 56% yield).
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2-Amino-N'-m-tolylbenzohydrazide (1c): White solid (1.52 g, 63% yield), mp 183-
184 oC. 1H NMR (500 MHz, CDCl3). δ 7.72 (s, 1H), 7.50-7.48 (m, 1H), 7.29-7.26 (m,
2H), 7.15-7.12 (m, 1H), 6.76-6.69 (m, 4H), 6.21-6.20 (m, 1H), 5.54 (s, 2H), 2.30 (s,
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3H); C NMR (125 MHz, CDCl3) δ 167.3, 149.4, 148.4, 139.3, 133.4, 129.3, 127.1,
122.5, 117.6, 116.8, 114.5, 113.3, 110.9, 21.7. HRMS (EI, 70 eV) calcd for
C14H15N3O [M+]: 241.1215, found 241.1215.
2-Amino-N'-(4-fluorophenyl)benzohydrazide (1e): White solid (1.47 g, 60% yield),
mp 141-143 oC. 1H NMR (500 MHz, CDCl3). δ 7.81 (s, 1H), 7.48-7.46 (m, 1H), 7.29-
7.27 (m, 1H), 6.97-6.92 (m, 2H), 6.91-6.88 (m, 2H), 6.72-6.68 (m, 2H), 6.27 (s, 1H),
5.53 (s, 2H); 13C NMR (125 MHz, CDCl3) δ 169.8, 159.1, 157.2, 149.4, 144.5, 133.5,
127.1, 117.7, 116.9, 116.0, 115.9, 115.2, 115.1, 113.0. HRMS (EI, 70 eV) calcd for
C13H12FN3O [M+]: 245.0964, found 245.0961.
2-Amino-N'-(4-(trifluoromethyl)phenyl)benzohydrazide (1g): White solid (1.59 g,
54% yield), mp 198-198 oC. 1H NMR (500 MHz, DMSO-d6) δ 10.19 (s, 1H), 8.44 (s,
1H), 7.68-7.66 (m, 1H), 7.48 (d, J = 8.5 Hz, 2H), 7.22-7.18 (m, 1H), 6.88 (d, J = 8.5
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Hz, 2H), 6.75-6.73 (m, 1H), 6.58-6.54 (m, 1H), 6.40 (s, 2H); C NMR (125 MHz,
DMSO-d6) δ 168.8, 152.9, 150.0, 132.4, 128.0, 126.2, 126.1, 124.0, 118.5, 118.3,
118.0, 117.8, 116.5, 114.7, 112.3, 11.5. HRMS (EI, 70 eV) calcd for C14H12F3N3O
[M+]: 295.0932, found 295.0935.
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2-Amino-3-methyl-N'-phenylbenzohydrazide (1j): White solid (1.20 g, 50% yield),
mp 171-173 oC. 1H NMR (500 MHz, DMSO-d6) δ 10.07 (d, J = 3.0 Hz, 1H), 7.79 (d,
J = 3.0 Hz, 1H), 7.54 (d, J = 7.5 Hz, 1H), 7.16-7.12 (m, 3H), 6.78-6.77 (m, 2H), 6.72-
6.69 (m, 1H), 6.52 (t, J = 7.5 Hz, 1H), 6.16 (s, 2H), 2.09 (s, 3H); 13C NMR (125 MHz,
DMSO-d6) δ 169.3, 149.8, 147.7, 132.9, 128.7, 125.8, 123.1, 118.5, 114.6, 112.9,
112.2, 17.6. HRMS (EI, 70 eV) calcd for C14H15N3O [M+]: 241.1215, found 241.1215.
2-Amino-5-methoxy-N'-phenylbenzohydrazide (1k): White solid (1.72 g, 67% yield),
mp 208-209 oC. 1H NMR (500 MHz, DMSO-d6). δ 10.10 (s, 1H), 7.78 (s, 1H), 7.24 (d,
J = 3.0 Hz, 1H), 7.17-7.14 (m, 2H), 6.90-6.88 (m, 1H), 6.80-6.78 (m, 2H), 6.73-6.68
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(m, 2H), 6.18 (s, 2H), 3.72 (s, 3H); C NMR (125 MHz, DMSO-d6) δ 168.5, 149.8,
149.3, 144.2, 128.7, 120.2, 118.5, 117.8, 112.8, 112.3, 111.4, 55.6. HRMS (EI, 70 eV)
calcd for C14H15N3O2 [M+]: 257.1164, found 257.1165.
2-Amino-4-fluoro-N'-phenylbenzohydrazide (1l): White solid (1.49 g, 61% yield),
mp 175-176 oC. 1H NMR (500 MHz, CDCl3) δ 7.65 (s, 1H), 7.50-7.47 (m, 1H), 7.28-
7.24 (m, 2H), 6.94-6.91 (m, 3H), 6.42-6.36 (m, 2H), 6.24 (d, J = 3.0 Hz, 1H), 5.72 (s,
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2H); C NMR (125 MHz, CDCl3) δ 165.1, 157.7, 156.9, 148.3, 135.3, 129.4, 129.3,
121.6, 113.8, 104.6, 104.4, 103.4, 103.2, 100.1. HRMS (EI, 70 eV) calcd for
C13H12FN3O [M+]: 245.0964, found 245.0967.
N-methyl-2-phenyl-3-(phenylamino)-2,3-dihydroquinazolin-4(1H)-one (6): White
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solid (0.41 g, 63% yield), mp 172-173 C. H NMR (500 MHz, DMSO-d6) δ 8.35 (s,
1H), 7.77-7.75 (m, 1H), 7.34-7.33 (m, 1H), 7.44-7.31 (m, 3H), 7.29-7.27 (m, 2H),
7.21-7.18 (m, 2H), 6.86-6.82 (m, 3H), 6.80-6.77 (m, 1H), 6.70 (d, J = 8.5Hz, 1H),
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5.88 (s, 1H), 2.93 (s, 3H); 13C NMR (125Mz, DMSO-d6) δ 161.7, 147.6, 146.7, 137.4,
134.2, 128.9, 128.7, 128.5, 127.7, 126.4, 119.3, 117.7, 115.5, 112.4, 112.2, 79.7, 35.1.
HRMS (EI, 70 eV) calcd for C21H19N3O [M+]: 329.1528, found 329.1531.
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5-Phenylindazolo[3,2-b]quinazolin-7(5H)-one (3a).7c White solid (54.7 mg, 88%
yield), mp 230-231 oC (lit. 227-228 oC); 1H NMR (500 MHz, CDCl3) δ 8.34-8.32 (m,
1H), 8.29 (d, J = 8.0 Hz, 1H), 7.91 (d, J = 8.5 Hz, 1H), 7.83-7.80 (m, 1H), 7.63-7.60
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(m, 1H), 7.50-7.35 (m, 7H), 7.21 (d, J=8.5Hz, 1H); C NMR (125 MHz, CDCl3) δ
156.5, 149.2, 148.8, 148.3, 141.9, 134.1, 133.5, 129.6, 128.7, 127.1, 126.8, 125.5,
124.7, 124.4, 123.4, 119.9, 118.9, 112.5.
5-p-Tolylindazolo[3,2-b]quinazolin-7(5H)-one (3b).7c White solid (56.6 mg, 87%
yield), mp 184-185 oC (lit. 184-185 oC); 1H NMR (500 MHz, CDCl3) δ 8.34-8.32 (m,
1H), 8.28 (d, J = 7.5 Hz, 1H), 7.91 (d, J = 8.0 Hz, 1H), 7.83-7.79 (m, 1H), 7.63-7.59
(m, 1H), 7.47-7.39 (m, 2H), 7.28-7.24 (m, 4H), 7.18 (d, J = 8.0 Hz, 1H), 2.40 (s, 3H);
13C NMR (125 MHz, CDCl3) δ 156.5, 149.4, 148.7, 148.3, 139.3, 138.8, 134.1, 135.5,
130.3, 127.0, 126.8, 125.4, 124.7, 124.3, 123.3, 119.9, 118.8, 112.5, 21.4.
5-m-Tolylindazolo[3,2-b]quinazolin-7(5H)-one (3c).7c White solid (53.3 mg, 82%
yield), mp 221-223 oC (lit. 241-242 oC); 1H NMR (500 MHz, CDCl3) δ 8.35-8.33 (m,
1H), 8.29 (d, J = 8.0 Hz, 1H), 7.92 (d, J = 8.0 Hz, 1H), 7.84-7.80 (m, 1H), 7.64-7.60
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(m, 1H), 7.48-7.34 (m, 3H), 7.22-7.16 (m, 3H), 7.14(s, 1H), 2.38 (s, 3H); C NMR
(125 MHz, CDCl3) δ 156.5, 149.3, 148.8, 148.4, 141.9, 139.8, 134.1, 133.5, 129.6,
129.4, 127.1, 126.8, 125.5, 125.0, 124.4, 123.3, 121.7, 119.9, 118.9, 112.6, 21.6.
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5-o-Tolylindazolo[3,2-b]quinazolin-7(5H)-one (3d).7c White solid (44.8 mg, 69%
yield), mp 219-221 oC (lit. 221-223 oC). 1H NMR (500 MHz, CDCl3) δ 8.32-8.29 (m,
2H), 7.91 (d, J = 8.5 Hz, 1H), 7.82-7.79 (m, 1H), 7.63-7.60 (m, 1H), 7.45-7.34 (m,
4H), 7.22-7.19 (m, 1H). 6.96-6.93 (m, 2H), 2.47 (s, 3H); 13C NMR (125 MHz, CDCl3)
δ 156.4, 148.8, 148.6, 148.0, 140.1, 136.7, 134.0, 133.6, 131.5, 129.5, 127.3, 127.1,
126.7, 125.5, 125.3, 123.8, 123.4, 119.8, 118.6, 111.9, 18.2.
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5-(4-Fluorophenyl)indazolo[3,2-b]quinazolin-7(5H)-one (3e).7c Light green solid
(54.6 mg, 83% yield), mp 197-198 oC (lit. 197-198 oC); 1H NMR (500 MHz, DMSO-
d6) δ 8.25 (d, J = 7.5 Hz, 1H), 8.17 (d, J = 8.0 Hz, 1H), 7.92-7.88 (m, 2H), 7.77-7.74
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(m, 1H), 7.57-7.49 (m, 4H), 7.33-7.30 (m, 3H); C NMR (125 MHz, DMSO-d6) δ
162.2, 160.2, 155.3, 148.4, 148.2, 147.6, 137.9, 134.0, 133.8, 126.9, 126.6, 126.5,
125.9, 125.3, 124.6, 122.9, 119.4, 118.3, 116.1, 115.9, 112.3.
5-(4-Chlorophenyl)indazolo[3,2-b]quinazolin-7(5H)-one (3f).7b Light yellow solid
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(62.6 mg, 91% yield), mp 240-242 C (lit. 236-237 C); H NMR (500 MHz, CDCl3)
δ 8.32-8.30 (m, 1H), 8.28 (d, J = 7.5 Hz, 1H), 7.90 (d, J = 8.5 Hz, 1H), 7.84-7.80 (m,
1H), 7.64-7.61 (m, 1H), 7.49-7.41 (m, 4H), 7.32-7.30 (m, 2H), 7.17 (d, J = 8.0 Hz,
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1H); C NMR (125 MHz, CDCl3) δ 156.5, 148.9, 148.7, 148.1, 140.5, 134.5, 134.2,
133.6, 129.9, 127.2, 126.8, 126.2, 125.7, 124.7, 123.5, 119.8, 119.0, 112.4.
5-(4-(Trifluoromethyl)phenyl)indazolo[3,2-b]quinazolin-7(5H)-one (3g).7c White
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solid (68.2 mg, 90% yield), mp 214-215 C (lit. 210-212 C); H NMR (500 MHz,
DMSO-d6) δ 8.27 (d, J = 8.0 Hz, 1H), 8.19 (d, J = 8.0 Hz, 1H), 7.94-7.90 (m, 2H),
7.86 (d, J = 8.5 Hz, 2H), 7.79-7.74 (m, 3H), 7.57-7.52 (m, 2H), 7.49 (d, J = 8.0 Hz,
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1H); 13C NMR (125 MHz, DMSO-d6) δ 155.3, 148.2, 147.7, 147.4, 144.9, 134.2,
133.9, 128.3, 128.0, 127.7, 127.5, 126.9, 126.4, 126.3, 126.0, 125.5, 125.1, 125.0,
124.3, 123.1, 122.8, 119.4, 118.6, 112.2.
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9-Methyl-5-phenylindazolo[3,2-b]quinazolin-7(5H)-one (3i).7c White solid (54.0
mg, 83% yield), mp 241-242 oC (lit. 236-238 oC); 1H NMR (500 MHz, CDCl3) δ 8.26
(d, J = 8.0 Hz, 1H), 8.11 (s, 1H), 7.81 (d, J = 8.0 Hz, 1H), 7.65-7.58 (m, 2H), 7.49-
7.46 (m, 2H), 7.42-7.38 (m, 2H), 7.36-7.34 (m, 2H), 7.21 (d, J = 8.5 Hz, 1H), 2.50 (s,
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3H); C NMR (125 MHz, CDCl3) δ 156.4, 149.2, 147.7, 146.8, 142.1, 135.8, 135.7,
133.3, 129.6, 128.5, 126.9, 126.1, 124.5, 124.4, 123.2, 119.7, 119.1, 112.5, 21.5.
11-Methyl-5-phenylindazolo[3,2-b]quinazolin-7(5H)-one (3j). White solid (41.6
mg, 64% yield), mp 175.7-177.3 oC. 1H NMR (500 MHz, CDCl3) δ 8.30 (d, J =7.5 Hz,
1H), 8.19-8.18 (m, 1H), 7.66 (d, J =8.0 Hz, 1H), 7.62-7.58 (m, 1H), 7.48-7.45 (m, 2H),
7.42-7.39 (m, 3H), 7.36-7.33 (m, 2H), 7.21 (d, J = 8.5 Hz, 1H), 2.80 (s, 3H); 13C
NMR (125 MHz, CDCl3) δ 156.8, 149.2, 147.5, 147.2, 142.1, 135.7, 134.5, 133.2,
129.6, 128.5, 125.1, 124.6, 124.5, 124.3, 123.4, 119.9, 119.5, 112.4, 18.0. IR(KBr):
3059, 2915, 2849, 1671, 1622, 1463, 1264, 1023 cm-1. HRMS (ESI) calcd for
C21H16N3O [M + H]+: 326.1288, found 326.1294.
9-Methoxy-5-phenylindazolo[3,2-b]quinazolin-7(5H)-one (3k).9 Light green solid
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(61.0 mg, 89% yield), mp 222-224 C (lit. 214-215 C); H NMR (500 MHz, CDCl3)
δ 8.24 (d, J = 8.0 Hz, 1H), 7.83 (d, J = 9.0 Hz, 1H), 7.67 (d, J = 3.0 Hz, 1H), 7.60-
7.57 (m, 1H), 7.49-7.46 (m, 2H), 7.43-7.35 (m, 5H), 7.19 (d, J = 8.0 Hz, 1H), 3.88 (s,
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3H); C NMR (125 MHz, CDCl3) 157.6, 156.1, 148.9, 146.5, 143.4, 142.1, 133.0,
129.6, 128.7, 128.6, 125.0, 124.7, 124.4, 123.0, 120.6, 119.1, 112.4, 105.6, 55.9.
10-Fluoro-5-phenylindazolo[3,2-b]quinazolin-7(5H)-one (3l).7c White solid (54.0
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mg, 82% yield), mp 214-215 C (lit. 214-215 C); H NMR (500 MHz, CDCl3) δ
8.33-8.30 (m, 1H), 8.26 (d, J = 8.0 Hz, 1H), 7.65-7.62 (m, 1H), 7.53-7.35 (m, 7H),
7.21-7.15 (m, 2H); 13C NMR (125 MHz, CDCl3) δ 167.5, 165.5, 155.9, 151.0, 150.9,
149.3, 149.2, 141.7, 133.8, 129.7, 129.5, 129.4, 128.8, 124.7, 124.6, 123.5, 118.5,
116.6, 114.6, 114.5, 112.5, 112.1, 111.9.
8-Fluoro-5-phenylindazolo[3,2-b]quinazolin-7(5H)-one (3m). White solid (51.3
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mg, 78% yield), mp 179-180 C; H NMR (500 MHz, CDCl3) δ 8.26 (d, J = 7.5 Hz,
1H), 7.95-7.89 (m, 2H), 7.64-7.61 (m, 1H), 7.56-7.52 (m, 1H), 7.50-7.47 (m, 2H).
7.44-7.41 (m, 2H), 7.36-7.34 (m, 2H), 7.20 (d, J = 8.0 Hz, 1H); 13C NMR (125 MHz,
CDCl3) δ 161.1, 159.1, 155.7, 149.1, 147.8, 145.5, 141.8, 133.6, 130.6, 129.7, 129.3,
128.8, 126.2, 124.8, 124.6, 123.3, 123.1, 122.9, 118.8, 118.0, 112.5, 114.4, 111.2. IR
(KBr):3064, 2921, 2853, 1674, 1624, 1483, 1269, 1035 cm-1. HRMS (ESI) calcd for
C20H12FN3O [M + H]+: 330.1037, found 330.1041.
10-Chloro-5-phenylindazolo[3,2-b]quinazolin-7(5H)-one (3n).7b Light yellow solid
(51.6 mg, 75% yield), mp 204-205 oC (lit. 208-209 oC ); 1H NMR (500 MHz, CDCl3)
δ 8.26 (d, J = 8.0 Hz, 1H), 8.23 (d, J =8.5 Hz, 1H), 7.89 (d, J = 1.5 Hz, 1H), 7.65-7.62
13
(m, 1H), 7.50-7.35 (m, 7H), 7.20 (d, J = 8.5 Hz, 1H); C NMR (125 MHz, CDCl3) δ
155.9, 149.6, 149.2, 141.5, 140.3, 133.9, 129.7, 128.9, 128.6, 128.2, 126.5, 126.1,
124.8, 124.6, 123.5, 118.5, 118.2, 112.4.
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3-Methyl-5-phenylindazolo[3,2-b]quinazolin-7(5H)-one (3o).7c White solid (55.2
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9
o
o
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mg, 85% yield), mp 254-255 C (lit. 248-250 C); H NMR (500 MHz, CDCl3) δ
8.32-8.31 (m, 1H), 8.16 (d, J = 8.5 Hz, 1H), 7.90 (d, J = 8.0 Hz, 1H), 7.82-7.79 (m,
1H), 7.50-7.40 (m, 4H), 7.36-7.35 (m 2H), 7.23 (d, J = 8.0 Hz, 1H), 6.98 (s, 1H), 2.46
(s, 3H); 13C NMR (125 MHz, CDCl3) δ 156.5, 149.6, 148.8, 148.4, 145.0, 142.0,
134.1, 129.6, 128.6, 126.9, 126.8, 126.2, 125.3, 124.6, 123.0, 119.7, 116.4, 112.4,
22.6.
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3-Chloro-5-phenylindazolo[3,2-b]quinazolin-7(5H)-one (3p).7c White solid (52.3
o
o
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mg, 76% yield), mp 212-213 C (lit. 255-256 C); H NMR (500 MHz, CDCl3) δ
8.34-8.30 (m, 2H), 7.92 (d, J = 8.0 Hz, 1H), 7.85-7.82 (m, 1H), 7.66-7.63 (m, 1H),
7.50-7.43 (m, 4H), 7.32-7.31 (m, 2H), 7.19-7.17(m, 1H); 13C NMR (125 MHz, CDCl3)
δ 156.3, 149.6, 148.6, 147.4, 141.2, 139.9, 134.3, 129.8, 129.1, 127.1, 126.8, 125.7,
125.3, 124.7, 124.4, 119.8, 117.4, 112.6.
ASSOCIATED CONTENT
Supporting Information
1H and 13C NMR spectra of all products and X-ray data of compounds 3a and 4a. This
material is available free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*E-mail: jiuxichen@wzu.edu.cn, huayuewu@wuz.edu.cn
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Notes
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The authors declare no competing financial interest.
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ACKNOWLEDGMENTS
We thank the National Natural Science Foundation of China (Nos. 21102105 and
21072153), Natural Science Foundation of Zhejiang Province (No. LY14B020009)
and Graduate Innovation Foundation of Wenzhou University for financial support.
REFERENCES
(1) (a) Cagir, A.; Jones, S. H.; Gao, R.; Eisenhauer, B. M. J. Am. Chem. Soc. 2003,
125, 13628. (b) Tseng, M.-C.; Chu, Y.-W.; Tsai, H.-P.; Lin, C.-M.; Hwang, J.;
Chu, Y.-H. Org. Lett. 2011, 13, 920. (c) Servais, A.; Azzouz, M.; Lopes, D.;
Courillon, C.; Malacria, M. Angew. Chem., Int. Ed. 2007, 46, 576.
(2) Vaidya, S. D.; Argade, N. P. Org. Lett. 2013, 15, 4006.
(3) (a) Dai, J.-R.; Carte, B. K.; Sidebottom, P. J.; Yew, A. L. S.; Ng, S.-B.; Huang,
Y.; Butler, M. S. J. Nat. Prod. 2001, 64, 125. (b) Kshirsagar, U. A.; Argade, N. P.
Org. Lett. 2010, 12, 3716.
(4) (a) Chiou, W.-F.; Liao, J.-F.; Chen, C.-F. J. Nat. Prod. 1996, 59, 374. (b) Zhang,
C.; De, C. K.; Mal, R.; Seidel, D. J. Am. Chem. Soc. 2008, 130, 416. (c) Granger,
B. A.; Kaneda, K.; Martin, S. F. Org. Lett. 2011, 13, 4542.
(5) Kamal, A.; Ramana, K. V.; Rao, M. V. J. Org. Chem. 2001, 66, 997.
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1
2
3
4
5
6
7
8
9
(6) (a) Jao, C.-W.; Lin, W.-C.; Wu, Y.-T.; Wu, P.-L. J. Nat. Prod. 2008, 71, 1275. (b)
Bandekar, P. P.; Roopnarine, K. A.; Parekh, V. J.; Mitchell, T. R.; Novak, M. J.;
Sinden, R. R. J. Med. Chem. 2010, 53, 3558.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
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41
42
43
44
45
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47
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49
50
51
52
53
54
55
56
57
58
59
60
(7) (a) Kumar, K. S.; Kumar, P. M.; Rao, V. S.; Jafar, A. A.; Meda, C. L. T.;
Kapavarapu, R.; Parsac, K. V. L.; Pal, M. Org. Biomol. Chem. 2012, 10, 3098. (b)
Chen, D.; Dou, G.; Li, Y.; Liu, Y.; Wang, X. J. Org. Chem. 2013, 78, 5700. (c)
Yang, W.; Ye, L.; Huang, D.; Liu, M.; Ding, J.; Chen, J.; Wu, H. Tetrahedron
2013, 69, 9852.
(8) For recent reviews on direct C−H amination, see: (a) Cho, S. H.; Kim, J. Y.;
Kwak, J.; Chang, S. Chem. Soc. Rev. 2011, 40, 5068. (b) Gephart III, R. T.;
Warren, T. H. Organometallics 2012, 31, 7728. (c) Jeffrey, J. L.; Sarpong, R.
Chem. Sci. 2013, 4, 4092. (d) Louillat, M.-L.; Patureau, F. W. Chem. Soc. Rev.
2014, 43, 901. (e) Zatolochnaya, O. V.; Gevorgyan, V. Nat. Chem. 2014, 6, 661.
(9) Yang, W.; Chen, J.; Huang, X.; Ding, J.; Liu, M.; Wu, H. Org. Lett. 2014, 16,
5418.
(10) Shen, Y.; Chen, J.; Liu, M.; Ding, J.; Gao, W.; Huang, X.; Wu, H. Chem.
Commun. 2014, 50, 4292.
(11) Duan, F.; Liu, M.; Chen, J.; Ding, J.; Hu, Y.; Wu, H. RSC Adv. 2013, 3, 24001.
(12) Benzotriazepin derivatives possess various pharmacological activities, see: (a)
Ibrahim, S. M.; Baraka, M. M.; El-Sabbagh, O. I.; Kothayer, H. Med. Chem. Res.
2013, 22, 1488. (b) Reddy, P. P.; Reddy, C. K.; Reddy, P. S. N. Bull. Chem. Soc.
Jpn. 1986, 59, 2827.
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(13) (a) Chen, X.; Li, J.; Hao, X.; Goodhue, C. E.; Yu, J. J. Am. Chem. Soc. 2006, 128,
78. (b) Boele, M. D. K.; van Strijdonck, G. P. F.; de Vries, A. H. M.; Kamer, P.
C. J.; de Vries, J. G.; van Leeuwen, P. W. N. M. J. Am. Chem. Soc. 2002, 124,
1586. (c) Chen, M. S.; Prabagaran, N.; Labenz, N. A.; White, M. C. J. Am. Chem.
Soc. 2005, 127, 6970. (d) Diao, T.; Stahl, S. S. Polyhedron 2014, 84, 96.
(14) Crystallographic data for compounds 3a and 4a have been deposited with the
Cambridge Crystallographic Data Centre as entry CCDC 939946 and 1022602,
respectively.
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(15) For selected examples of six-membered palladacycles, see: (a) Moulin, S.;
Pellerin, O.; Toupet, L.; Paul, F. C. R. Chimie 2014, 17, 521. (b) Nonoyama, M.
Transition Met. Chem. 1982, 7, 281. (c) Vicente, J.; Saura-Llamas, I.; Cuadrado,
J. Organometallics 2003, 22, 5513. (d) Burke, B. J.; Overman, L. E. J. Am. Chem.
Soc. 2004, 126, 16820.
(16) (a) Tsang, W. C. P.; Zheng, N.; Buchwald, S. L. J. Am. Chem. Soc. 2005, 127,
14560. (b) Shibata, T.; Takayasu, S.; Yuzawa, S.; Otani, T. Org. Lett. 2012, 14,
5106. (c) Tsang, W. C. P.; Munday, R. H.; Brasche, G.; Zheng, N.; Buchwald, S.
L. J. Org. Chem. 2008, 73, 7603. (d) Jordan-Hore, J. A.; Johansson, C. C. C.;
Gulias, M.; Beck, E. M.; Gaunt, M. J. J. Am. Chem. Soc. 2008, 130, 16184.
(17) For a review on “rollover” cyclometalation, see: Butschke, B.; Schwarz, H.
Chem. Sci. 2012, 3, 308.
(18) For selected reviews on organopalladium(IV) chemistry, see: (a) Sehnal, P.;
Taylor, R. J. K.; Fairlamb, I. J. S. Chem. Rev. 2010, 110, 824. (b) Xu, L.; Li, B.;
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7
Yang, Z.; Shi, Z. Chem. Soc. Rev. 2010, 39, 712. (c) Malinakova, H. C. Top.
Organomet. Chem. 2011, 35, 85.
8
9
(19) (a) de Silva, A. P.; Gunaratne, H. Q. N.; Gunnlaugsson, T.; Huxley, A. J. M.;
McCoy, C. P.; Rademacher, J. T.; Rice, T. E. Chem. Rev. 1997, 97, 1515. (b)
Lian, Y.; Bergman, R. G.; Lavis, L. D.; Ellman, J. A. J. Am. Chem. Soc. 2013,
135, 7122. (c) Jayakumar, J.; Parthasarathy, K.; Chen, Y. H.; Lee, T. H.; Chuang,
S. C.; Cheng, C. H. Angew. Chem., Int. Ed. 2014, 53, 9889.
10
11
12
13
14
15
16
17
18
19
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25
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27
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(20) Neto, B. A. D; Lapis, A. A. M.; Mancilha, F. S.; Vasconcelos, I. B.; Thum, C.;
Basso, L. A.; Santos, D. S.; Dupont, J. Org. Lett. 2007, 9, 4001.
(21) Lin, W.; Yuan, L.; Cao, Z.; Feng, J.; Feng, Y. Dyes Pigm. 2009, 83, 14.
(22) Patil, N. T.; Lakshmi, P. G. V. V.; Sridhar, B.; Patra, S.; Bhadra, M. P.; Patra,C.
R. Eur. J. Org. Chem. 2012, 1790.
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