Palladium-catalyzed one pot 2-arylquinazoline formation via hydrogen-transfer strategy

Article abstract of DOI:10.1039/c4ob01296h

The palladium catalytic system was first applied to 2-arylquinazoline synthesis via hydrogen transfer methodology. Various (E)-2-nitrobenzaldehyde O-methyl oximes reacted easily with alcohols or benzyl amines to provide N-heterocyclic compounds in good to

Full text of DOI:10.1039/c4ob01296h

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Palladium-catalyzed one pot 2-arylquinazoline
formation via hydrogen-transfer strategy†
Cite this: DOI: 10.1039/c4ob01296h
Huamin Wang, Hui Chen, Ya Chen and Guo-Jun Deng*
The palladium catalytic system was first applied to 2-arylquinazoline synthesis via hydrogen transfer metho-
dology. Various (E)-2-nitrobenzaldehyde O-methyl oximes reacted easily with alcohols or benzyl amines
to provide N-heterocyclic compounds in good to high yields. Similarly, the heterocyclic products could
be prepared by the reaction of 1-(2-nitrophenyl)ethanone, urea and benzyl alcohols. In these reactions,
the nitro group was reduced in situ by hydrogen generated from the alcohol dehydrogenation step.
Received 22nd June 2014,
Accepted 6th August 2014
DOI: 10.1039/c4ob01296h
www.rsc.org/obc
Introduction
Quinazolines represent a class of annulated N-heterocycles
and are widespread in natural products and pharmaceuticals.1
These nitrogen-containing chemicals have been widely investi-
gated for their physiological and biological properties, such as
their antibacterial, antitubercular, antiviral and anticancer
activities. Therefore, a variety of methods have been developed
to synthesize quinazoline and its derivatives, especially 2-sub-
stituted quinazolines.2 Conventional synthetic methods for the
synthesis of quinazolines mainly rely on the condensation and
subsequent cyclization of amino group with carbonyl com-
pounds.3 The oxidative reaction of 2-aminobenzylamines with
aldehydes,4 amidines with o-halogen benzyl amines or other
bi-functional substrates,5 amides with o-halogen benzyl
amines,6 and other novel approaches7 have successfully been
employed for quinazoline preparation. The dehydrogenation
of unsaturated N-heterocycles also serves as a useful alterna-
tive approach for preparing quinazolines.8 Recently, the aryla-
tion of quinazoline or its halogenated derivatives provided an
efficient route for 2-arylquinazolines.9 Ellman and co-workers
found that a combination of cross-coupling and dehydrogena-
tion of dihydroquinazoline with phenyl halides could provide
2-phenylquinazoline in one pot.10
Scheme 1 2-Arylquinazoline formation from nitroarenes.
stable amino group, would be highly desirable. Recently, there
has been significant interest in the transition-metal-catalyzed
C–N bond-forming reactions from amines and alcohols (or
benzyl amines) via hydrogen transfer methodology.11 This
methodology provides an efficient and environmentally benign
approach for amine preparation. We and other groups have
successfully developed various methods for amine and amide
formation directly from aromatic nitro compounds and alco-
hols via hydrogen transfer strategy.12 We also synthesized
various diaryl amines from nitroarenes using cyclohexanones
as hydrogen and aryl sources.13 In this kind of reaction,
the nitro group was reduced in situ by hydrogen produced
from alcohol or cyclohexanone oxidation. Very recently, oximes
have emerged as very promising substrates for the construc-
tion of heterocycles.14 Various N-heterocycles could easily be
synthesized from oximes via transition-metal-catalyzed N–O
bond cleavage and subsequent C–N bond formation.15
Because of the importance of substituted quinazolines in
natural products and pharmaceuticals, herein, we report
new approaches for synthesizing 2-arylquinazolines from
(E)-2-nitrobenzaldehyde O-methyl oximes and alcohols or benzyl
amines (Scheme 1, a) or from 1-(2-nitrophenyl)ethanone, urea
and benzyl alcohols via hydrogen transfer methodology
(Scheme 1, b).
Despite the progress that has been made in substituted qui-
nazoline syntheses, most of the methods rely on using amines
(direct or indirect) as starting materials under oxidative con-
ditions. The preparation of N-heterocycles from other stable
functionalized substrates, rather than from an active and less
Key Laboratory of Environmentally Friendly Chemistry and Application of Ministry of
Education, College of Chemistry, Xiangtan University, Xiangtan 411105, China.
E-mail: gjdeng@xtu.edu.cn; Fax: (+86)0731-5829-2251; Tel: (+86)0731-5829-8601
†Electronic supplementary information (ESI) available. See DOI: 10.1039/c4ob01296h
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to significant decrease in the catalytic activity of the Pd(OAc)2/
dppf system (entries 19–20).
Results and discussion
We initiated the study with the reaction of (E)-2-nitrobenzalde-
Based on the optimized reaction conditions, the substrate
hyde O-methyl oxime (1a) and benzyl alcohol (2a) in toluene to scope with respect to (E)-2-nitrobenzaldehyde O-methyl oxime
optimize the reaction conditions. The iron catalyst, dppf, was (1a) and benzylic substrates (2) was studied (Table 2). Substi-
first investigated for this kind of reaction because it showed tuted benzylic alcohols with electron-donating groups on the
good efficiency in N-heterocycle preparation using nitroarenes aromatic ring such as methyl and methoxy could be smoothly
as starting materials.12h,i As shown in Table 1, when a mixture transformed into the quinazoline products with high yields
of 1a (0.2 mmol) and 2a (0.6 mmol) was heated in a sealed (entries 2 and 3). Halogen substituents such as chloro and
tube under argon at 160 °C using dppf as the sole catalyst, the fluoro were compatible (entries 4 and 5). However, a bromo
desired product 2-phenylquinazoline (3a) was obtained in 19% substituent at the para position of benzyl alcohol significantly
yield as determined by GC-MS and GC analysis (entry 1). decreased the reaction yield to 30% because of the cleavage of
Repeating the reaction with Pd(OAc)2 as a co-catalyst signifi- C–Br bond (entry 6). The position of the substituent profoundly
cantly improved the reaction yield to 72% (entry 2). Other affected the reaction yield. When 2-methylbenzyl alcohol (2g)
palladium salts such as PdCl2, Pd(acac)2, Pd(COD)Cl2 and was employed, the corresponding product 3g was obtained in
Pd(TFA)2 were also screened in the presence of dppf, and they only 38% yield, which was much lower than that of 3b and 3h
showed lower catalytic activity compared to Pd(OAc)2 (entries (entries 2, 7 and 8). The hindered substrate 1-naphthalene-
3–6). Replacement of dppf with other phosphine ligands sig- methanol (2i) could easily react with 1a and afforded product
nificantly decreased the reaction yield, and no desired product
was determined when nitrogen containing ligand 1,10-phenan-
throline was used (entries 7–13). The impact of solvent on the
Table 2 Reactions of 1a with benzylic alcohols and aminesa
reaction yield was also investigated. Slightly lower yield was
obtained when the reaction was carried out in other organic
solvents such as NMP, diglyme, DMF and DMA (entries 14–17).
Anisole was proved to be a suitable reaction media for this
kind of transformation, and its use afforded the product in
Yieldb
(%)
90% yield (entry 18). Decreasing the reaction temperature to
140 °C or performing the reaction under an air atmosphere led
Entry
Alcohol or amine
Product
Table 1 Screening for the optimal conditionsa
1
2
R1 = H
2a
2b
2c
2d
2e
2f
3a
3b
3c
3d
3e
3f
85
88
85
79
73
30
38
68
R1 = 4-Me
R1 = 4-OMe
R1 = 4-F
3
4c
5c
6c
7
R1 = 4-Cl
R1 = 4-Br
R1 = 2-Me
R1 = 3-Me
2g
2h
3g
3h
Yieldb
(%)
8
Entry
Catalyst
Ligand
Solvent
9c
2i
3i
70
1
2
3
dppf
dppf
dppf
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
NMP
Diglyme
DMF
DMA
Anisole
Anisole
Anisole
19
72
24
20
24
62
16
7
Pd(OAc)2
PdCl2
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19c
20d
Pd(acac)2
Pd(COD)Cl2
Pd(TFA)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
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
dppf
dppf
dppf
PCy3HBF4
PPh3
Xantphos
DPEphos
dppe
dppe
1,10-Phen
dppf
dppf
dppf
dppf
dppf
dppf
dppf
10c
11c
2j
3j
48
43
20
8
2k
3k
16
11
Trace
70
48
64
47
90
22
43
12
13
14
15
16
R1 = H
2l
3a
3b
3c
3d
3e
84
88
85
82
80
R1 = 4-Me
R1 = 4-OMe
R1 = 4-F
2m
2n
2o
2p
R1 = 4-Cl
a Conditions: 1a (0.2 mmol), 2 (0.6 mmol), Pd(OAc)2 (5 mol%), dppf
a Conditions: 1a (0.2 mmol), 2a (0.6 mmol), catalyst (5 mol%), ligand (10 mol%), anisole (0.5 mL), 160 °C, 48 h under argon. For entries
(10 mol%), solvent (0.5 mL), 48 h, 160 °C under argon. b GC yield. c At 12–16, PdCl2 (5 mol%) was used. b Isolated yields based on 1a. c Pd
140 °C. d Under air.
(OAc)2 (7.5 mol%) and dppf (15 mol%) were used.
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3i in fair yield (entry 9). Hetero benzylic alcohols, i.e. pyridin- such as fluoro and chloro were tolerated and afforded the sub-
3-ylmethanol (2j) and furan-2-ylmethanol (2k), also partici- stituted quinazolines 3m and 3n in 82% and 72% yields,
pated in the reaction to provide the corresponding quinazo- respectively (entries 2 and 3). Again, a bromo substituent sig-
lines 3j and 3k in moderate yields (entries 10 and 11).
nificantly decreased the reaction yield (entry 4). The reaction
Unfortunately, simple aliphatic alcohols, such as cyclohexa- resulted in poor activity when a methyl substituent was located
nol and 1-butanol, were not active under the current reaction in the CvN bond (entry 5). In addition to methoxy group, a
conditions. To our delight, benzyl amines also could be benzoxy group also could serve as an efficient leaving group to
smoothly condensed with 1a under the modified reaction con- afford product 3a in good yield (entry 6). Very low yield was
ditions using PdCl2 as the catalyst precursor to afford 2-aryl- observed when (E)-2-nitrobenzaldehyde oxime (1h) reacted
quinazolines in high yields (entries 12–16). The pattern of the with benzyl alcohol (entry 7).
substituents did not make considerable difference to the reac-
To our surprise, the three-component reaction of 1-(2-nitro-
tion yields.
phenyl)ethanone (1i), urea and benzyl alcohol (2a) in the pres-
To further examine the scope and the limitations of the ence of Pd(OAc)2/dppf also could provide 4-methyl-2-
reaction, substituted (E)-2-nitrobenzaldehyde O-methyl oximes phenylquinazoline (3p) in 86% yield (Table 4, entry 1). Various
(1) were treated with 2a under the standard conditions benzylic alcohols with electron-donating substituents could
(Table 3). When (E)-5-methoxy-2-nitrobenzaldehyde O-methyl efficiently involve the reaction to provide the corresponding
oxime (1b) reacted with benzyl alcohol, the desired product 3l products in good yields (entries 2–4). Lower yields were
was obtained in 88% yield (entry 1). Halogen substituents observed when halogen substituents were presented at the
para position of benzyl alcohols (entries 5–7). The position of
the substituent significantly affected the reaction and only
35% yield was obtained when the methyl group was located at
the ortho position of benzyl alcohol (entry 8). Similarly, the
Table 3 Reactions of 2a with various oximesa
hindered substrate 1-naphthalenemethanol (2i) reacted with 1i
and afforded the corresponding product 3y in low yield (entry 10).
Moreover, 2-phenylquinazolin-4(3H)-one (3z) was obtained
in 75% isolated yield when 2-nitrobenzonitrile (1j) was treated
with 2a (Scheme 2).
Yieldb
(%)
To gather more information about the possible reaction
mechanism, some control experiments were carried out under
Entry
1
Oxime
Product
88
Table 4 Reactions of 1i with various benzylic alcoholsa
2
3
82
72
Yieldb
(%)
Entry
Alcohol
Product
4
5
43
61
1
2
3
4
5
6
7
8
9
R1 = H
2a
2b
2c
2q
2d
2e
2f
3p
3q
3r
3s
3t
3u
3v
3w
3x
86
88
90
89
48
42
21
35
75
R1 = 4-Me
R1 = 4-OMe
R1 = 4-CH(CH3)2
R1 = 4-F
R1 = 4-Cl
R1 = 4-Br
6
7
77
8c
R1 = 2-Me
R1 = 3-Me
2g
2h
10
2i
3y
30
a Conditions: 1 (0.2 mmol), 2a (0.6 mmol), Pd(OAc)2 (5 mol%), dppf
a Conditions: 1i (0.2 mmol), 2 (0.6 mmol), urea (0.3 mmol), Pd(OAc)2
(10 mol%), anisole (0.5 mL), 160 °C, 48 h under argon. b Isolated yields (7.5 mol%), dppf (5 mol%), diglyme (0.5 mL), 160 °C, 24 h under
based on 1. c GC yield.
argon. b Isolated yields based on 1i.
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Scheme 2 2-Phenylquinazolin-4(3H)-one formation from 2-nitrobenzo-
nitrile.
Scheme 4 Possible mechanism.
the imidoyl C–H bond of D forms the cyclized intermediate E
and generates methanol as a by-product. Finally, reductive
elimination of E yields the desired product 3a and releases the
active Pd(0) catalyst to complete the catalytic cycle.
Conclusions
In conclusion, we have demonstrated a Pd/Fe-catalyzed 2-aryl-
quinazoline formation from (E)-2-nitrobenzaldehyde O-methyl
oximes or 1-(2-nitrophenyl)ethanone and alcohols or amines
via the hydrogen transfer strategy. In this transformation, the
alcohol (or amine) dehydrogenation, nitro reduction, and cycli-
zation were realized in one pot. Because nitroarenes and
benzyl alcohols or amines are readily available and stable
chemicals, this method can afford an efficient approach for
the preparation of 2-arylquinazolines. The scope and mecha-
nism of this reaction is under investigation in our laboratory.
Scheme 3 Investigation of the reaction mechanism under various con-
ditions (a–d).
various conditions (Scheme 3). During the optimization
process of the reaction conditions, we observed a small
amount of nitrile intermediate 4a.16 Further treatment of 4a
under the standard reaction conditions did not afford the
corresponding product 3a (Scheme 3, a). This indicates that
the cyclization reaction did not involve a cyano intermediate
pathway, which is identical with the reaction result of 2-nitro-
benzonitrile (1j) and 2a (Scheme 2). An imine compound I was
prepared and treated under the standard reaction conditions
to afford the corresponding product 3p in 97% yield, as deter-
mined by GC analysis. Considerably lower yields were observed
when the same compound was treated with Pd(OAc)2 or dppf
separately (Scheme 3, b). Treatment of 1a with benzaldehyde
only gave the product in 8% yield, whereas the reaction of com-
pound B with benzaldehyde provided the product in 80% yield
(Scheme 3, c and d). This indicates that the alcohol acted as
the hydrogen donor to reduce the nitro group as we expected.
Based on these results, a plausible mechanism for 2-aryl-
quinazolines is proposed in Scheme 4. The dehydrogenation
of benzyl alcohol (2a) generates benzaldehyde A and reduces
1a to intermediate B. The condensation of benzaldehyde with
intermediate B affords an imine intermediate C. The oxidative
addition of C to Pd(0) affords complex D.17 The palladation of
Experimental section
General methods
All experiments were carried out under an atmosphere of
argon. Flash column chromatography was performed over
silica gel 48–75 µm. 1H NMR and 13C NMR spectra were
recorded on a Bruker-AV (400 and 100 MHz, respectively)
instrument, which was internally referenced to SiMe4 or
chloroform signals. MS analyses were performed on an Agilent
5975 GC-MS instrument (EI). The new compounds were
characterized by 1H NMR, 13C NMR, MS and HRMS. The struc-
tures of known compounds were further corroborated by com-
1
paring their H NMR, 13C NMR data and MS data with those
found in the literature. All reagents were used as received from
commercial sources without further purification. Solvents were
used as received without further purification.
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General procedure for the preparation of substrates (1a–1g)18
159.5, 159.2, 149.8, 133.1, 129.7 (d, J = 9.0 Hz), 127.6, 126.2,
126.1, 125.1, 122.5, 114.5 (d, J = 21.0 Hz); MS (EI) m/z (%) 315
(100), 223, 196, 120, 77; MS (EI) m/z (%) 224 (100), 197, 170,
112, 76.
To a 250 mL round bottom flask, 2-nitrobenzaldehyde (5.0 g,
33.1 mmol), methoxylamine hydrochloride (3.0 g, 35.9 mmol)
and ethanol (50 mL) were added. The reaction mixture was
refluxed with stirring under a nitrogen atmosphere for 3 h and
then allowed to stand at room temperature overnight. The reac-
tion mixture was concentrated in vacuo to obtain a yellow
solid. The crude product was partitioned between dichloro-
methane and water. The layers were separated and the organic
phase was washed with water, followed by saturated sodium
chloride. The organic phase was dried over magnesium
sulfate, filtered and the filtrate was concentrated in vacuo to
obtain 5.46 g of (E)-O-methyloxime-2-nitrobenzaldehyde (1a)
(CAS: 135436-97-4). Other substrates were synthesized simi-
larly. (E)-2-Nitrobenzaldehyde oxime (1h) was purchased from
Alfa-Aesar and used as received without further purification.
2-(4-Chlorophenyl)quinazoline (3e).19 A pale yellow solid;
yield 73%; 1H NMR (400 MHz, CDCl3, ppm) δ 9.46 (s, 1H), 8.58
(d, J = 8.0 Hz, 2H), 8.09–8.07 (m, 1H), 7.95–7.91 (m, 2H),
7.65–7.62 (m, 1H), 7.52–7.49 (m, 2H); 13C NMR (100 MHz,
CDCl3, ppm) δ 160.5, 160.1, 150.8, 136.9, 136.6, 134.2, 130.0,
128.8, 128.7, 127.4, 127.1, 123.7; MS (EI) m/z (%) 240 (100),
213, 178, 151, 120.
2-(4-Bromophenyl)quinazoline (3f, CAS: 1222094-28-1).20
A
1
pale yellow solid; yield 30%; H NMR (400 MHz, CDCl3, ppm)
δ 9.46 (s, 1H), 8.51 (d, J = 8.0 Hz, 2H), 8.08 (d, J = 8.0 Hz, 1H),
7.95–7.91 (m, 2H), 7.68–7.62 (m, 3H); 13C NMR (100 MHz,
CDCl3, ppm) δ 160.5, 160.2, 150.8, 137.1, 134.2, 131.8, 130.2,
128.7, 127.5, 127.2, 125.4, 123.7; MS (EI) m/z (%) 284 (100),
257, 205, 178, 76.
General procedure: 2-phenylquinazoline (3a)
2-(o-Tolyl)quinazoline (3g, CAS: 1208259-15-7).21 A brown
A 10 mL oven-dried reaction vessel was charged with Pd solid; yield 38%; 1H NMR (400 MHz, CDCl3, ppm) δ 9.51
(OAc)2 (2.2 mg, 0.01 mmol), dppf (11.0 mg, 0.02 mmol), (E)-2- (s, 1H), 8.10 (d, J = 8.0 Hz, 1H), 7.99–7.89 (m, 3H), 7.67 (t, J =
nitrobenzaldehyde O-methyl oxime (1a, 36.0 mg, 0.2 mmol) 8.0 Hz, 1H), 7.38–7.33 (m, 3H), 2.61 (s, 3H); 13C NMR
and benzyl alcohol (2a, 62.0 µL, 0.6 mmol). The reaction (100 MHz, CDCl3, ppm) δ 164.1, 160.0, 150.5, 138.6, 137.5,
vessel was purged three times with argon, and anisole 134.1, 131.3, 130.7, 129.3, 128.6, 127.5, 127.1, 126.0, 123.0,
(0.5 mL) was added to the sealed reaction vessel by a syringe. 21.1; MS (EI) m/z (%) 219 (100), 190, 165, 110, 77.
The resulting solution was stirred for 48 h at 160 °C. After
2-(m-Tolyl)-3,4-dihydroquinazoline (3h).22
A
pale yellow
cooling to room temperature, the volatiles were removed solid; yield 68%; 1H NMR (400 MHz, CDCl3, ppm) δ 9.47
under vacuum and the residue was purified by column (s, 1H), 8.43–8.40 (m, 2H), 8.10 (d, J = 8.0 Hz, 1H), 7.95–7.90
chromatography (neutral aluminum oxide, petroleum ether– (m, 2H), 7.62 (t, J = 8.0 Hz, 1H), 7.44 (t, J = 8.0 Hz, 1H), 7.34–7.32
ethyl acetate = 30 : 1) to obtain 3a as pale yellow solid; yield: (m, 1H), 2.50 (s, 3H); 13C NMR (100 MHz, CDCl3, ppm)
35.1 mg (85%).
δ 161.3, 160.4, 150.9, 138.3, 138.1, 134.0, 131.4, 129.2, 128.7,
2-Phenylquinazoline (3a, CAS: 25855-20-3).19 1H NMR 128.6, 127.2, 127.1, 125.9, 123.6, 21.5; MS (EI) m/z (%) 220
(400 MHz, CDCl3, ppm) δ 9.48 (s, 1H), 8.63–8.62 (m, 2H), (100), 193, 165, 110, 76.
8.11–8.09 (m, 1H), 7.95–7.90 (m, 2H), 7.64–7.61 (m, 1H),
2-(Naphthalen-1-yl)quinazoline (3i, CAS: 93656-11-2).20
A
7.55–7.53 (m, 3H); 13C NMR (100 MHz, CDCl3, ppm) δ 161.0, brown solid; yield 70%; 1H NMR (400 MHz, CDCl3, ppm)
160.4, 150.7, 138.0, 134.0, 130.6, 128.6, 128.5, 127.2, 127.2, δ 9.60 (s, 1H), 8.70 (d, J = 8.0 Hz, 1H), 8.19–8.17 (m, 2H),
127.1, 123.5; MS (EI) m/z (%) 206 (100), 179, 152, 103, 76.
8.04–7.93 (m, 4H), 7.71 (t, J = 8.0 Hz, 1H), 7.63 (t, J = 8.0 Hz,
2-(p-Tolyl)quinazoline (3b).19 A pale yellow solid; yield 88%; 1H), 7.57–7.51 (m, 2H); 13C NMR (100 MHz, CDCl3, ppm)
1H NMR (400 MHz, CDCl3, ppm) δ 9.45 (s, 1H), 8.51 (d, J = δ 164.2, 161.0, 151.3, 137.0, 134.9, 132.0, 131.5, 131.1, 130.4,
8.0 Hz, 2H), 8.08–8.06 (m, 1H), 7.93–7.88 (m, 2H), 7.60 (t, J = 129.4, 129.2, 128.4, 127.8, 127.5, 126.7, 126.6, 126.0, 123.9; MS
8.0 Hz, 1H), 7.36–7.34 (m, 2H), 2.45 (s, 3H); 13C NMR (EI) m/z (%) 311 (100), 221, 192, 120, 77; MS (EI) m/z (%) 255
(100 MHz, CDCl3, ppm) δ 162.2, 160.4, 150.9, 140.8, 135.4, (100), 228, 153, 128, 77.
134.0, 129.4, 128.6, 128.6, 127.1, 127.0, 123.6, 21.5; MS (EI)
2-(Pyridin-3-yl)quinazoline (3j).20 A pale yellow solid; yield
48%; 1H NMR (400 MHz, CDCl3, ppm) δ 9.86 (s, 1H), 9.54
(s, 1H), 8.92 (d, J = 8.0 Hz, 1H), 8.79–8.78 (m, 1H), 8.17–8.15
m/z (%) 220 (100), 193, 165, 110, 76.
2-(4-Methoxyphenyl)quinazoline (3c, CAS: 67205-04-3).19
A
1
pale yellow solid; yield 85%; H NMR (400 MHz, CDCl3, ppm) (m, 1H), 8.02–7.98 (m, 2H), 7.73–7.70 (m, 1H), 7.53–7.50
δ 9.43 (s, 1H), 8.58 (d, J = 8.0 Hz, 2H), 8.06–8.04 (m, 1H), (m, 1H); 13C NMR (100 MHz, CDCl3, ppm) δ 161.3, 159.9,
7.91–7.87 (m, 2H), 7.58 (t, J = 8.0 Hz, 1H), 7.05 (d, J = 8.0 Hz, 151.9, 151.4, 151.0, 136.5, 135.0, 134.3, 129.4, 128.4, 127.8,
2 H), 3.91 (s, 3H); 13C NMR (100 MHz, CDCl3, ppm) δ 161.9, 124.5, 124.0; MS (EI) m/z (%) 207 (100), 179, 153, 103, 76.
160.9, 150.9, 147.7, 134.0, 130.9, 130.3, 128.5, 127.1, 126.8,
123.4, 114.0, 55.4; MS (EI) m/z (%) 236 (100), 221, 193, 166, 76.
2-(Furan-2-yl)quinazoline (3k).20 A pale green solid; yield
43%; 1H NMR (400 MHz, CDCl3, ppm) δ 9.40 (s, 1H), 8.12–8.10
(m, 1H), 7.92–7.90 (m, 2H), 7.70 (s, 1H), 7.63–7.60 (m, 1H),
2-(4-Fluorophenyl)quinazoline (3d, CAS: 1208259-07-7).20
A
pale yellow solid; yield 79%; H NMR (400 MHz, CDCl3, ppm) 7.47 (s, 1H), 6.63 (s, 1H); 13C NMR (100 MHz, CDCl3, ppm)
δ 9.45 (s, 1H), 8.65–8.61 (m, 2H), 8.08–8.06 (m, 1H), 7.94–7.90 δ 161.4, 154.9, 153.3, 151.2, 146.0, 135.1, 129.5, 129.1, 127.9,
(m, 2H), 7.62 (t, J = 8.0 Hz, 1H), 7.21 (t, J = 8.0 Hz, 2H); 124.1, 114.8, 113.0; MS (EI) m/z (%) 196 (100), 168, 140,
13C NMR (100 MHz, CDCl3, ppm) δ 163.7 (d, J = 249.0 Hz), 114, 76.
1
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General procedure for benzyl amine substrates (3a)
diglyme (0.5 mL) was added to the sealed reaction vessel by
syringe. The resulting solution was stirred for 24 h at 160 °C.
After cooling to room temperature, the volatiles were removed
under vacuum and the residue was purified by column chrom-
atography (neutral aluminum oxide, petroleum ether–ethyl
acetate = 100 : 1) to obtain 3p as pale yellow solid; yield:
37.8 mg (86%).
A 10 mL oven-dried reaction vessel was charged with PdCl2
(1.8 mg, 0.01 mmol), dppf (11.0 mg, 0.02 mmol), (E)-2-nitro-
benzaldehyde O-methyl oxime (1a, 36.0 mg, 0.2 mmol) and
benzylamine (2l, 65.6 µL, 0.6 mmol). The reaction vessel was
purged with argon three times, and anisole (0.5 mL) was
added to the sealed reaction vessel by syringe. The resulting
solution was stirred for 48 h at 160 °C. After cooling to room
temperature, the volatiles were removed under vacuum and the
residue was purified by column chromatography (neutral
aluminum oxide, petroleum ether–ethyl acetate = 30 : 1) to
obtain 3a as pale yellow solid; yield: 34.6 mg (84%).
4-Methyl-2-(p-tolyl)quinazoline (3q, CAS: 1400697-35-9).25
A
1
pale yellow solid; yield 88%; H NMR (400 MHz, CDCl3, ppm)
δ 8.52 (d, J = 4.0 Hz, 2H), 8.09–8.04 (m, 2H), 7.85 (t, J = 8.0 Hz,
1H), 7.56 (t, J = 8.0 Hz, 1H), 7.34–7.32 (m, 2H), 3.01 (s, 3H),
2.44 (s, 3H); 13C NMR (100 MHz, CDCl3, ppm) δ 168.1, 160.2,
150.5, 140.6, 135.6, 133.4, 129.3, 129.2, 128.6, 126.6, 125.0,
123.0, 22.0, 21.5; MS (EI) m/z (%) 234(100), 219, 193, 117, 89.
2-(4-Methoxyphenyl)-4-methylquinazoline (3r, CAS: 84570-
78-5).25 A pale yellow solid; yield 90%; 1H NMR (400 MHz,
CDCl3, ppm) δ 8.59 (d, J = 12.0 Hz, 2H), 8.06–8.01 (m, 2H), 7.83
(t, J = 8.0 Hz, 1H), 7.53 (t, J = 8.0 Hz, 1H), 7.04 (d, J = 8.0 Hz,
2H), 3.89 (s, 3H), 2.99 (s, 3H); 13C NMR (100 MHz, CDCl3,
ppm) δ 168.0, 161.7, 156.8, 150.5, 133.4, 131.1, 130.2, 129.1,
126.4, 125.0, 122.8, 113.9, 55.4, 22.0; MS (EI) m/z (%) 250 (100),
235, 209, 192, 103.
6-Methoxy-2-phenylquinazoline (3l, CAS: 34637-66-6).19
A
1
pale yellow solid; yield 88%; H NMR (400 MHz, CDCl3, ppm)
δ 9.38 (s, 1H), 8.57 (d, J = 8.0 Hz, 2H), 8.02–7.99 (m, 1H),
7.58–7.52 (m, 4H), 7.17 (s, 1H), 3.98 (s, 3H); 13C NMR
(100 MHz, CDCl3, ppm) δ 158.5, 157.8, 157.3, 146.1, 137.3,
129.2, 129.2, 127.6, 127.2, 126.1, 123.5, 103.0, 54.7; MS (EI)
m/z (%) 236 (100), 221, 193, 106, 63.
6-Fluoro-2-phenylquinazoline (3m, CAS: 1399327-71-9).19
A
1
pale yellow solid; yield 82%; H NMR (400 MHz, CDCl3, ppm)
δ 9.44 (s, 1H), 8.61–8.59 (m, 2H), 8.13–8.09 (m, 1H), 7.71–7.66
(m, 1H), 7.56–7.53 (m, 4H); 13C NMR (100 MHz, CDCl3, ppm)
δ 160.4 (J = 250.0 Hz), 160.7, 159.8 (J = 6.0 Hz), 148.0, 137.8,
131.4 (J = 8.0 Hz), 130.7, 128.7, 128.5, 124.4 (J = 26.0 Hz),
123.9 (J = 8.0 Hz), 110.1 (J = 22.0 Hz); MS (EI) m/z (%) 224
(100), 197, 170, 112, 77.
2-(4-Isopropylphenyl)-4-methylquinazoline (3s).26
A
pale
yellow solid; yield 89%; 1H NMR (400 MHz, CDCl3, ppm)
δ 8.52 (d, J = 8.0 Hz, 2H), 8.07 (t, J = 8.0 Hz, 2H), 7.85 (t, J =
8.0 Hz, 1H), 7.58–7.55 (m, 1H), 7.38 (d, J = 8.0 Hz, 2H), 3.01
(s, 3H), 1.31 (d, J = 8.0 Hz, 6H), 1.26 (s, 1H); 13C NMR
(100 MHz, CDCl3, ppm) δ 168.0, 160.4, 151.4, 150.6, 136.1,
133.3, 129.3, 128.7, 126.6, 126.5, 124.9, 123.0, 34.1, 23.9, 21.9;
MS (EI) m/z (%) 262 (100), 247, 232, 117, 77.
6-Chloro-2-phenylquinazoline (3n, CAS: 58058-53-0).23
A
1
pale yellow solid; yield 72%; H NMR (400 MHz, CDCl3, ppm)
δ 9.41 (s, 1H), 8.61–8.60 (m, 2H), 8.05–8.03 (m, 1H), 7.92
(s, 1H), 7.85–7.83 (m, 1H), 7.55–7.53 (m, 3H); 13C NMR
(100 MHz, CDCl3, ppm) δ 162.1, 160.2, 150.0, 138.4, 135.7,
133.5, 131.5, 131.1, 129.4, 129.3, 126.5, 124.7; MS (EI) m/z (%)
240 (100), 213, 178, 120, 75.
2-(4-Fluorophenyl)-4-methylquinazoline (3t, CAS: 1315314-
55-6).25 A pale yellow solid; yield 48%; 1H NMR (400 MHz,
CDCl3, ppm) δ 8.65–8.62 (m, 2H), 8.07 (q, J = 8.0 Hz, 2H),
7.88–7.85 (m, 1H), 7.60–7.57 (m, 1H), 7.22–7.18 (m, 2H), 3.01
(s, 3H); 13C NMR (100 MHz, CDCl3, ppm) δ 168.2, 164.6 (d, J =
248.0 Hz), 159.3, 150.5, 134.5 (d, J = 3.0 Hz), 133.5, 130.7 (d, J =
9.0 Hz), 129.2, 126.8, 125.0, 122.9, 115.4 (d, J = 21 Hz), 21.9;
MS (EI) m/z (%) 315 (100), 223, 196, 120, 77; MS (EI) m/z (%)
238 (100), 223, 197, 119, 76.
2-(4-Chlorophenyl)-4-methylquinazoline (3u, CAS: 1315314-
54-5).25 A pale yellow solid; yield 42%; 1H NMR (400 MHz,
CDCl3, ppm) δ 8.58 (d, J = 8.0 Hz, 1H), 8.08 (q, J = 8.0 Hz, 2H),
7.89–7.86 (m, 1H), 7.60 (t, J = 8.0 Hz, 1H), 7.49 (d, J = 8.0 Hz,
2H), 7.33–7.30 (m, 1H), 3.01 (s, 3H); 13C NMR (100 MHz,
CDCl3, ppm) δ 168.3, 150.4, 136.9, 136.6, 133.6, 129.9, 129.3,
128.7, 128.7, 127.0, 125.0, 123.1, 21.9; MS (EI) m/z (%) 254
(100), 239, 213, 178, 102.
7-Bromo-2-phenylquinazoline (3o). A pale yellow solid; yield
43%; 1H NMR (400 MHz, CDCl3, ppm) δ 9.45 (s, 1H), 8.61
(s, 2H), 8.30 (s, 1H), 7.82–7.80 (m, 1H), 7.73–7.70 (m, 1H), 7.54
(s, 3H); 13C NMR (100 MHz, CDCl3, ppm) δ 161.9, 160.3, 151.5,
137.7, 131.2, 131.0, 131.0, 128.9, 128.8, 128.7, 128.3, 122.2; MS
(EI) m/z (%) 284 (100), 257, 178, 151, 75; HRMS calcd for:
C14H9BrN2 [M + H]+ = 285.0022, found = 285.0020.
4-Methyl-2-phenylquinazoline (3p, CAS: 1806-66-2).24 A pale
yellow solid; yield 61%; 1H NMR (400 MHz, CDCl3, ppm)
δ 8.62 (d, J = 8.0 Hz, 2H), 8.09 (t, J = 8.0 Hz, 2H), 7.88–7.85
(m, 1H), 7.60–7.51 (m, 4H), 3.02 (s, 3H); 13C NMR (100 MHz,
CDCl3, ppm) δ 168.2, 160.3, 150.5, 138.4, 133.5, 130.4, 129.4,
128.6, 128.5, 126.8, 125.0, 123.1, 22.0; MS (EI) m/z (%) 220
(100), 205, 179, 110, 76.
2-(4-Bromophenyl)-4-methylquinazoline (3v, CAS: 1054478-
98-6).26 A pale white solid; yield 21%; 1H NMR (400 MHz,
CDCl3, ppm) δ 8.51 (d, J = 8.0 Hz, 2H), 8.07 (q, J = 8.0 Hz, 2H),
7.87 (t, J = 8.0 Hz, 1H), 7.66–7.58 (m, 3H), 3.01 (s, 3H);
General procedure for Table 4 (3p) substrates
A 10 mL oven-dried reaction vessel was charged with Pd(OAc)2 13C NMR (100 MHz, CDCl3, ppm) δ 168.3, 159.3, 150.4, 137.3,
(3.4 mg, 0.075 mmol), dppf (5.5 mg, 0.05 mmol), 1-(2-nitro- 133.6, 131.7, 130.2, 129.3, 127.0, 125.1, 125.0, 123.1, 21.9; MS
phenyl)ethanone (1i, 27.0 µL, 0.2 mmol), urea (18.0 mg, (EI) m/z (%) 298 (100), 283, 257, 178, 102.
0.3 mmol) and benzyl alcohol (2a, 62.0 µL, 0.6 mmol). The
4-Methyl-2-(o-tolyl)quinazoline (3w). A pale yellow solid;
reaction vessel was purged with argon three times, and yield 35%; 1H NMR (400 MHz, CDCl3, ppm) δ 8.14 (d, J = 8.0 Hz,
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1H), 8.08 (d, J = 8.0 Hz, 1H), 7.91–7.84 (m, 2H), 7.65–7.64
(m, 1H), 7.32 (s, 3H), 3.02 (s, 3H), 2.58 (s, 3H); 13C NMR
(100 MHz, CDCl3, ppm) δ 167.8, 163.4, 150.2, 139.0, 137.3,
133.5, 131.2, 130.5, 129.3, 129.1, 127.1, 125.9, 124.9, 122.4,
21.8, 20.9; MS (EI) m/z (%) 233 (100), 218, 165, 116, 89; HRMS
calcd for: C16H15N2 [M + H]+ = 235.12298, found = 235.12313.
4-Methyl-2-(m-tolyl)quinazoline (3x). A pale yellow solid;
yield 75%; 1H NMR (400 MHz, CDCl3, ppm) δ 8.43–8.41
(m, 2H), 8.10–8.07 (m, 2H), 7.86 (t, J = 8.0 Hz, 1H), 7.58 (t, J =
8.0 Hz, 1H), 7.42 (t, J = 8.0 Hz, 1H), 7.32–7.30 (m, 1H), 3.03
(s, 3H), 2.49 (s, 3H); 13C NMR (100 MHz, CDCl3, ppm) δ 168.1,
160.4, 150.5, 138.3, 138.1, 133.4, 131.2, 129.3, 129.1, 128.5,
126.8, 125.8, 125.0, 123.0, 22.0, 21.5; MS (EI) m/z (%) 234 (100),
Notes and references
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235.12298, found = 235.12312.
=
4-Methyl-2-(naphthalen-1-yl)quinazoline (3y). A pale yellow
1
solid; yield 30%; H NMR (400 MHz, CDCl3, ppm) δ 8.64–8.61
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(m, 2H), 7.53–7.51 (m, 2H), 3.08 (s, 3H); 13C NMR (100 MHz,
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130.1, 129.4, 129.3, 128.4, 127.3, 126.6, 126.2, 125.8, 125.3,
125.0, 122.6, 21.9; MS (EI) m/z (%) 270 (100), 255, 228, 153,
127; HRMS calcd for: C19H15N2 [M + H]+ = 271.12298, found =
271.12316.
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Procedure for 3z formation
A 10 mL oven-dried reaction vessel was charged with Pd(OAc)2
(2.2 mg, 0.05 mmol), dppf (11.0 mg, 0.1 mmol), anhydrous
potassium acetate (19.6 mg, 0.2 mmol), 2-nitrobenzonitrile (1j,
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argon, and anisole (0.5 mL) was added to the sealed reaction
vessel by syringe. The resulting solution was stirred at for 40 h
160 °C. After cooling to room temperature, the volatiles were
removed under vacuum and the residue was purified by
column chromatography (neutral aluminum oxide, petroleum
ether–ethyl acetate = 5 : 1) to give 3z as pale yellow solid; yield:
33.3 mg (75%).
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2-Phenylquinazolin-4(3H)-one (3z, CAS: 1022-45-3).27 1H NMR
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8.21–8.20 (m, 2H), 7.86–7.80 (m, 2H), 7.60 (s, 3H), 7.52
(t, J = 8.0 Hz, 1H); 13C NMR (100 MHz, CDCl3, ppm) δ 164.5,
152.4, 150.3, 135.5, 133.6, 132.3, 129.7, 128.7, 128.1, 127.5,
127.1, 121.6; MS (EI) m/z (%) 206 (100), 179, 152, 103, 76.
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Acknowledgements
This work was supported by the National Natural Science
Foundation of China (21372187), the New Century Excellent
Talents in University from Ministry of Education of China
(NCET-11-0974), the Research Fund for the Doctoral Program
of Higher Education of China (20124301110005) and the Scien-
tific Research Foundation for Returned Scholars, Ministry of
Education of China (2011-1568).
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