Pd-Catalyzed tandem reaction of N-(2-cyanoaryl)benzamides with arylboronic acids: synthesis of quinazolines

Article abstract of DOI:10.1039/c8ob02421a

The synthesis of 2,4-disubstituted quinazolines by a palladium-catalyzed reaction of arylboronic acids with N-(2-cyanoaryl)benzamides has been developed with moderate to excellent yields. The method shows good functional group tolerance. In particular, ha

Full text of DOI:10.1039/c8ob02421a

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Pd-Catalyzed tandem reaction of N-(2-cyanoaryl)
benzamides with arylboronic acids: synthesis of
quinazolines†
Cite this: Org. Biomol. Chem., 2018,
16, 8596
Jianghe Zhu,‡ Yinlin Shao,‡ Kun Hu, Linjun Qi, Tianxing Cheng and Jiuxi Chen
*
The synthesis of 2,4-disubstituted quinazolines by a palladium-catalyzed reaction of arylboronic acids
with N-(2-cyanoaryl)benzamides has been developed with moderate to excellent yields. The method
shows good functional group tolerance. In particular, halogen and hydroxyl substituents, which are
amenable for further synthetic elaborations, are well tolerated. Moreover, the present synthetic route
could be readily scaled up to gram quantity without difficulty. The mechanism possibly involves nucleo-
philic addition to the nitrile function, forming an imine intermediate followed by an intramolecular
addition to the amide and dehydration to the quinazoline ring.
Received 28th September 2018,
Accepted 24th October 2018
DOI: 10.1039/c8ob02421a
rsc.li/obc
and Liu13b independently developed one-pot synthesis of qui-
nazolines via [2 + 2 + 2] cascade annulation of diaryliodonium
Introduction
The transition-metal-catalyzed transformation of nitriles pro- salts (or aryldiazonium salts) with two nitriles (Scheme 1a).
vides a highly attractive approach to generate carbon–carbon Novák developed a copper-catalyzed oxidative ring-closing reac-
and carbon–heteroatom bonds for organic chemistry research tion of N-(2-cyanoaryl)benzamides with diaryliodonium salts
and the fine chemical industry.1 Remarkable progress over the for the synthesis of iminobenzoxazines (Scheme 1b).14
past few decades in the transition-metal-catalyzed addition of Recently, Mo and co-workers reported the synthesis of 2-aryl-
organoboron reagents to nitriles2 has been documented since substituted benzoxazinones by intramolecular condensation in
the pioneering work on the addition of arylpalladium species the presence of sulfuric acid (Scheme 1c).15 However, efficient
to the cyano group reported by Larock and co-workers.3 In catalytic transformation of N-(2-cyanoaryl)benzamides toward
recent years, we also developed the palladium-catalyzed quinazolines has not been realized yet. Only a few groups have
addition of organoboron reagents to nitriles for access to alkyl developed strategies for the synthesis of quinazolines via
aryl ketones, diketones, 2-aminobenzophenones, benzofurans,
and indoles.4
Quinazolines occur in natural products,5 biologically active
molecules,6 and functionalized materials.7 Because of their
great value, numerous methodologies for the synthesis of qui-
nazolines have been reported, which mainly start from ortho-
functionalized anilines,8 amidines9 or ortho-functionalized-
halide,10 generally with multiple-step reactions.11 In 2013, our
group developed copper-catalyzed direct access to 2-substi-
tuted quinazolines by a copper-catalyzed tandem reaction of
(2-aminophenyl)methanols, aldehydes, and ammonium chlor-
ide.12 However, only sporadic examples of the tandem reaction
of commercially available nitriles for access to 2,4-di-
substituted quinazolines have been reported to date. Chen13a
College of Chemistry & Materials Engineering, Wenzhou University, Wenzhou
325035, P. R. China. E-mail: jiuxichen@wzu.edu.cn
†Electronic supplementary information (ESI) available: 1H and 13C NMR spectra
for products. See DOI: 10.1039/c8ob02421a
‡These authors contributed equally.
Scheme 1 Design of a new approach to quinazolines.
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quantitative addition of organometallics with N-(2-cyanoaryl) acid resulted in only trace amounts of 3a, acetic acid or
amides,16 implying that the development of a practical cata- benzoic acid led to 27% and 31% yield of the desired product,
lytic approach to quinazoline using aryl nitriles and amides as respectively (entries 1–3). The yield was further improved to
substrates remains a challenging area for exploration.
71% and 84% when D-camphorsulfonic acid (CSA) and trifluoro-
Very recently, we developed tandem addition/cyclization for acetic acid (TFA) were used, respectively. However, the reaction
access to isoquinolines,17a,b isoquinolones,17b and quinazo- failed to deliver the desired product when using hydro-
lines (Scheme 1d)17c,d via catalytic carbopalladation of nitriles. chloric acid as an additive (entry 6). An investigation of the
Inspired by these results, we envisioned that sequential cata- effect of Pd(II) catalysts (entries 5, 7–10) revealed that the use
lytic carbopalladation of N-(2-cyanoaryl)benzamides with aryl- of Pd(OAc)2 as a catalyst achieved the best result (95%, entry
boronic acids followed by an intramolecular cyclization would 10), with only a trace amount of byproduct (biphenyl). In con-
result in a tandem procedure for the preparation of structurally trast, this transformation did not work using Pd(0), such as
diverse quinazolines (Scheme 1e).
Pd(PPh3)4, as a catalyst (entry 11). Replacement of 2,2′-bipyridine
(L1) with other ligands, including 5,5′-dimethyl-2,2′-bipyridine
(L2), 6,6′-dimethyl-2,2′-bipyridine (L3) and 1,10-phenanthro-
line (L4), resulted in relatively lower yields (entries 10, 12–14).
Other solvents, including toluene, hexane, 1,4-dioxane, DMF
and 1,2-dichloroethane, were less efficient (entries 15–19).
Decreasing the amount of boronic acid reduced the yield to
some extent (entry 20). In addition, the desired product 3a was
isolated in lower yield when the procedure was carried out
under a N2 atmosphere (entry 21). No desired product was
observed if either palladium catalyst or ligand was absent
(entries 22 and 23). Other reaction parameters including the
amount of TFA and reaction temperature were also examined
(see Table S1 in the ESI†). The results showed that 2 equiva-
lents of TFA were sufficient. The yield was decreased to some
extent when the reaction was performed at a lowered or
elevated temperature.
Results and discussion
To test this hypothesis, we initiated our investigations by
examining the reaction of easily accessible N-(2-cyanophenyl)
benzamide (1a) with phenylboronic acid (2a) to identify the
optimal conditions (Table 1). We tested the formation of the
desired product 2,4-diphenylquinazoline (3a) in the presence
of different acid additives in THF, with Pd(acac)2 as the catalyst
and 2,2′-bipyridine (L1) as the ligand. While methanesulfonic
Table 1 Optimization of the reaction conditionsa
With the optimized conditions in hand, we began to test
this reaction of N-(2-cyanophenyl)benzamide (1a) with various
arylboronic acids 2 to examine the scope and generality of this
protocol (Table 2). The reaction was found to work well with a
variety of arylboronic acids. First, the reactivities of para-,
meta-, and ortho-tolylboronic acids were evaluated, and the
results demonstrated that the steric effect of the substituent
had an obvious impact on the reaction. For example, treatment
of 1a with para- and meta-tolylboronic acids provided 96% and
98% yields of 3b and 3c, respectively (entries 2 and 3), while
the ortho-tolylboronic acid afforded the desired product 3d
with a diminished yield of 76% (entry 4). Similarly, substrate
(4-(tert-butyl)phenyl)boronic acid afforded the desired product
3e in 99% yield (entry 5). The electronic properties of the sub-
stituents on the phenyl ring of the arylboronic acids affected
the yields of the reaction to some extent. In general, the sub-
strates bearing an electron-donating substituent provided a
slightly higher yield than those bearing halogenated phenyl-
boronic acids (entries 6–13). For example, moderate yields of
the halogen-substituted (e.g. –F, –Cl, –Br, –I) products 3f–3j
were obtained, while good to excellent yields of the methoxy-,
phenoxy- or hydroxyl-substituted products 3k–3m were
obtained. The method tolerates the entire range of halogen
substituents, which makes this method particularly appealing.
Boronic acids with strong electron-withdrawing substituents
decreased the efficiency obviously (entries 14 and 15). For
example, (4-(ethoxycarbonyl)phenyl)boronic acid could afford
the desired product only in 23% yield, while (4-nitrophenyl)
Yieldb
(%)
Entry [Pd]
Ligand Additive
Solvent
1
2
3
4
5
6
7
Pd(acac)2
L1
L1
L1
L1
L1
L1
L1
CH3SO3H THF
CH3SO2H THF
Trace
27
31
71
84
0
11
15
87
95
0
92
38
58
53
41
25
76
Pd(acac)2
Pd(acac)2
Pd(acac)2
Pd(acac)2
Pd(acac)2
PdCl2
PhCO2H
CSA
TFA
HCl
TFA
TFA
TFA
TFA
TFA
TFA
TFA
TFA
TFA
TFA
TFA
TFA
TFA
TFA
TFA
TFA
TFA
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
Toluene
Hexane
1,4-Dioxane
DMF
8
9
Pd(CH3CN)2Cl2 L1
Pd(CF3CO2)2
Pd(OAc)2
Pd(PPh3)4
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
L1
L1
L1
L2
L3
L4
L1
L1
L1
L1
L1
L1
L1
L1
10
11
12
13
14
15
16
17
18
19
20c
21e
22
23
ClCH2CH2Cl 59
THF
THF
THF
THF
34(85)d
24(63)f
0
0
Pd(OAc)2
a Conditions: 1a (0.2 mmol), 2a (0.4 mmol), Pd catalyst (5 mol%),
ligand (10 mol%), additive (2 equiv.), solvent (1 mL), 80 °C, 24 h, air.
b Isolated yield. c 1.0 equivalent of 2a was used. d 1.5 equivalents of 2a
were used. e 1.0 equivalent of 2a was used, under N2. f 2.0 equivalent of
2a were used, under N2.
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Table 2 Reaction of various arylboronic acids with N-(2-cyanophenyl)
amidea
Table 3 Reaction of various N-(2-cyanoaryl)amides with phenylboronic
acida
a Conditions: 1 (0.2 mmol), 2 (0.4 mmol), Pd(OAc)2 (5 mol%), L1
(10 mol%), TFA (2 equiv.), THF (1 mL), 80 °C, 24 h, air. Isolated yield.
and 76% yields, respectively, while 4c possessing an ortho-
methyl group was obtained in 63% yield (entries 1–3). Not only
electron-donating groups, such as methyl (4a–4c) and methoxy
(4d), but also electron-withdrawing groups, such as fluoro (4e),
chloro (4f), bromo (4g), nitro (4h) and trifluoromethyl (4i) on
the phenyl ring at the para position, were tolerated in this
a Conditions: 1 (0.2 mmol), 2 (0.4 mmol), Pd(OAc)2 (5 mol%), L1
(10 mol%), TFA (2 equiv.), THF (1 mL), 80 °C, 24 h, air. Isolated yield.
boronic acid was an inefficient substrate. Naphthalen-1-ylboronic transformation. In contrast, aliphatic substrates (R = alkyl)
acid, naphthalen-2-ylboronic acid, and biphenyl-4-ylboronic acid made the reactions less effective, which may arise from the
were also good partners and coupled with 1a efficiently, decreased reactivity of carbonyl on the amide moiety (entries
affording the corresponding products 3p–3r in good to excellent 10–14). Functional groups (R1) such as fluoro, bromo, chloro,
yields (entries 16–18). However, the reaction failed to deliver the and methoxy on the ‘left’ side phenyl ring of the substrates
desired product when methylboronic acid or (E)-styrylboronic were well tolerated, affording the corresponding products 4o–
acid was used as the substrate (entries 19 and 20).
4r in good to excellent yields (entries 15–18). Notably, the pres-
We next turned our attention to the effect of the reactions ence of the halogen substituents in products 4o–4q is useful
between other N-(2-cyanoaryl)benzamides 1 and phenylboronic for further synthetic manipulations. However, the reaction
acid (2a) under standard conditions (Table 3). The influence of failed to deliver the desired product when a heterocycle-con-
substitutions on the amide moiety (R = aryl) was first investi- taining substrate namely N-(3-cyanopyridin-2-yl)benzamide
gated. The steric effects of the substituents affected the yields was used (entry 19).
of this transformation to some extent. For example, when sub-
Additionally, the tandem reaction of N-(4-bromo-2-cyano-
strates bearing a para-, meta-, and ortho-methyl group on the phenyl)benzamide bearing a bromo group with naphthalen-1-
phenyl ring were examined, 4a and 4b were obtained in 77% ylboronic acid was performed to produce the desired product
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Conclusions
In summary, we have developed a new strategy for the syn-
thesis of quinazolines in moderate to excellent yields by the
Pd-catalyzed tandem addition/cyclization of N-(2-cyanoaryl)
benzamides with arylboronic acids. This protocol provides an
alternative synthetic pathway to access 2,4-disubstituted quina-
zolines. Further efforts to extend this catalytic system to the
preparation of other useful heterocyclic compounds are cur-
rently underway in our laboratories.
Scheme 2 Synthesis of product 4t bearing a bromo group.
Experimental section
Scheme 3 Gram-scale synthesis of 3a.
General methods
1
Melting points are uncorrected. H NMR and 13C NMR spectra
were recorded on a 500 MHz spectrometer (1H NMR at
500 MHz, 13C NMR at 125 MHz), using 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-resolu-
tion mass spectra were recorded on an ESI-Q-TOF mass
spectrometer. N-(2-Cyanoaryl)benzamides were synthesized
from 2-aminobenzonitrile derivatives and the appropriate acyl
chloride or anhydride according to modified literature pro-
cedures.14,18 Other commercially obtained reagents were used
without further purification. All reactions were conducted
under a nitrogen atmosphere using standard Schlenk tech-
niques. Column chromatography was performed using EM
silica gel 60 (300–400 mesh).
Scheme 4 Plausible reaction mechanism for the formation of
quinazolines.
General procedure for the synthesis of N-(2-cyanophenyl)
benzamides
6-bromo-4-(naphthalen-1-yl)-2-phenylquinazoline (4t) in 72% To a Schlenk tube were added N-(2-cyanoaryl) benzamides 1
yield (Scheme 2).
(0.2 mmol), arylboronic acids (0.4 mmol), Pd(OAc)2
2
The efficiency of this catalytic system was further demon- (5 mol%), L1 (10 mol%), TFA (2 equiv.) and THF (1 mL) under
strated by running the transformation on a laboratory prepara- air. The reaction mixture was stirred vigorously at 80 °C for
tive scale. For example, we performed the model reaction on a 24 h under air. The mixture was poured into ethyl acetate,
gram scale (5 mmol), and 3a was obtained in 87% isolated which was washed with saturated NaHCO3 (2 × 10 mL) and
yield, albeit with a prolonged reaction time (48 h) (Scheme 3).
then brine (1 × 10 mL). After the aqueous layer was extracted
A possible reaction mechanism for the formation of quina- with ethyl acetate, the combined organic layers were dried over
zolines from N-(2-cyanoaryl)benzamides and arylboronic acids anhydrous Na2SO4 and evaporated under vacuum. The residue
as a representative example is shown in Scheme 4. The follow- was purified by flash column chromatography with petroleum
ing key steps are included in the catalytic pathway: (i) transme- ether/ethyl acetate (30 : 1 to 10 : 1) to afford the desired
tallation of the palladium species with arylboronic acids to products.
form the palladium-aryl species A, which was followed by (ii)
2,4-Diphenylquinazoline (3a). Yellow solid (53.6 mg, 95%),
the coordination of N-(2-cyanoaryl)benzamides 1 to give inter- mp 116–117 °C (lit.8e 117–119 °C). H NMR (500 MHz, CDCl3)
mediate B; (iii) carbopalladation of the cyano group to result δ 8.71 (d, J = 8.0 Hz, 2H), 8.20 (d, J = 8.0 Hz, 1H), 8.14 (d, J =
in the formation of the corresponding ketimine palladium 8.0 Hz, 1H), 7.92–7.88 (m, 3H), 7.64–7.59 (m, 3H), 7.58–7.48
intermediate C; and (iv) protonation of intermediate C by TFA (m, 4H); 13C NMR (125 MHz, CDCl3) δ 168.4, 160.2, 151.9,
to afford the N-(2-(imino(aryl)methyl)aryl)benzamide (D) and 138.2, 137.7, 133.6, 130.5, 130.2, 129.9, 129.1, 128.7, 128.5,
regenerate the palladium catalyst. Next, the nucleophilic attack 127.0, 121.7.
1
of the resulting imine on the carbonyl group generates the
2-Phenyl-4-(p-tolyl)quinazolines (3b). Yellow solid (56.9 mg,
1
dihydroquinazolin-2-ol (E). Finally, dehydration of the dihydro- 96%), mp 125–127 °C (lit.8e 128–130 °C). H NMR (500 MHz,
quinazolin-2-ol (E) would deliver the corresponding quinazo- CDCl3) δ 8.71 (d, J = 7.0 Hz, 2H) 8.17 (t, J = 9.0 Hz, 2H), 7.88
lines as the desired products.
(m, 1H), 7.81 (d, J = 8.0 Hz, 2H), 7.58–7.48 (m, 4H), 7.41 (d, J =
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7.5 Hz, 2H), 2.51 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 168.4, 1H), 8.07 (d, J = 8.5 Hz, 1H), 7.90 (t, J = 7.5 Hz, 1H), 7.80 (d, J =
160.2, 151.9, 140.2, 138.2, 134.9, 133.5, 130.5, 130.2, 129.3, 8.0 Hz, 2H), 7.54 (d, J = 8.0 Hz, 2H), 7.59–7.50 (m, 4H); 13C
129.1, 128.7, 128.5, 127.1, 126.9, 121.7, 21.5.
NMR (125 MHz, CDCl3) δ 166.2, 159.2, 150.9, 136.9, 135.5,
2-Phenyl-4-(m-tolyl)quinazolines (3c). Yellow solid (58.1 mg, 132.8, 130.8, 130.7, 129.7, 128.2, 127.7, 127.6, 126.2, 125.5,
1
98%), mp 81–83 °C (lit.19 84 °C). H NMR (500 MHz, CDCl3) 123.7, 120.4.
δ 8.71 (d, J = 7.0 Hz, 2H), 8.18 (d, J = 7.5 Hz, 1H), 8.13 (d, J =
4-(4-Iodophenyl)-2-phenylquinazoline (3j). Yellow solid
7.5 Hz, 1H), 7.89 (t, J = 7.5 Hz, 1H), 7.71 (s, 1H), 7.66 (d, J = (44.9 mg, 55%), mp 139–140 °C. 1H NMR (500 MHz, CDCl3)
7.5 Hz, 1H), 7.58–7.46 (m, 5H), 7.41 (d, J = 7.5 Hz, 1H), 2.52 δ 8.69 (d, J = 7.5 Hz, 2H), 8.23 (d, J = 8.0 Hz, 1H), 8.08 (d, J =
(s, 3H); 13C NMR (125 MHz, CDCl3) δ 168.7, 160.3, 151.9, 8.0 Hz, 1H), 7.96 (d, J = 8.0 Hz, 2H), 7.92 (t, J = 7.5 Hz, 1H),
138.4, 138.3, 137.7, 133.5, 130.7, 130.7, 130.5, 129.1, 128.8, 7.63 (d, J = 8.0 Hz, 2H), 7.58 (t, J = 8.0 Hz, 1H), 7.55–7.50 (m,
128.5, 128.4, 127.4, 127.1, 126.9, 121.8, 21.5.
3H); 13C NMR (125 MHz, CDCl3) δ 166.4, 159.2, 150.9, 136.8,
2-Phenyl-4-(o-tolyl)quinazolines (3d). Yellow solid (45.1 mg, 136.8, 136.1, 132.8, 130.8, 129.7, 128.2, 127.7, 127.6, 126.3,
1
76%), mp 140–141 °C (lit.19 143–145 °C). H NMR (500 MHz, 125.5, 120.4, 95.6. HRMS (ESI) calcd for C20H14IN2 [M + H]+:
CDCl3) δ 8.68 (d, J = 7.0 Hz, 2H), 8.21 (d, J = 8.0 Hz, 1H), 7.90 409.0196, found: 409.0223.
(t, J = 7.5 Hz, 1H), 7.70 (d, J = 8.5 Hz, 1H), 7.55–7.49 (m, 4H),
4-(4-Methoxyphenyl)-2-phenylquinazoline (3k). Yellow solid
7.46 (t, J = 7.5 Hz, 1H), 7.41 (d, J = 7.5 Hz, 2H), 7.38 (d, J = 8.5 (50.6 mg, 81%), mp 120–121 °C (lit.8g 118–119 °C). 1H NMR
Hz, 1H), 2.24 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 170.0, (500 MHz, CDCl3) δ 8.71 (d, J = 7.0 Hz, 2H), 8.16 (t, J = 9.5 Hz,
160.3, 151.3, 138.1, 136.9, 136.5, 133.8, 130.8, 130.6, 129.7, 2H), 7.90 (d, J = 8.5 Hz, 2H), 7.86 (d, J = 8.0 Hz, 1H), 7.55–7.50
129.3, 128.9, 128.8, 128.6, 127.1, 127.1, 125.6, 122.7, 20.0.
4-(4-(tert-Butyl)phenyl)-2-phenylquinazoline (3e).
(m, 4H), 7.12 (d, J = 8.5 Hz, 2H), 3.93 (s, 3H); 13C NMR
Oil (125 MHz, CDCl3) δ 167.8, 161.3, 160.1, 152.0, 138.3, 133.4,
1
(67.0 mg, 99%). H NMR (500 MHz, CDCl3) δ 8.74 (d, J = 7.0 131.9, 130.5, 130.2, 129.1, 128.7, 128.5, 127.1, 126.9, 121.7,
Hz, 2H), 8.18 (m, 2H), 7.90–7.85 (m, 3H), 7.64 (d, J = 8.0 Hz, 114.1, 55.5.
2H), 7.58–7.50 (m, 4H), 1.45 (s, 9H); 13C NMR (125 MHz,
4-(4-Phenoxyphenyl)-2-phenylquinazoline (3l). Yellow solid
CDCl3) δ 168.3, 160.3, 153.3, 125.0, 138.3, 134.9, 133.4, 130.5, (72.6 mg, 97%), mp 106–108 °C. 1H NMR (500 MHz, CDCl3)
130.1, 129.1, 128.7, 128.5, 127.2, 126.9, 125.6, 121.8, 34.9, 31.4. δ 8.69 (d, J = 7.0 Hz, 2H), 8.17 (d, J = 8.0 Hz, 2H), 7.92–7.86 (m,
HRMS (ESI) calcd for C24H23N2 [M + H]+: 333.1856, found: 3H), 7.58–7.48 (m, 4H), 7.41 (t, J = 8.0 Hz, 2H), 7.19 (t, J = 8.0
333.1857.
Hz, 3H), 7.15 (d, J = 7.5 Hz, 2H); 13C NMR (125 MHz, CDCl3)
4-(4-Fluorophenyl)-2-phenylquinazoline (3f). Yellow solid δ 166.5, 159.2, 158.4, 155.3, 151.0, 137.2, 132.5, 131.3, 131.0,
(46.8 mg, 78%), mp 132–134 °C (lit.9b 134–136 °C). 1H NMR 129.5, 129.0, 128.2, 127.7, 127.5, 126.0, 125.9, 123.1, 120.6,
(500 MHz, CDCl3) δ 8.69 (d, J = 7.5 Hz, 2H), 8.19 (d, J = 8.5 Hz, 118.7, 117.2. HRMS (ESI) calcd for C26H19N2O [M + H]+:
2H), 8.11 (d, J = 8.5 Hz, 1H), 7.95–7.88 (m, 3H), 7.60–7.49 (m, 375.1492, found: 375.1497.
4H), 7.30 (t, J = 8.5 Hz, 2H); 13C NMR (125 MHz, CDCl3)
δ 167.2, 165.0, 163.0, 160.2, 152.0, 138.1, 133.8, 133.8, 133.7, (54.8 mg, 91%), 193–194 °C. H NMR (500 MHz, CDCl3) δ 8.68
133.2, 133.2, 130.6, 129.3, 128.7, 128.6, 127.2, 126.7, 121.6, (d, J = 7.0 Hz, 2H), 8.17 (m, 2H), 7.88–7.84 (m, 3H), 7.56–7.52
4-(2-Phenylquinazolin-4-yl)phenol (3m). Yellow solid
1
115.8, 115.6.
(m, 4H), 7.04 (d, J = 8.0 Hz, 2H), 5.66 (s, 1H); 13C NMR
4-(3-Fluorophenyl)-2-phenylquinazoline (3g). Yellow solid (125 MHz, CDCl3) δ 167.8, 160.2, 157.5, 133.5, 132.1, 130.5,
(39.0 mg, 65%), mp 104–105 °C. 1H NMR (500 MHz, CDCl3) 130.3, 129.2, 129.1, 128.7, 128.5, 127.2, 127.1, 126.96, 121.6,
δ 8.69 (d, J = 7.0 Hz, 2H), 8.19 (d, J = 8.5 Hz, 1H), 8.11 (d, J = 115.6. HRMS (ESI) calcd for C20H15N2O [M + H]+: 299.1179,
8.5 Hz, 1H), 7.91 (t, J = 7.5 Hz, 1H), 7.67 (d, J = 7.5 Hz, 1H), found: 299.1190.
7.63 (t, J = 9.5 Hz, 1H), 7.60–7.50 (m, 5H), 7.30 (t, J = 8.5 Hz,
Ethyl-4-(2-phenylquinazolin-4-yl)benzoate (3n). Yellow solid
1H); 13C NMR (125 MHz, CDCl3) δ 167.0, 163.8, 161.8, 160.2, (16.7 mg, 23%), mp 141–142 °C. 1H NMR (500 MHz, CDCl3)
151.9, 139.8, 139.7, 137.8, 133.8, 130.7, 130.2, 130.1, 129.2, δ 8.69 (d, J = 7.0 Hz, 2H), 8.28 (d, J = 8.0 Hz, 2H), 8.22 (d, J =
128.7, 128.6, 127.3, 126.6, 126.0, 125.9, 121.5, 117.3, 117.1, 6.0 Hz, 1H), 8.06 (d, J = 8.0 Hz, 1H), 8.00–7.87 (m, 3H),
117.0, 116.9. HRMS (ESI) calcd for C20H14FN2Na [M + Na]+: 7.61–7.47 (m, 4H), 4.46 (q, J = 7.1 Hz, 2H), 1.46 (t, J = 7.1 Hz,
323.0961, found: 323.0964.
3H). 13C NMR (125 MHz, CDCl3) δ 167.5, 166.2, 160.3, 151.9,
4-(4-Chlorophenyl)-2-phenylquinazoline (3h). Yellow solid 141.8, 137.9, 133.9, 131.8, 130.8, 130.2, 129.7, 129.3, 128.7,
(36.7 mg, 58%), mp 136–137 °C (lit.20 146–147 °C). 1H NMR 127.4, 126.6, 121.6, 61.3, 14.4.
(500 MHz, CDCl3) δ 8.70 (d, J = 7.0 Hz, 2H), 8.24 (d, J = 8.0 Hz,
4-(Naphthalen-1-yl)-2-phenylquinazoline (3p). Yellow solid
1H), 8.09 (d, J = 8.0 Hz, 1H), 7.92 (t, J = 7.5 Hz, 1H), 7.85 (d, J = (60.5 mg, 91%), mp 178–180 °C. 1H NMR (500 MHz, CDCl3)
8.0 Hz, 2H), 7.58 (t, J = 7.5 Hz, 3H), 7.56–7.50 (m, 3H); 13C δ 8.68 (d, J = 5.5 Hz, 2H), 8.23 (d, J = 8.0 Hz, 1H), 8.07 (m, 1H),
NMR (125 MHz, CDCl3) δ 167.2, 160.2, 152.0, 137.9, 136.4, 7.99 (d, J = 8.0 Hz, 1H), 7.90 (t, J = 7.0 Hz, 1H), 7.69–7.62 (m,
136.1, 133.8, 131.5, 130.7, 129.3, 128.9, 128.7, 128.6, 127.3, 4H), 7.56–7.48 (m, 4H), 7.45–7.37 (m, 2H); 13C NMR (125 MHz,
126.6, 121.5.
CDCl3) δ 169.1, 160.4, 151.4, 138.1, 134.9, 133.9, 133.8, 131.7,
4-(4-Bromophenyl)-2-phenylquinazoline (3i). Yellow solid 130.6, 129.8, 129.0, 128.9, 128.6, 128.4, 128.0, 127.3, 127.1,
(40.4 mg, 56%), mp 146–148 °C (lit.8e 154–156 °C). 1H NMR 126.7, 126.3, 125.8, 125.1, 123.4. HRMS (ESI) calcd for
(500 MHz, CDCl3) δ 8.68 (d, J = 7.0 Hz, 2H), 8.17 (d, J = 9.0 Hz, C24H17N2 [M + H]+: 333.1386, found: 333.1385.
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4-(Naphthalen-2-yl)-2-phenylquinazoline (3q). Yellow solid
2-(4-Chlorophenyl)-4-phenylquinazoline (4f). Yellow solid
(54.5 mg, 82%), mp 161–162 °C (lit.8g 164–166 °C). 1H NMR (33.6 mg, 53%), mp 180–181 °C (lit.9b 175–176 °C). 1H NMR
(500 MHz, CDCl3) δ 8.75 (d, J = 7.0 Hz, 2H), 8.37 (s, 1H), 8.20 (500 MHz, CDCl3) δ 8.68 (d, J = 8.0 Hz, 2H), 8.23 (d, J = 7.5 Hz,
(t, J = 11.0 Hz, 2H), 8.08 (d, J = 8.0 Hz, 1H), 8.05–7.95 (m, 3H), 1H), 8.14 (t, J = 9.0 Hz, 1H), 7.94–7.87 (m, 3H), 7.62–7.57 (m,
7.91 (m, J = 7.0 Hz, 1H), 7.65–7.60 (m, 2H), 7.59–7.49 (m, 4H); 4H), 7.50 (d, J = 8.5 Hz, 2H); 13C NMR (125 MHz, CDCl3)
13C NMR (125 MHz, CDCl3) δ 168.3, 160.3, 152.0, 138.2, 135.1, δ 168.4, 159.3, 152.0, 137.6, 136.8, 136.7, 133.7, 130.2, 130.1,
134.0, 133.6, 133.0, 130.6, 130.3, 129.2, 128.7, 128.6, 128.4, 130.0, 129.2, 128.7, 128.6, 127.2, 127.1, 121.8.
127.8, 127.3, 127.3, 127.1, 127.1, 126.7, 121.9.
2-(4-Bromophenyl)-4-phenylquinazoline (4g). Yellow solid
4-([1,1′-Biphenyl]-4-yl)-2-phenylquinazoline (3r). Yellow solid (40.5 mg, 56%), mp 185–186 °C (lit.8g 192–194 °C). 1H NMR
(68.1 mg, 95%), mp 217–218 °C (lit.17c 217–218 °C). H NMR (500 MHz, CDCl3) δ 8.59 (d, J = 8.5 Hz, 2H), 8.16 (d, J = 8.0 Hz,
1
(500 MHz, CDCl3) δ 8.73 (d, J = 7.5 Hz, 2H), 8.21 (d, J = 8.0 Hz, 1H), 8.14 (d, J = 8.5 Hz, 1H), 7.93–7.85 (m, 3H), 7.65 (d, J =
2H), 8.00 (d, J = 7.5 Hz, 2H), 7.91 (t, J = 7.5 Hz, 1H), 7.84 (d, J = 8.5 Hz, 2H), 7.60 (t, J = 8.0 Hz, 3H), 7.57 (t, J = 8.0 Hz, 1H);
7.5 Hz, 2H), 7.72 (d, J = 7.5 Hz, 2H), 7.60–7.50 (m, 6H), 7.43 (t, 13C NMR (125 MHz, CDCl3) δ 168.5, 159.3, 151.8, 137.5, 137.1,
J = 7.5 Hz, 1H); 13C NMR (125 MHz, CDCl3) δ 167.0, 159.2, 133.8, 131.7, 130.3, 130.2, 130.1, 129.1, 128.6, 127.3, 127.1,
150.9, 141.9, 139.4, 137.1, 135.6, 132.6, 129.7, 129.6, 128.2, 125.4, 121.8.
127.9, 127.7, 127.5, 126.8, 126.3, 12.63, 126.0, 126.0, 120.7.
2-(4-Nitrophenyl)-4-phenylquinazoline (4h). Yellow solid
HRMS (ESI) calcd for C26H19N2 [M + H]+: 359.1543, found: (43.9 mg, 63%), mp 207–209 °C (lit.9b 198–199 °C). 1H NMR
359.1543. (500 MHz, CDCl3) δ 8.89 (d, J = 9.0 Hz, 2H), 8.36 (d, J = 8.5 Hz,
+
4-Phenyl-2-(p-tolyl)quinazolines (4a). Yellow solid (45.6 mg, 2H), 8.22 (d, J = 8.5 Hz, 1H), 8.18 (d, J = 8.5 Hz, 1H), 7.96 (t, J =
1
77%), mp 162–165 °C (lit.8e 166–168 °C). H NMR (500 MHz, 7.5 Hz, 1H), 7.92–7.86 (m, 2H), 7.67–7.60 (m, 4H); 13C NMR
CDCl3) δ 8.60 (d, J = 8.0 Hz, 2H), 8.20 (s, 1H), 8.12 (d, J = 8.0 (125 MHz, CDCl3) δ 168.9, 158.0, 151.7, 149.3, 144.0, 137.2, 134.1,
Hz, 1H), 7.90–7.87 (m, 3H), 7.61–7.59 (m, 3H), 7.54 (t, J = 8.0 130.3, 130.2, 129.6, 129.3, 128.7, 128.1, 127.2, 123.7, 122.0.
Hz, 1H),7.34 (t, J = 7.5 Hz, 2H), 2.44 (s, 3H); 13C NMR
4-Phenyl-2-(4-(trifluoromethyl)phenyl)quinazolines
(4i).
(125 MHz, CDCl3) δ 168.4, 160.3, 151.8, 140.8, 137.8, 135.4, Yellow solid (51.9 mg, 74%), mp 115–116 °C (lit.9b
1
133.5, 130.2, 129.5, 129.3, 129.0, 128.7, 128.5, 127.0, 126.8, 123–126 °C). H NMR (500 MHz, CDCl3) δ 8.83 (d, J = 8.0 Hz,
121.6, 21.5.
2H), 8.21 (d, J = 8.0 Hz, 1H), 8.17 (d, J = 8.5 Hz, 1H), 7.93 (t, J =
4-Phenyl-2-(m-tolyl)quinazolines (4b). Yellow solid (45.0 mg, 8.5 Hz, 1H), 7.90–7.88 (m, 2H), 7.78 (d, J = 8.0 Hz, 2H),
1
76%), mp 112–114 °C (lit.8e 115–117 °C). H NMR (500 MHz, 7.62–7.59 (m, 4H); 13C NMR (125 MHz, CDCl3) δ 168.7, 158.8,
CDCl3) δ 8.50 (d, J = 8.5 Hz, 2H), 8.17 (d, J = 8.5 Hz, 1H), 8.13 151.7, 141.4, 137.4, 133.9, 132.3, 132.0, 130.2 (d, J = 3.75 Hz),
(d, J = 8.5 Hz, 1H), 7.90–7.87 (m, 3H), 7.63–7.58 (m, 3H), 7.55 129.2, 129.0, 128.6, 127.7, 127.1, 125.5 (q, J = 7.5 Hz), 123.2,
(t, J = 8.5 Hz, 1H), 7.43 (t, J = 7.5 Hz, 1H), 7.32 (d, J = 7.5 Hz, 122.0, 100.0
1H), 2.50 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 168.3, 160.4,
2-(tert-Butyl)-4-phenylquinazoline
152.0, 138.1, 137.7, 133.5, 131.4, 130.2, 129.9, 129.2, 129.1, (27.0 mg, 51%), mp 68–71 °C (lit.8e 70–72 °C). 1H NMR
128.6, 128.5, 127.0, 126.9, 126.0, 121.7, 22.6. (500 MHz, CDCl3) δ 8.09 (t, J = 8.0 Hz, 2H), 7.84 (m, 3H), 7.56
(4j).
Yellow
solid
4-Phenyl-2-(o-tolyl)quinazolines (4c). Yellow solid (37.3 mg, (m, 3H), 7.51 (t, J = 7.5 Hz, 1H), 1.57 (s, 9H); 13C NMR
63%), mp 73–75 °C (lit.8e 72–74 °C). 1H NMR (500 MHz, CDCl3) (125 MHz, CDCl3) δ 172.9, 167.4, 151.4, 138.0, 132.9, 130.2,
δ 8.18 (t, J = 8.0 Hz, 2H), 7.98 (d, J = 7.5 Hz, 1H), 7.92 (t, J = 129.6, 128.9, 128.3, 126.7, 126.4, 120.9, 39.7, 29.7. HRMS (ESI)
8.0 Hz, 1H), 7.87 (d, J = 7.5 Hz, 2H), 7.63–7.55 (m, 4H), 7.39–7.31 calcd for C18H19N2 [M + H]+: 263.1543, found: 263.1545.
(m, 3H), 2.67 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 168.1, 163.4,
151.6, 138.7, 137.5, 137.5, 133.6, 131.3, 130.8, 130.2, 129.9, 129.3, 38%). 1H NMR (500 MHz, CDCl3) δ 8.02 (d, J = 7.5 Hz, 1H),
129.0, 128.6, 127.3, 127.0, 126.0, 121.0, 21.3. 7.98 (d, J = 7.5 Hz, 1H), 7.84–7.73 (m, 3H), 7.56 (m, 3H), 7.46
2-Cyclopropyl-4-phenylquinazoline (4k). Yellow oil (18.6 mg,
2-(4-Methoxyphenyl)-4-phenylquinazoline (4d). Yellow solid (d, J = 6.0 Hz, 1H), 2.46 (s, 1H), 1.33 (m, 2H), 1.13 (m, 2H);
(23.1 mg, 36%), mp 159–160 °C (lit.9b 160–161 °C). 1H NMR 13C NMR (125 MHz, CDCl3) δ 168.2, 167.6, 151.4, 137.6, 133.5,
(500 MHz, CDCl3) δ 8.67 (d, J = 8.5 Hz, 2H), 8.14 (d, J = 8.0 Hz, 130.0, 129.8, 128.5, 127.5, 127.0, 126.1, 121.3, 18.6, 10.6.
1H), 8.10 (d, J = 8.5 Hz, 1H), 7.89–7.85 (m, 3H), 7.60 (t, J = HRMS (ESI) calcd for C17H15N2 [M + H]+: 247.1230, found:
9.0 Hz, 3H), 7.51 (t, J = 8.0 Hz, 1H), 7.04 (d, J = 9.0 Hz, 2H), 247.1228.
3.90 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 168.3, 161.9, 160.0,
151.9, 147.2, 137.8, 133.6, 130.4, 130.2, 129.9, 128.8, 128.5, 31%). 1H NMR (500 MHz, CDCl3) δ 8.06 (m, 2H), 7.85 (t, J =
127.0, 126.6, 121.4, 113.96, 55.4. 7.5 Hz, 1H), 7.78 (m, 2H), 7.56 (m, 3H), 7.51 (t, J = 7.5 Hz, 1H),
2-Cyclohexyl-4-phenylquinazoline (4l). Yellow oil (17.6 mg,
2-(4-Fluorophenyl)-4-phenylquinazoline (4e). Yellow solid 3.21 (t, J = 11.5 Hz, 1H), 2.13 (m, 2H), 1.92–1.74 (m, 5H),
(30.6 mg, 51%), mp 144–145 °C (lit.8f 153–155 °C). 1H NMR 1.53–1.43 (m, 2H), 1.41–1.32 (m, 1H); 13C NMR (125 MHz,
(500 MHz, CDCl3) δ 8.71 (t, J = 8.0 Hz, 2H), 8.17–8.10 (m, 2H), CDCl3) δ 170.3, 168.4, 151.4, 137.7, 133.3, 130.0, 129.8, 128.5,
7.92–7.85 (m, 3H), 7.60 (s, 3H), 7.55 (t, J = 7.5 Hz, 1H), 7.20 (t, 128.4, 126.9, 126.6, 121.4, 47.8, 32.0, 26.3, 26.1. HRMS (ESI)
J = 8.0 Hz, 2H); 13C NMR (125 MHz, CDCl3) δ 168.5, 165.7, calcd for C20H21N2 [M + H]+: 289.1699, found: 289.1702.
163.7, 159.3, 151.9, 137.6, 134.3, 133.7, 130.9, 130.8, 130.2,
130.0, 129.0, 128.6, 127.1, 121.6, 115.5, 115.4.
2-Methyl-4-phenylquinazoline (4m). Yellow solid (16.7 mg,
38%), mp 47–48 °C (lit.16a 48–49 °C). 1H NMR (500 MHz,
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CDCl3) δ 8.00 (t, J = 9.0 Hz, 2H), 7.83 (t, J = 8.0 Hz, 1H),
7.74–7.70 (m, 2H), 7.56–7.42 (m, 4H), 2.93 (s, 3H); 13C NMR
Acknowledgements
(125 MHz, CDCl3) δ 168.6, 163.8, 151.4, 137.3, 133.7, 129.9, We thank the National Natural Science Foundation of China
128.6, 128.1, 127.0, 126.7, 121.1, 26.6. (No. 21572162), the Natural Science Foundation of Zhejiang
4-Phenyl-2-(trifluoromethyl)quinazoline (4n). Yellow solid Province (No. LY16B020012 and LQ18B020006), the Science
(11.6 mg, 22%), mp 87–88 °C (lit.16a 92 °C). 1H NMR and Technology Project of Zhejiang Province (No. 2016C31022)
(500 MHz, CDCl3) δ 8.26 (t, J = 9.0 Hz, 2H), 8.03 (t, J = 7.0 Hz, and the Xinmiao Talent Planning Foundation of Zhejiang
1H), 7.87–7.80 (m, 2H), 7.76 (t, J = 8.0 Hz, 1H), 7.61 (m, 3H). Province (No. 2017R426052) for financial support.
13C NMR (126 MHz, CDCl3) δ 170.2, 152.5, 152.24 (s), 150.9,
136.2, 134.7, 130.7, 130.3, 129.6, 128.8, 127.3, 123.3, 121.2,
119.0.
References
6-Fluoro-2,4-diphenylquinazoline
(4o).
Yellow
solid
(55.9 mg, 93%), mp 173–174 °C (lit.9b 172–173 °C). 1H NMR
(500 MHz, CDCl3) δ 8.69 (d, J = 8.0 Hz, 2H), 8.21 (m, 1H), 7.88
(m, 2H), 7.78–7.73 (m, 1H), 7.70–7.65 (m, 1H), 7.64–7.59 (m,
3H), 7.56–7.48 (m, 3H); 13C NMR (125 MHz, CDCl3) δ 167.9,
161.4, 159.9, 159.4, 149.0, 137.8, 137.3, 131.7 (d, J = 8.5 Hz),
130.7, 130.2, 130.0, 128.7, 128.6 (d, J = 5.0 Hz), 124.0 (d, J =
25.5 Hz), 122.2 (d, J = 8.875 Hz), 110.5 (d, J = 23.0 Hz).
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7-Chloro-2,4-diphenylquinazoline
(4p).
Yellow
solid
(49.4 mg, 78%), mp 151–152 °C. (lit17c 151–152 °C). H NMR
(500 MHz, CDCl3) δ 8.69 (d, J = 7.5 Hz, 2H), 8.18 (s, 1H), 8.06
(d, J = 9.0 Hz, 1H), 7.86 (d, J = 2.5 Hz, 2H), 7.61 (d, J = 2.0 Hz,
3H), 7.53 (d, J = 6.0 Hz, 3H), 7.49 (d, J = 9.0 Hz, 1H); 13C NMR
(125 MHz, CDCl3) δ 168.4, 161.2, 152.6, 139.8, 137.7, 137.3,
130.9, 130.2, 130.1, 128.9, 128.7, 128.6, 128.5, 128.1, 128.0,
120.1. HRMS (ESI) calcd for C20H14ClN2 [M + H]+: 317.0840,
found: 317.0841.
1
6-Bromo-2,4-diphenylquinazoline
(4q).
Yellow
solid
(60.0 mg, 83%), mp 204–205 °C (lit.9b 204–205 °C). 1H NMR
(500 MHz, CDCl3) δ 8.69 (d, J = 8.0 Hz, 2H), 8.27 (s, 1H), 8.00
(d, J = 9.0 Hz, 1H), 7.95 (d, J = 9.0 Hz, 1H), 7.87 (t, J = 9.0 Hz,
2H), 7.63 (m, 3H), 8.53 (m, 3H); 13C NMR (125 MHz, CDCl3)
δ 167.5, 160.5, 150.6, 137.7, 137.1, 130.9, 130.9, 130.3, 130.1,
129.1, 128.8, 128.6, 127.7, 120.7.
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659; (c) Y. Bansal and O. Silakari, Bioorg. Med. Chem., 2012,
20, 6208 and references therein.
6,7-Dimethoxy-2,4-diphenylquinazoline (4r). Yellow solid
(63.0 mg, 92%), mp 176–178 °C (lit.8e 178–180 °C). 1H NMR
(500 MHz, CDCl3) δ 8.63 (d, J = 7.5 Hz, 2H), 7.89 (d, J = 6.5 Hz,
2H), 7.62–7.55 (m, 3H), 7.53–7.45 (m, 4H), 7.34 (s, 1H), 4.10 (s,
3H), 3.91 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 165.2, 159.3,
155.7, 150.0, 149.8, 138.4, 138.2, 130.1, 129.8, 129.7, 128.6,
128.5, 128.3, 117.1, 107.4, 104.2, 56.4, 56.1.
6-Bromo-4-(naphthalen-1-yl)-2-phenylquinazoline (4t). Yellow
solid (59.2 mg, 52%), mp 189–190 °C (lit.17c 189–190 °C).
1H NMR (500 MHz, CDCl3) δ 8.68 (d, J = 3.5 Hz, 2H), 8.09 (d,
J = 8.0 Hz, 2H), 8.01 (d, J = 8.0 Hz, 1H), 7.95 (d, J = 9.0 Hz, 1H),
7.82 (s, 1H), 7.69–7.65 (m, 3H), 7.56 (t, J = 8.0 Hz, 1H), 7.52 (s,
3H), 7.44 (t, J = 8.0 Hz, 1H); 13C NMR (125 MHz, CDCl3)
δ 168.2, 160.7, 150.4, 137.8, 137.4, 134.2, 133.9, 131.6, 130.9,
130.8, 130.1, 129.3, 128.9, 128.7, 128.5, 128.1, 127.0, 126.5,
125.6, 125.1, 124.4, 120.7.
6 For selected examples, see: (a) M. K. Krapf, J. Gallus and
M. Wiese, Eur. J. Med. Chem., 2017, 139, 587;
(b) S. V. Eswararao, V. Venkataramireddy, M. Srinivasareddy
and P. Kumar, Asian J. Chem., 2017, 29, 1434; (c) I. Khan,
A. Ibrar, W. Ahmed and A. Saeed, Eur. J. Med. Chem., 2015,
90, 124; (d) A. Machara, V. Lux, M. Kozisek, K. G. Saskova,
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P. Sehr, J. Lewis, B. Müller, H. G. Kräusslich and
J. Konvalinka, J. Med. Chem., 2016, 59, 545.
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Conflicts of interest
There are no conflicts of interest to declare.
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Paper
Y. W. Bai, T. C. Pan, X. Chen and W. Yu, J. Org. Chem.,
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