Synthesis of Quinazolines from N,N′-Disubstituted Amidines via I2/KI-Mediated Oxidative C-C Bond Formation

Article abstract of DOI:10.1021/acs.joc.6b02100

An I₂/KI-promoted oxidative C-C bond formation reaction from C(sp³)-H and C(sp²)-H bonds has been used to construct quinazoline skeletons from N,N′-disubstituted amidines. The required substrates are readily prepared from the corresponding acyl chlorides, anilines, and alkyl/benzylamines by sequential amidation, chlorination, and amination reactions. Under the optimal oxidative cyclization conditions, all these amidines were conveniently transformed into the expected products in moderate to good yields. This practical and environmentally benign approach works well with crude amidine intermediates and can also be carried out on a gram scale.

Full text of DOI:10.1021/acs.joc.6b02100

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Article
Synthesis of Quinazolines from N,N'-Disubstituted
Amidines via I2/KI-Mediated Oxidative C-C Bond Formation
Zhigang Lv, Bingnan Wang, Zhiyuan Hu, Yiming Zhou, Wenquan Yu, and Junbiao Chang
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.6b02100 • Publication Date (Web): 27 Sep 2016
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Synthesis of Quinazolines from N,N'ꢀDisubstituted Amidines
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via I2/KIꢀMediated Oxidative C−C Bond Formation
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Zhigang Lv, Bingnan Wang, Zhiyuan Hu, Yiming Zhou, Wenquan Yu,* and Junbiao
Chang*
College of Chemistry and Molecular Engineering, Zhengzhou University, Zhengzhou,
Henan Province 450001, China
Abstract: An I2/KIꢀpromoted oxidative C−C bond formation reaction from C(sp3)−H
and C(sp2)−H bonds has been used to construct quinazoline skeletons from
N,N'ꢀdisubstituted amidines. The required substrates are readily prepared from the
corresponding acyl chlorides, anilines, and alkyl/benzylamines by sequential
amidation, chlorination and amination reactions. Under the optimal oxidative
cyclization conditions, all these amidines were conveniently transformed into the
expected products in moderate to good yields. This practical and environmentally
benign approach works well with crude amidine intermediates and can also be carried
out on a gram scale.
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■ INTRODUCTION
Quinazoline is an important structural motif occurring frequently in natural products1
and synthetic molecules with diverse pharmacological properties,2 including
anticonvulsant,3 antiꢀinflammatory,4 anticancer,5 and antimicrobial activities.6
Vasicine, a natural quinazoline alkaloid isolated from Adhatoda vasica, displays
bronchodilatory activity both in vitro and in vivo.7 Prazosin is an orally available
sympatholytic drug for the treatment of hypertension, anxiety, and postꢀtraumatic
stress disorder. Vandetanib is the first drug approved by FDA to treat lateꢀstage
medullary thyroid cancer and recently, 2ꢀarylquinazolines were identified as novel
inhibitors of HIVꢀ1 capsid assembly8 (Figure 1).
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Figure 1. Representative bioactive quinazoline derivatives.
There are two general strategies for construction of the quinazoline skeleton (Scheme
1). For example, substituted quinazolines can be prepared from easily available
orthoꢀfunctionalized
anilines,
such
as
2ꢀaminobenzylamines9
and
2ꢀaminobenzoketones.10 Alternatively, reactions to access quinazoline derivatives
have been developed using Nꢀarylamidines as substrates, in which preꢀactivation at
the orthoꢀposition of the Nꢀaryl ring is unnecessary. In 2005, Mahajan11 reported a
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microwaveꢀpromoted synthesis of quinazolines from Nꢀarylamidines and aldehydes.
Several transition metalꢀcatalyzed reactions12 have been established to produce
quinazolines. In 2014, Long13 described a PhI(OAc)2ꢀmediated synthesis of
multisubstituted quinazolines from arylamidines; later, Tang14 achieved such an
oxidative cyclization reaction using visible light.
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Scheme 1. Construction of Quinazoline Skeletons from orthoꢀFunctionalized Anilines
and NꢀArylamidines
Molecular iodine, an inexpensive and lowꢀtoxic oxidant, enables various oxidative
C–X (X = C, N, O, or S) bond construction reactions from C–H bonds enabling
synthesis of heterocyclic compounds.15 In particular, I2ꢀmediated oxidative C–C bond
formation is a valuable tool for the synthesis of complex structures in an atomꢀ and
stepꢀeconomic fashion. For example, Ma et al.15e have developed a series of
iodineꢀmediated intramolecular dearomative oxidative coupling (IDOC) reactions of
indoles for the total synthesis of indoline alkaloids and Wu and coꢀworkers16 exploited
oxidative crossꢀcoupling reactions of aryl methyl ketones with different aromatic
rings utilizing molecular iodine. In 2010, Li17 reported an I2ꢀpromoted 3Hꢀindole
synthesis from Nꢀaryl enamines. In this paper, we report an I2/KIꢀmediated oxidative
C−C bond formation reaction to produce quinazolines from N,N'ꢀdisubstituted
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amidines.
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■ RESULTS AND DISCUSSION
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Amidine substrates (1) can be readily prepared from the corresponding acyl chlorides,
anilines, and alkyl/benzylamines by sequential amidation, chlorination and
amination reactions.13, 18 Initially, amidine 1b was chosen as the model substrate for
the optimization of the reaction conditions (Table 1). Screening of commonlyꢀused
solvents (entries 1‒4) suggested that DMSO is the most effective medium for this
I2ꢀmediated oxidative cyclization of 1b to the quinazoline 2b in the presence of
potassium carbonate (K2CO3). Total consumption of the substrate requires at least 2.4
equiv. of iodine and the optimal reaction temperature is 100 ºC (entry 4). Addition of
potassium iodide (KI)19 to the reaction system further improves the yield of the
desired product (2b) (entry 8).
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Table 1. Reaction Conditions Optimization for the Synthesis of Quinazoline 2ba
entry I2/equiv. additive
solvent
CH2Cl2
temp./ temp/h yieldb
1
2
3
4
5
6
2.4
2.4
2.4
2.4
2.0
2.4
‒
‒
‒
‒
‒
‒
reflux
6
5
2
2
5
3
trace
28%
32%
93%
79%
72%
1,4ꢀdioxane reflux
MeCN
DMSO
DMSO
DMSO
reflux
100 ºC
100 ºC
80 ºC
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2.4
‒
DMSO
120 ºC
1.5
78%
5
6
8
2.4
KI
DMSO
100 ºC
4
97%
7
8
9
aOptimal reaction conditions (entry 8): To a wellꢀstirred mixture of I2 (0.96 mmol) and KI (0.96
mmol) in DMSO (2.5 mL) was added substrate 1b (0.4 mmol), K2CO3 (1 mmol) and another 2.5
mL of DMSO in sequence, and then the mixture was heated to 100 °C for 4 h. bIsolated yields are
given.
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With the optimized conditions (Table 1, entry 8) in hand, we investigated the substrate
scope of N'ꢀaryl substituted amidines to determine the scope and generality of this
method (Scheme 2). All the substrates tested were smoothly converted to the
corresponding quinazolines (2a−j) in moderate to excellent yield. This methodology
is compatible with both electronꢀdonating groups (EDG) and electronꢀwithdrawing
groups (EWG) on the N'ꢀphenyl ring. The substrate containing a nitro group (1g), the
strongest EWG, was also successfully cyclized to the expected quinazoline product
(2g), although in somewhat lower yield. Regioselective formation of quinazoline 2i
rather than 2i' was observed during the cyclization of metaꢀmethyl substrate (1i), and
this could be due to steric hindrance during the formation of 5ꢀmethyl product (2i').
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Scheme 2. Substrate Scope of R1 Group on the N'ꢀPhenyl Ringa
5
Ph
Ph
6
7
8
9
I2/KI, K2CO3
DMSO, 100 °C
39-98%
HN
Ph
N
R1
R1
N
Ph
N
1
2
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Ph
Ph
Ph
R1
Cl
N
N
N
Ph
N
Ph
N
Ph
N
2b (R1 = Me), 97%
2c (R1 = OMe), 77%
2d
, 89%
2a, 90%
Ph
Ph
Ph
Br
CN
NO2
N
N
N
Ph
N
Ph
N
Ph
N
2e, 96%
2f, 92%
2g, 39%
Ph
Ph
Ph Me
N
N
N
Me
Ph
N
Ph
2i
N
Ph
N
Me
Me
2i'
(7-Me)/ (5-Me),
83% (9:1)b
2h, 83%
2j, 98%
aOptimal reaction conditions: To a wellꢀstirred mixture of I2 (0.96 mmol) and KI (0.96 mmol) in
DMSO (2.5 mL) was added substrate 1 (0.4 mmol), K2CO3 (1 mmol) and another 2.5 mL of
b
DMSO in sequence, and then it was heated to 100 °C (isolated yields are given). The ratio was
determined by 1H NMR.
In light of these encouraging results, we further examined the substituent effect of the
R2 and R3 moieties on this I2/KIꢀmediated oxidative C–C bond formation reaction
(Scheme 3). When R2 is an aromatic ring, it can tolerate both EDGs (2k–l) and EWGs
(2m–n). 4ꢀ(4ꢀPyridyl)quinazoline (2o) is also obtained in acceptable yield from the
corresponding substrate. Replacement of the aryl groups at the R2 position with
aliphatic groups led to 4ꢀalkyl quinazolines (2p–q) in somewhat lower yields.
Substrates bearing substituted phenyl (1r–t), αꢀnaphthyl (1u), and 2ꢀfuryl groups (1v)
at the R3 position are all cyclized into the expected products (2r−v) in good yields. In
addition, the 2ꢀtertꢀbutyl substituted quinazoline (2w) was also successfully prepared
from the corresponding amidine.
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Scheme 3. Substrate Scope of R2 and R3 Groupsa
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aOptimal reaction conditions: To a wellꢀstirred mixture of I2 (0.96 mmol) and KI (0.96 mmol) in
DMSO (2.5 mL) was added substrate 1 (0.4 mmol), K2CO3 (1 mmol) and another 2.5 mL of
b
DMSO in sequence, and then it was heated to 100 °C (isolated yields are given). The reaction
was performed at 110 °C.
To assess the practicality of the present methodology, we performed the quinazoline
synthesis directly from simple amines and acyl chlorides, omitting purification of the
amidine intermediate. The reaction of 4ꢀmethylaniline and benzoyl chloride at the 6
mmol scale afforded the desired product (2b) in gram scale via sequential amidation,
chlorination and amination, followed by I2/KIꢀmediated oxidative cyclization
(Scheme 4). The overall yield of this sequential synthetic process is comparable to
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that of the reactions via a purified amidine (1b).
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Scheme 4. Gramꢀscale Synthesis of Quinazoline 2b Omitting the Isolation of Amidine
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Intermediate
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A tentative reaction mechanism for the oxidative cyclization of the amidine (1) to
quinazoline (2) is proposed in Scheme 5. First, oxidation of substrate 1 by molecular
iodine under basic conditions gives an imine intermediate B. Then, iodineꢀmediated
iodocyclization of this imine (B) generates a plausible Nꢀiodo species C, containing a
new C–C bond. Finally, baseꢀpromoted deprotonation followed by elimination of one
molecule of hydrogen iodide (HI) produces the quinazoline framework (2).
Scheme 5. Proposed Mechanism for the Formation of Quinazoline 2
■ CONCLUSIONS
In summary, we have developed an I2/KIꢀmediated oxidative C−C bond formation
reaction from C(sp3)−H and C(sp2)−H bonds. This practical and transition metalꢀfree
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approach provides facile access to a variety of multisubstituted quinazoline
derivatives from readily accessible N,N'ꢀdisubstituted amidines. Sequential synthesis
of the products from simple amines and acyl chlorides without isolation of the
amidine intermediates can be conveniently conducted on a gram scale.
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■ EXPERIMENTAL SECTIONS
1
General Information. H and 13C NMR spectra were recorded on a 400 MHz (100
MHz for 13C NMR) spectrometer. Chemical shift values are given in parts per million
(ppm) relative to the internal standard, tetramethylsilane (TMS). The peak patterns are
indicated as follows: s, singlet; d, doublet; t, triplet; q, quartet; quint, quintet; sext,
sextet; hept, heptet; m, multiplet; dd, doublet of doublets; dt, doublet of triplets. The
coupling constants (J) are reported in Hertz (Hz). Melting points were determined on
a micromelting point apparatus and are uncorrected. Highꢀresolution mass spectra
(HRMSꢀESI) were obtained on a TOFꢀQ mass spectrometer. Flash column
chromatography was performed over silica gel 200‒300 mesh and the solvents were
distilled prior to use. CH2Cl2, used in the preparation of substrates (1), was dried over
calcium hydride (CaH2) and distilled prior to use; DMSO, used in the synthesis of
quinazolines (2), was analytical reagent grade and used without any pretreatment. All
the chemicals (AR grade) were purchased from commercial sources and used without
further purification.
General Procedure A for the Preparation of Substrates 1a‒j. At 0 ºC, a mixture of
amine 4 (3.0 mmol) and Et3N (0.5 mL, 3.6 mmol) in anhydrous CH2Cl2 (10 mL) was
treated slowly with acyl chloride 3 (3.3 mmol), and stirred at 0 ºC for 10 min, then at
room temperature for another 20 min. The reaction was quenched with H2O (20 mL)
and extracted with CH2Cl2 (20 mL × 3). The combined organic layer was dried over
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anhydrous Na2SO4, and then concentrated to afford the amide (5) as a white solid.
This crude amide was stirred in thionyl chloride (5 mL) at reflux for 6 h and then
concentrated. The resulting residue was redissolved in toluene (5 mL × 2) and
evaporated again to provide the imidoyl chloride (6) as a yellow oil/solid. A mixture
of an aniline (7, 3.3 mmol) and Et3N (0.84 mL, 6 mmol) in anhydrous CH2Cl2 (10 mL)
was stirred at 0 ºC for 10 min, and then treated with a solution of the above imidoyl
chloride (6) in anhydrous CH2Cl2 (5 mL). The reaction was stirred at 0 ºC for 10 min,
and then heated at reflux for another 2 h. After cooling to room temperature, it was
quenched with H2O (20 mL) and extracted with CH2Cl2 (20 mL × 3). The combined
organic layers were dried over anhydrous Na2SO4, concentrated, and purified through
silica gel column chromatography to afford substrates 1a‒j (see Scheme S1 in
Supporting Information).
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General Procedure B for the Preparation of Substrates 1k‒w. At 0 ºC, a mixture
of aniline 7 (3.0 mmol) and Et3N (0.5 mL, 3.6 mmol) in anhydrous CH2Cl2 (10 mL)
was treated slowly with acyl chloride 3 (3.3 mmol) and stirred at 0 ºC for 10 min, then
at room temperature for another 20 min. The reaction was quenched with H2O (20 mL)
and extracted with CH2Cl2 (20 mL × 3). The combined organic layer was dried over
anhydrous Na2SO4, and then concentrated to afford the amide (8) as a white solid. The
crude amide (8) was stirred in thionyl chloride (5 mL) at reflux for 6 h and then
concentrated. The resulting residue was redissolved in toluene (5 mL × 2) and
evaporated again to provide the imidoyl chloride (9) as a yellow oil/solid. A mixture
of an amine (4, 3.3 mmol) and Et3N (0.84 mL, 6 mmol) in anhydrous CH2Cl2 (10 mL)
was stirred at 0 ºC for 10 min, and then treated with a solution of the above imidoyl
chloride (9) in anhydrous CH2Cl2 (5 mL). The reaction was stirred at 0 ºC for 10 min,
and then heated to reflux for another 2 h. After cooling to room temperature, it was
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quenched with H2O (20 mL) and extracted with CH2Cl2 (20 mL × 3). The combined
organic layer was dried over anhydrous Na2SO4, concentrated, and purified through
silica gel column chromatography to afford substrates 1k‒w (see Scheme S2 in
Supporting Information).
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NꢀBenzylꢀN'ꢀphenylbenzimidamide (1a). Eluent: EtOAc/petroleum ether (PE) 15:85;
1
yield: 456 mg, 53%; white solid, mp 98ꢀ99 °C (lit13 99ꢀ100 °C); H NMR (400 MHz,
CDCl3) δ 7.44 (s, 1H), 7.43 (s, 1H), 7.36 (t, J = 6.8 Hz, 2H), 7.31ꢀ7.22 (m, 6H,
overlapped with the peak of chloroform), 7.06 (t, J = 6.4 Hz, 2H), 6.83ꢀ6.80 (m, 1H),
6.68ꢀ6.66 (m, 2H), 4.78 (br, s, 1H), 4.69 (s, 2H); 13C NMR (100 MHz, CDCl3) δ 157.2,
150.8, 139.0, 135.1, 129.2, 128.7, 128.6, 128.4, 128.3, 128.2, 127.5, 123.1, 121.4,
46.2; HRMS (m/z) [M+H]+ calcd for C20H19N2, 287.1543, found 287.1543.
NꢀBenzylꢀN'ꢀ(pꢀtolyl)benzimidamide (1b). Eluent: EtOAc/PE 15:85; yield: 496 mg,
1
55%; white solid, mp 125ꢀ126 °C (lit14 126ꢀ127 °C); H NMR (400 MHz, CDCl3) δ
7.44 (s, 1H), 7.43 (s, 1H), 7.36 (t, J = 7.2 Hz, 2H), 7.31ꢀ7.23(m, 6H, overlapped with
the peak of chloroform), 6.86 (d, J = 7.6 Hz, 2H), 6.56 (d, J = 6.8 Hz, 2H), 4.69 (s,
3H), 2.19 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 157.1, 148.1, 139.1, 135.3, 130.5,
129.1, 129.0, 128.7, 128.6, 128.3, 128.2, 127.4, 122.9, 46.2, 20.8; HRMS (m/z)
[M+H]+ calcd for C21H21N2, 301.1699, found 301.1697.
NꢀBenzylꢀN'ꢀ(4ꢀmethoxyphenyl)benzimidamide (1c). Eluent: EtOAc/PE 33:67;
1
yield: 722mg, 76%; white solid, mp 123ꢀ124 °C (lit14 115ꢀ117 °C); H NMR (400
MHz, CDCl3) δ 7.44 (s, 1H), 7.42 (s, 1H), 7.36 (t, J = 7.2 Hz, 2H), 7.31ꢀ7.22 (m, 6H,
overlapped with the peak of chloroform), 6.64ꢀ6.57 (m, 4H), 4.68 (s, 3H), 3.68 (s, 3H);
13C NMR (100 MHz, CDCl3) δ 157.3, 154.5, 144.0, 139.1, 135.3, 129.1, 128.7, 128.6,
128.3, 128.1, 127.4, 123.8, 113.7, 55.4, 46.2; HRMS (m/z) [M+H]+ calcd for
C21H21N2O, 317.1648, found 317.1646.
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NꢀBenzylꢀN'ꢀ(4ꢀchlorophenyl)benzimidamide (1d). Eluent: EtOAc/PE 10:90; yield:
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568 mg, 59%; white solid, mp 104ꢀ105 °C (lit13 101ꢀ102 °C); H NMR (400 MHz,
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CDCl3) δ 7.41 (s, 2H), 7.36 (t, J = 7.2 Hz, 2H), 7.32ꢀ7.21 (m, 6H, overlapped with the
peak of chloroform), 7.00 (d, J = 8.0 Hz, 2H), 6.58 (d, J = 7.6 Hz, 2H), 4.84 (br, s,
1H), 4.67 (s, 2H); 13C NMR (100 MHz, CDCl3) δ 157.6, 149.5, 138.7, 134.7, 129.4,
128.8, 128.50, 128.47, 128.4, 128.1, 127.5, 126.5, 124.3, 46.2; HRMS (m/z) [M+H]+
calcd for C20H18ClN2, 321.1153, found 321.1156.
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NꢀBenzylꢀN'ꢀ(4ꢀbromophenyl)benzimidamide (1e). Eluent: EtOAc/PE 10:90; yield:
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669 mg, 61%; gray solid, mp 105ꢀ106°C (lit14 105ꢀ106 °C); H NMR (400 MHz,
CDCl3) δ 7.42 (s, 2H), 7.37 (t, J = 7.2 Hz, 2H), 7.32ꢀ7.22 (m, 6H, overlapped with the
peak of chloroform), 7.15 (d, J = 7.6 Hz, 2H), 6.54 (d, J = 6.8 Hz, 2H), 4.83 (br, s,
1H), 4.67 (s, 2H); 13C NMR (100 MHz, CDCl3) δ 157.6, 150.0, 138.7, 134.6, 131.4,
129.5, 128.8, 128.5, 128.1, 127.6, 124.8, 114.2, 46.2; HRMS (m/z) [M+H]+ calcd for
C20H18BrN2, 365.0648, found 365.0650.
NꢀBenzylꢀN'ꢀ(4ꢀcyanophenyl)benzimidamide (1f). Eluent: EtOAc/PE 10:90; yield:
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738 mg, 79%; white solid, mp 113ꢀ114 °C (lit14 117ꢀ119 °C); H NMR (400 MHz,
CDCl3) δ 7.42ꢀ7.20 (m, 12H, overlapped with the peak of chloroform), 6.69 (d, J =
13
8.4 Hz, 2H), 5.07 (s, 1H), 4.68 (s, 2H); C NMR (100 MHz, CDCl3) δ 157.9, 155.6,
138.3, 134.0, 132.7, 130.0, 128.8, 128.7, 128.4, 128.1, 127.7, 123.6, 120.0, 104.0,
46.3; HRMS (m/z) [M+H]+ calcd for C21H18N3, 312.1495, found 312.1499.
NꢀBenzylꢀN'ꢀ(4ꢀnitrophenyl)benzimidamide (1g).14 Eluent: EtOAc/PE 10:90; yield:
487 mg, 49%; yellow solid, mp 131ꢀ132 °C; 1H NMR (400 MHz, CDCl3) δ 7.97ꢀ7.93
(m, 2H), 7.43ꢀ7.22 (m, 10H, overlapped with the peak of chloroform), 6.69 (d, J = 8.8
Hz, 2H), 5.14 (br, s, 1H), 4.70 (s, 1H), 4.69 (s, 1H); 13C NMR (100 MHz, CDCl3) δ
158.0, 141.9, 138.2, 133.9, 130.1, 128.9, 128.8, 128.4, 128.1, 127.7, 124.7, 123.0,
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46.4; HRMS (m/z) [M+H]+ calcd for C20H18N3O2, 332.1394, found 332.1405.
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78%; white solid, mp 71ꢀ72 °C; H NMR (400 MHz, CDCl3) δ 7.43ꢀ7.18 (m, 10H,
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overlapped with the peak of chloroform), 7.01 (d, J = 5.2 Hz, 1H), 6.82 (s, 1H), 6.73
(s, 1H), 6.39 (s, 1H), 4.82 (br, s, 1H), 4.70 (s, 2H), 2.17 (s, 3H); 13C NMR (100 MHz,
CDCl3) δ 156.0, 149.5, 139.4, 135.4, 130.1, 129.8, 129.3, 128.7, 128.3, 128.1, 127.3,
125.9, 122.4, 121.6, 46.0, 18.5; HRMS (m/z) [M+H]+ calcd for C21H21N2, 301.1699,
found 301.1691.
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NꢀBenzylꢀN'ꢀ(mꢀtolyl)benzimidamide (1i). Eluent: EtOAc/PE 10:90; yield: 757 mg,
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84%; white solid, mp 110ꢀ111 °C (lit14 106ꢀ107 °C); H NMR (400 MHz, CDCl3) δ
7.45ꢀ7.24 (m, 10H, overlapped with the peak of chloroform), 6.92 (t, J = 7.2 Hz, 1H),
6.63 (d, J = 6.8 Hz, 1H), 6.57 (s, 1H), 6.42 (s, 1H), 4.76 (br, s, 1H), 4.69 (s, 2H), 2.18
(s, 3H); 13C NMR (100 MHz, CDCl3) δ 157.0, 150.7, 139.1, 138.0, 135.2, 129.2,
128.7, 128.6, 128.3, 128.1, 127.4, 123.9, 122.2, 120.0, 46.2, 21.4; HRMS (m/z)
[M+H]+ calcd for C21H21N2, 301.1699, found 301.1696.
NꢀBenzylꢀN'ꢀ(3,5ꢀdimethylphenyl)benzimidamide (1j). Eluent: EtOAc/PE 15:85;
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yield: 557mg, 59%; white solid, mp 84ꢀ85 °C; H NMR (400 MHz, CDCl3) δ
7.42ꢀ7.23 (m, 9H), 6.46 (s, 2H), 6.31 (s, 2H), 4.67 (s, 3H), 2.12 (s, 6H); 13C NMR
(100 MHz, CDCl3) δ 156.8, 150.5, 139.2, 137.7, 135.2, 129.1, 128.7, 128.5, 128.3,
128.1, 127.4, 123.1, 120.8, 46.2, 21.3; HRMS (m/z) [M+H]+ calcd for C22H23N2,
315.1856, found 315.1856.
Nꢀ(4ꢀMethylbenzyl)ꢀN'ꢀ(pꢀtolyl)benzimidamide (1k). Eluent: EtOAc/PE 20:80;
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yield: 585mg, 62%; white solid, mp 98ꢀ99 °C; H NMR (400 MHz, CDCl3) δ
7.31ꢀ7.15 (m, 9H, overlapped with the peak of chloroform), 6.85 (d, J = 7.2 Hz, 2H),
6.56 (d, J = 6.4 Hz, 2H), 4.63 (s, 3H), 2.34 (s, 3H), 2.19 (s, 3H); 13C NMR (100 MHz,
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CDCl3) δ 157.1, 148.1, 137.1, 136.0, 135.4, 130.5, 129.4, 129.1, 128.6, 128.3, 128.2,
122.9, 46.1, 21.2, 20.8; HRMS (m/z) [M+H]+ calcd for C22H23N2, 315.1856, found
315.1858.
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Nꢀ(4ꢀMethoxybenzyl)ꢀN'ꢀ(pꢀtolyl)benzimidamide (1l). Eluent: EtOAc/PE 30:70;
yield: 971 mg, 98%; light yellow solid, mp 117ꢀ118 °C; 1H NMR (400 MHz, CDCl3)
δ 7.36ꢀ7.22 (m, 7H, overlapped with the peak of chloroformR), 6.90ꢀ6.85 (m, 4H),
6.56 (d, J = 6.4 Hz, 2H), 4.61 (s, 3H), 3.80 (s, 3H), 2.19 (s, 3H); 13C NMR (100 MHz,
CDCl3) δ 159.0, 157.1, 148.1, 135.4, 131.1, 130.5, 129.5, 129.1, 129.0, 128.6, 128.3,
122.9, 114.1, 55.3, 45.7, 20.8; HRMS (m/z) [M+H]+ calcd for C22H23N2O, 331.1805,
found 331.1806.
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Nꢀ(4ꢀChlorobenzyl)ꢀN'ꢀ(pꢀtolyl)benzimidamide (1m). Eluent: EtOAc/PE 20:80;
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yield: 633 mg, 63%; white solid, mp 94ꢀ95 °C; H NMR (400 MHz, CDCl3) δ
7.38ꢀ7.32 (m, 9H, overlapped with the peak of chloroform), 6.86 (d, J = 7.6 Hz, 2H),
6.54 (d, J = 5.2 Hz, 2H), 4.65 (s, 3H), 2.19 (s, 3H); 13C NMR (100 MHz, CDCl3) δ
156.9, 137.7, 135.1, 133.1, 130.7, 129.4, 129.2, 129.0, 128.8, 128.5, 128.3, 122.7,
45.3, 20.8; HRMS (m/z) [M+H]+ calcd for C21H20ClN2, 335.1310, found 335.1318.
N'ꢀ(pꢀTolyl)ꢀNꢀ(3ꢀ(trifluoromethyl)benzyl)benzimidamide (1n). Eluent: EtOAc/PE
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20:80; yield: 685 mg, 62%; white solid, mp 75ꢀ76 °C; H NMR (400 MHz, CDCl3) δ
7.71 (s, 1H), 7.63 (d, J = 6.4 Hz, 1H), 7.55ꢀ7.44 (m, 2H), 7.25 (m, 5H, overlapped
with the peak of chloroform), 6.86 (d, J = 6.8 Hz, 2H), 6.55 (s, 2H), 4.74 (s, 3H), 2.19
(s, 3H); 13C NMR (100 MHz, CDCl3) δ 156.8, 147.7, 140.4, 135.0, 131.4, 131.2 (d, J
= 31.7 Hz, partially overlapped with other peaks), 130.8, 130.4, 129.3, 129.1, 128.5,
128.4, 124.7, 124.16 (q, J = 271.1 Hz, partially overlapped with other peaks), 124.10
(q, J = 3.6 Hz), 122.7, 45.4, 20.8; HRMS (m/z) [M+H]+ calcd for C22H20F3N2,
369.1573, found 369.1571.
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Nꢀ(Pyridinꢀ4ꢀylmethyl)ꢀN'ꢀ(pꢀtolyl)benzimidamide (1o). Eluent: EtOAc/PE 20:80;
yield: 488 mg, 54%; white solid, mp 212ꢀ213 °C; 1H NMR (400 MHz, CDCl3) δ 8.54
(s, 1H), 8.53 (s, 1H), 7.33ꢀ7.25 (m, 7H, overlapped with the peak of chloroform), 6.86
(d, J = 4.8 Hz, 2H), 6.52 (s, 2H), 5.02 (br, s, 1H), 4.70 (s, 2H), 2.19 (s, 3H); 13C NMR
(100 MHz, CDCl3) δ 156.8, 149.9, 148.5, 134.8, 130.9, 129.4, 129.1, 128.4, 122.5,
44.6, 20.8; HRMS (m/z) [M+H]+ calcd for C20H20N3, 302.1652, found 302.1650.
NꢀButylꢀN'ꢀ(pꢀtolyl)benzimidamide (1p). Eluent: EtOAc/PE 33:67; yield: 607 mg,
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76%; white solid, mp 91ꢀ92 °C; H NMR (400 MHz, CDCl3) δ 7.24ꢀ7.20 (m, 5H),
6.83 (d, J = 7.6 Hz, 2H), 6.51 (d, J = 7.6 Hz, 2H), 4.44 (br, s, 1H), 3.49 (s, 2H), 2.17
(s, 3H), 1.68ꢀ1.60 (m, 2H), 1.51ꢀ1.41 (m, 2H), 0.98 (t, J = 7.2 Hz, 3H); 13C NMR (100
MHz, CDCl3) δ 157.5, 148.3, 135.7, 130.3, 128.9, 128.6, 128.2, 122.9, 121.7, 41.7,
31.5, 20.8, 20.4, 14.0; HRMS (m/z) [M+H]+ calcd for C18H23N2, 267.1856, found
267.1858.
NꢀIsobutylꢀN'ꢀ(pꢀtolyl)benzimidamide (1q). Eluent: EtOAc/PE 30:70; yield: 631
1
mg, 79%; white solid, mp 84ꢀ85 °C; H NMR (400 MHz, CDCl3, mixture of
tautomers, *peaks of the minor one) δ 7.61* (m, 0.3H), 7.42* (m, 0.5H), 7.24ꢀ7.22 (m,
4.3H), 7.15* (m, 0.3H), 6.85* (m, 0.3H), 6.83 (d, J = 7.6 Hz, 1.7H), 6.51 (d, J = 7.2
Hz, 1.7H), 4.68* (br, s, 0.2H), 4.49 (br, s, 0.8H), 3.34 (s, 1.7H), 2.83* (s, 0.3H), 2.33*
(s, 0.5H), 2.17 (s, 2.6H), 1.96 (hept, J = 6.4 Hz, 1H), 1.02 (d, J = 6.4 Hz, 5.2H), 0.75*
(m, 0.9H); 13C NMR (100 MHz, CDCl3, mixture of tautomers, *peaks of the minor
one) δ 159.4*, 157.6, 148.4, 146.9*, 136.2*, 135.9, 132.0*, 130.2, 129.5*, 128.9,
128.6, 128.2, 122.9, 121.7, 52.4*, 49.2, 30.0*, 28.3, 20.7, 20.5, 19.8*; HRMS (m/z)
[M+H]+ calcd for C18H23N2, 267.1856, found 267.1856.
NꢀBenzylꢀ4ꢀmethylꢀN'ꢀ(pꢀtolyl)benzimidamide (1r). Eluent: EtOAc/PE 20:80; yield:
877 mg, 93%; white solid, mp 76ꢀ77 °C; 1H NMR (400 MHz, CDCl3) δ 7.36ꢀ7.24 (m,
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5H), 7.14 (s, 2H), 7.05 (s, 2H), 6.89 (s, 2H), 6.60 (s, 2H), 4.65 (s, 3H), 2.28 (s ,3H),
2.21 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 157.3, 148.1, 139.0, 132.1, 130.5, 129.1,
128.7, 128.5, 128.0, 127.4, 122.8, 120.4, 46.3, 21.4, 20.8; HRMS (m/z) [M+H]+ calcd
for C22H23N2, 315.1856, found 315.1854.
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NꢀBenzylꢀ4ꢀchloroꢀN'ꢀ(pꢀtolyl)benzimidamide (1s). Eluent: EtOAc/PE 10:90; yield:
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723 mg, 72%; white solid, mp 92ꢀ93 °C; H NMR (400 MHz, CDCl3) δ 7.39 (s, 2H),
7.34 (t, J = 7.2 Hz, 2H), 7.28 (d, J = 6.8 Hz, 1H), 7.15 (m, 4H), 6.86 (d, J = 7.2 Hz,
2H), 6.52 (d, J = 6.8 Hz, 2H), 4.74 (br, s, 1H), 4.63 (s, 2H), 2.19 (s, 3H); 13C NMR
(100 MHz, CDCl3) δ 155.9, 147.8, 139.0, 135.1, 133.6, 130.8, 130.0, 129.2, 128.8,
128.6, 128.2, 127.5, 122.7, 46.2, 20.8; HRMS (m/z) [M+H]+ calcd for C21H20ClN2,
335.1310, found 335.1309.
NꢀBenzylꢀN'ꢀ(pꢀtolyl)ꢀ3ꢀ(trifluoromethyl)benzimidamide (1t). Eluent: EtOAc/PE
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5:95; yield: 1.006g, 91%; white solid, mp 103ꢀ104 °C; H NMR (400 MHz, CDCl3,
mixture of tautomers, *peaks of the minor one) δ 7.89ꢀ7.67* (m, 0.8H), 7.53ꢀ7.23 (m,
8H, overlapped with the peak of chloroform), 7.13ꢀ7.12* (m, 0.8H), 6.86 (d, J = 6.8
Hz, 1.6H), 6.82ꢀ6.81* (m, 0.2H), 6.52 (d, J = 6.0 Hz, 1.6H), 5.04* (br, s, 0.2H), 4.77
(br, s, 0.8H), 4.67 (s, 1.6H), 4.17ꢀ4.16* (m, 0.3H), 2.30* (s, 0.6H), 2.18 (s, 2.4H); 13C
NMR (100 MHz, CDCl3, mixture of tautomers, *peaks of the minor one) δ 157.6*,
155.5, 147.5, 146.1*, 138.7, 138.6*, 136.6*, 136.0, 132.7*, 132.1, 131.7*, 131.0,
130.7 (q, J = 32.2 Hz), 130.3*, 129.2, 129.0*, 128.8, 128.2, 127.6, 126.9*, 126.5*,
125.8 (d, J = 3.5 Hz), 125.3 (d, J = 3.7 Hz), 123.7 (q, J = 271.0 Hz), 122.7, 121.3*,
48.9*, 46.3, 20.9*, 20.7; HRMS (m/z) [M+H]+ calcd for C22H20F3N2, 369.1573, found
369.1575.
NꢀBenzylꢀN'ꢀ(pꢀtolyl)ꢀ1ꢀnaphthimidamide (1u). Eluent: EtOAc/PE 20:80; yield:
967 mg, 92%; light yellow solid, mp 96ꢀ97 °C; 1H NMR (400 MHz, CDCl3) δ 7.84 (s,
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1H), 7.74 (t, J = 8.4 Hz, 2H), 7.60 (d, J = 8.4 Hz, 1H), 7.45 (m, 4H), 7.37 (t, J = 7.2
Hz, 2H), 7.30 (d, J = 6.8 Hz, 1H), 7.22ꢀ7.17 (m, 1H), 6.82 (d, J = 7.6 Hz, 2H), 6.61 (d,
J = 7.2 Hz, 2H), 4.86 (br, s, 1H), 4.73 (s, 2H), 2.15 (s, 3H); 13C NMR (100 MHz,
CDCl3) δ 157.0, 148.0, 139.1, 133.3, 133.0, 132.8, 130.6, 129.1, 128.7, 128.3, 128.2,
128.1, 127.81, 127.77, 127.5, 126.9, 126.5, 126.0, 122.9, 46.4, 20.8; HRMS (m/z)
[M+H]+ calcd for C25H23N2, 351.1856, found 351.1855.
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NꢀBenzylꢀN'ꢀ(pꢀtolyl)furanꢀ2ꢀcarboximidamide (1v).20 Eluent: EtOAc/PE 5:95;
yield: 610 mg, 70%; white solid, mp 74ꢀ75 °C; 1H NMR (400 MHz, CDCl3) δ 7.45 (s,
1H), 7.43 (s, 1H), 7.37 (t, J = 7.6 Hz, 2H), 7.31ꢀ7.24 (m, 2H, overlapped with the
peak of chloroform), 7.07 (d, J = 8.4 Hz, 2H), 6.72 (d, J = 8.0 Hz, 2H), 6.21 (s, 1H),
5.67 (s, 1H), 5.55 (br, s, 1H), 4.66 (s, 2H), 2.32 (s, 3H); 13C NMR (100 MHz, CDCl3)
δ 149.0, 145.7, 144.6, 141.6, 139.1, 131.4, 129.7, 128.7, 128.2, 127.4, 121.3, 114.6,
111.6, 45.5, 20.9; HRMS (m/z) [M+H]+ calcd for C19H19N2O, 291.1492, found
291.1493.
NꢀBenzylꢀN'ꢀ(pꢀtolyl)pivalimidamide (1w). Eluent: EtOAc/PE 30:70; yield: 606 mg,
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72%; white solid, mp 41ꢀ42 °C; H NMR (400 MHz, CDCl3) δ 7.31ꢀ7.21 (m, 3H,
overlapped with the peak of chloroform), 7.16 (d, J = 6.8 Hz, 2H), 6.96 (d, J = 7.6 Hz,
2H), 6.69 (d, J = 8.4 Hz, 2H), 4.52 (s, 1H), 3.98 (s, 2H), 2.26 (s, 3H), 1.24 (s, 9H); 13C
NMR (100 MHz, CDCl3) δ 160.4, 148.7, 139.4, 129.8, 129.0, 128.6, 127.8, 127.4,
121.0, 48.5, 38.8, 29.3, 20.8; HRMS (m/z) [M+H]+ calcd for C19H25N2, 281.2012,
found 281.2014.
General Procedure for the Synthesis of Products (2). A mixture of iodine (244 mg,
0.96 mmol) and KI (160 mg, 0.96 mmol) in DMSO (2.5 mL) was stirred at room
temperature for 10 min and then treated with substrate 1 (0.40 mmol), followed by
addition of K2CO3 (139 mg, 1 mmol) and a further 2.5 mL of DMSO. The reaction
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was heated to 100 °C until TLC indicated the conversion was complete. After cooling
to room temperature, it was quenched with 5% Na2S2O3 (15 mL), and then extracted
with EtOAc (15 mL × 3). The combined organic layer was dried over anhydrous
Na2SO4, concentrated, and then purified through silica gel column chromatography to
afford the desired product 2.
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2,4ꢀDiphenylquinazoline (2a). 3 h; eluent: EtOAc/PE 1:99; yield: 102 mg, 90%;
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white solid, mp 109ꢀ110 °C (lit14 112ꢀ113 °C); H NMR (400 MHz, CDCl3) δ
8.71ꢀ8.68 (m, 2H), 8.17ꢀ8.11 (m, 2H), 7.90ꢀ7.85 (m, 3H), 7.61ꢀ7.49 (m, 7H); 13C
NMR (100 MHz, CDCl3) δ 168.4, 160.3, 152.0, 138.2, 137.7, 133.6, 130.5, 130.2,
130.0, 129.2, 128.7, 128.6, 127.0, 121.7; HRMS (m/z) [M+H]+ calcd for C20H15N2,
283.1230, found 283.1230.
6ꢀMethylꢀ2,4ꢀdiphenylquinazoline (2b). The 0.5 mmol scale reaction was carried
out using purified substrate 1b, 4 h; yield: 115 mg, 97%; the 6 mmol scale synthesis
was performed using crude substrate 1b (obtained via General Procedure A), 5 h;
overall yield: 1.077 g, 61% (from 4ꢀmethylaniline). Eluent: EtOAc/PE 2:98; white
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solid, mp 174ꢀ176 °C (lit14 167ꢀ170 °C); H NMR (400 MHz, CDCl3) δ 8.67 (d, J =
7.2 Hz, 2H), 8.06 (d, J = 8.8 Hz, 1H), 7.87 (m, 3H), 7.72 (d, J = 8.8 Hz, 1H),
7.61ꢀ7.59 (m, 3H), 7.54ꢀ7.48 (m, 3H), 2.52 (s, 3H); 13C NMR (100 MHz, CDCl3) δ
167.7, 159.7, 150.7, 138.4, 138.0, 137.3, 135.9, 130.4, 130.3, 129.9, 129.0, 128.67,
128.65, 128.64, 125.7, 121.8, 22.0; HRMS (m/z) [M+H]+ calcd for C21H17N2,
297.1386, found 297.1384.
6ꢀMethoxyꢀ2,4ꢀdiphenylquinazoline (2c). 3.5 h; eluent: EtOAc/PE 3:97; yield: 96
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mg, 77%; light yellow solid, mp 141ꢀ142 °C (lit14 142ꢀ144 °C); H NMR (400 MHz,
CDCl3) δ 8.66ꢀ8.63 (m, 2H), 8.06 (d, J = 9.2 Hz, 1H), 7.91ꢀ7.88 (m, 2H), 7.60ꢀ7.46
(m, 7H), 7.38 (d, J = 2.8 Hz, 1H), 3.84 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 166.6,
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158.7, 158.1, 148.2, 138.4, 138.0, 130.7, 130.1, 129.9, 129.8, 128.6, 128.5, 128.3,
126.2, 122.5, 104.4, 55.7; HRMS (m/z) [M+H]+ calcd for C21H17N2O, 313.1335,
found 313.1336.
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6ꢀChloroꢀ2,4ꢀdiphenylquinazoline (2d). 5 h; eluent: EtOAc/PE 1:99; yield: 113 mg,
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89%; white solid, mp 195ꢀ196 °C (lit14 194ꢀ195 °C); H NMR (400 MHz, CDCl3) δ
8.68ꢀ8.65 (m, 2H), 8.10ꢀ8.07 (m, 2H), 7.87ꢀ7.84 (m, 2H), 7.79 (dd, J = 9.2, 2.4 Hz,
1H), 7.62ꢀ7.59 (m, 3H), 7.54ꢀ7.49 (m, 3H); 13C NMR (100 MHz, CDCl3) δ 167.6,
160.5, 150.5, 137.8, 137.1, 134.5, 132.6, 130.9, 130.8, 130.3, 130.1, 128.8, 128.7,
128.6, 125.8, 122.2; HRMS (m/z) [M+H]+ calcd for C20H14ClN2, 317.0846, found
317.0857.
6ꢀBromoꢀ2,4ꢀdiphenylquinazoline (2e). 4.5 h; eluent: EtOAc/PE 1:99; yield: 139 mg,
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96%; white solid, mp 205ꢀ207 °C (lit14 203ꢀ205 °C); H NMR (400 MHz, CDCl3) δ
8.68ꢀ8.65 (m, 2H), 8.25 (d, J = 2.0 Hz, 1H), 8.03ꢀ8.00 (m, 1H), 7.95ꢀ7.91 (m, 1H),
7.87ꢀ7.84 (m, 2H), 7.62ꢀ7.60 (m, 3H), 7.54ꢀ7.50 (m, 3H); 13C NMR (100 MHz,
CDCl3) δ 167.5, 160.5, 150.7, 137.8, 137.12, 137.06, 131.0, 130.8, 130.3, 130.1,
129.1, 128.8, 128.7, 128.6, 122.7, 120.7; HRMS (m/z) [M+H]+ C20H14BrN2 calcd for,
363.0316, found 363.0305.
2,4ꢀDiphenylquinazolineꢀ6ꢀcarbonitrile (2f). 7 h; eluent: EtOAc/PE 3:97; yield: 113
mg, 92%; white solid, mp 231ꢀ233 °C (lit14 224ꢀ225 °C); 1H NMR (400MHz, CDCl3)
δ 8.71 (s, 2H), 8.50 (s, 1H), 8.21 (d, J = 7.6 Hz, 1H), 7.99 (d, J = 7.2 Hz, 1H), 7.86 (s,
2H), 7.66 (s, 3H), 7.55 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 169.0, 162.5, 153.3,
137.2, 136.4, 134.1, 133.7, 131.6, 130.83, 130.76, 130.2, 129.1, 129.0, 128.7, 121.2,
118.3, 110.4; HRMS (m/z) [M+H]+ calcd for C21H14N3, 308.1182, found 308.1173.
6ꢀNitroꢀ2,4ꢀdiphenylquinazoline (2g). 6 h; eluent: EtOAc/PE 3:97; yield: 51 mg,
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39%; white solid, mp 246ꢀ248 °C (lit14 245ꢀ257 °C); H NMR (400 MHz, CDCl3) δ
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9.06 (d, J = 2.4 Hz, 1H), 8.75ꢀ8.72 (m, 2H), 8.64 (dd, J = 9.2, 2.4 Hz, 1H), 8.25 (d, J
= 9.2 Hz, 1H), 7.93 ꢀ7.90 (m, 2H), 7.68ꢀ7.65 (m, 3H), 7.58ꢀ7.54 (m, 3H); 13C NMR
(100MHz, CDCl3) δ 170.5, 162.9, 154.5, 145.5, 137.1, 136.4, 131.8, 131.04, 130.99,
130.3, 129.2, 129.1, 128.8, 127.0, 124.3, 120.5; HRMS (m/z) [M+H]+ calcd for
C20H14N3O2, 328.1081, found 328.1078.
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8ꢀMethylꢀ2,4ꢀdiphenylquinazoline (2h). 5 h; eluent: EtOAc/PE 1:99; yield: 98 mg,
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83%; white solid, mp 115ꢀ117 °C (lit21 123 °C); H NMR (400 MHz, CDCl3) δ
8.76ꢀ8.73 (m, 2H), 7.93 (d, J = 8.4 Hz, 1H), 7.87ꢀ7.84 (m, 2H), 7.70 (d, J = 6.8 Hz,
1H), 7.58ꢀ7.54 (m, 3H), 7.52ꢀ7.48 (m, 3H), 7.40 (t, J = 7.6 Hz, 1H), 2.91 (s, 3H); 13C
NMR (100MHz, CDCl3) δ 168.4, 159.0, 151.0, 138.6, 138.1, 137.5, 133.3, 130.4,
130.3, 129.7, 128.7, 128.49, 128.46, 126.5, 124.7, 121.6, 17.6; HRMS (m/z) [M+H]+
calcd for C21H17N2, 297.1386, found 297.1382.
7ꢀMethylꢀ2,4ꢀdiphenylquinazoline (2i)
&
5ꢀmethylꢀ2,4ꢀdiphenylquinazoline
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(2i').13 5 h; eluent: EtOAc/PE 3:97; yield: 83 mg, 70% (2i:2i’ = 9:1 by H NMR);
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white solid, mp 155ꢀ157 °C; H NMR (400 MHz, CDCl3, *peaks of 2i') δ 8.69ꢀ8.66
(m, 1.8H), 8.65ꢀ8.63* (m, 0.2H), 8.01* (m, 0.1H), 8.00 (d, J = 8.4 Hz, 0.9H), 7.93 (s,
0.9H), 7.89ꢀ7.86 (m, 1.8H), 7.76ꢀ7.72* (m, 0.2H), 7.60ꢀ7.57 (m, 3.1H), 7.54ꢀ7.48 (m,
3.1H), 7.36 (dd, J = 8.8, 1.6 Hz, 0.9H), 7.32ꢀ7.31* (m, 0.1H), 2.59 (s, 2.7H), 2.08* (s,
0.3H); 13C NMR (100 MHz, CDCl3, *peaks of 2i') δ 168.6*,167.8, 160.3, 158.6*,
153.1*, 152.3, 144.5, 142.1*, 138.4, 137.9, 136.2*, 133.2*, 130.4, 130.2, 129.8, 129.3,
129.1*, 129.0*, 128.6, 128.52, 128.51, 128.3*, 128.1, 127.5*, 126.7, 122.1*, 119.9,
23.9*, 22.1; HRMS (m/z) [M + H]+ calcd for C21H17N2, 297.1386, found 297.1381.
5,7ꢀDimethylꢀ2,4ꢀdiphenylquinazoline (2j).22 3 h; eluent: EtOAc/PE 2:98; yield: 122
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mg, 98%; white solid, mp 149ꢀ151°C; H NMR (400 MHz, CDCl3) δ 8.64ꢀ8.60 (m,
2H), 7.80 (s, 1H), 7.56ꢀ7.45 (m, 8H), 7.15 (s, 1H), 2.53 (s, 3H), 2.04 (s, 3H); 13C
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NMR (100 MHz, CDCl3) δ 168.2, 158.8, 153.5, 143.9, 142.2, 138.0, 135.7, 132.5,
130.3, 129.02, 128.97, 128.6, 128.5, 128.2, 126.5, 120.3, 23.8, 21.9; HRMS (m/z) [M
+ H]+ calcd for C22H19N2, 311.1543, found 311.1543.
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6ꢀMethylꢀ2ꢀphenylꢀ4ꢀ(pꢀtolyl)quinazoline (2k).23 5 h; eluent: EtOAc/PE 2:98; yield:
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123 mg, 99%; white solid, mp 179ꢀ181 °C; H NMR (400 MHz, CDCl3) δ 8.68ꢀ8.65
(m, 2H), 8.05 (d, J = 8.8 Hz, 1H), 7.90 (s, 1H), 7.79 (d, J = 8.0 Hz, 2H), 7.73ꢀ7.69 (m,
1H), 7.54ꢀ7.48 (m, 3H), 7.41 (d, J = 8.0 Hz, 2H), 2.51 (s, 3H), 2.50 (s, 3H); 13C NMR
(100 MHz, CDCl3) δ 167.6, 159.6, 150.5, 140.0, 138.4, 137.0, 135.7, 135.1, 130.3,
130.1, 129.3, 128.8, 128.6, 128.5, 125.7, 121.7, 21.9, 21.5; HRMS (m/z) [M + H]+
calcd for C22H19N2, 311.1543, found 311.1527.
4ꢀ(4ꢀMethoxyphenyl)ꢀ6ꢀmethylꢀ2ꢀphenylquinazoline (2l). 2.5 h; eluent: EtOAc/PE
3:97; yield: 90 mg, 69%; white solid, mp 167ꢀ168 °C (lit24 160ꢀ165 °C); H NMR
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(400 MHz, CDCl3) δ 8.67 (d, J = 6.8 Hz, 2H), 8.04 (d, J = 8.8 Hz, 1H), 7.92 (s, 1H),
7.88 (d, J = 8.4 Hz, 2H), 7.71 (d, J = 8.4 Hz, 1H)，7.54ꢀ7.48 (m, 3H), 7.12 (d, J = 8.4
Hz, 2H), 3.94 (s, 3H), 2.52 (s, 3H); 13C NMR (100MHz, CDCl3) δ 167.1, 161.2, 159.5,
150.5, 138.4, 137.0, 135.7, 131.8, 130.4, 130.3, 128.8, 128.54, 128.50, 125.7, 121.6,
114.0, 55.5, 21.9; HRMS (m/z) [M + H]+ calcd for C22H19N2O, 327.1492, found
327.1499.
4ꢀ(4ꢀChlorophenyl)ꢀ6ꢀmethylꢀ2ꢀphenylquinazoline (2m). 5 h; eluent: EtOAc/PE
2:98; yield: 112mg, 85%; white solid, mp 189ꢀ191 °C (lit24 181ꢀ183 °C); H NMR
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(400 MHz, CDCl3) δ 8.64 (d, J = 6.8 Hz, 2H), 8.04 (d, J = 8.4 Hz, 1H), 7.83ꢀ7.80 (m,
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3H), 7.71 (d, J = 8.8 Hz, 1H), 7.58ꢀ7.48 (m, 5H), 2.51 (m, 3H); C NMR (100MHz,
CDCl3) δ 166.3, 159.6, 150.7, 138.2, 137.4, 136.3, 136.1, 136.0, 131.5, 130.4, 129.0,
128.9, 128.6, 128.5, 125.2, 121.5, 21.9. HRMS (m/z) [M + H]+ calcd for C21H16ClN2,
331.0997, found 331.0992.
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6ꢀMethylꢀ2ꢀphenylꢀ4ꢀ(3ꢀ(trifluoromethyl)phenyl)quinazoline (2n). 5 h; eluent:
EtOAc/PE 2:98; yield: 144mg, 99%; white solid, mp 203ꢀ204 °C; 1H NMR (400MHz,
CDCl3) δ 8.65 (d, J = 6.4 Hz, 2H), 8.15 (s, 1H), 8.05 (t, J = 8.8 Hz, 2H), 7.84 (d, J =
6.8 Hz, 1H), 7.74ꢀ7.51 (m, 6H), 2.50 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 165.9,
159.6, 150.7, 138.7, 138.0, 137.7, 136.1, 133.4, 131.2 (q, JCꢀF = 32.2 Hz), 130.5,
129.1, 129.0, 128.6, 128.5, 126.9 (q, JCꢀF = 3.6 Hz), 126.4 (q, JCꢀF = 3.6 Hz), 124.9,
124.0 (q, JCꢀF = 270.8 Hz), 121.4, 22.0; HRMS (m/z) [M + H]+ calcd for C22H16F3N2,
365.1260, found 365.1250.
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6ꢀMethylꢀ2ꢀphenylꢀ4ꢀ(pyridinꢀ4ꢀyl)quinazoline (2o). 3.5 h; eluent: EtOAc/PE 80:20;
yield: 117 mg, 99%; brown solid, mp 134ꢀ136 °C; 1H NMR (400 MHz, CDCl3) δ 8.88
(d, J = 5.6 Hz, 2H), 8.66ꢀ8.63 (m, 2H), 8.09 (d, J = 9.2 Hz, 1H), 7.78ꢀ7.57 (m, 4H),
7.55ꢀ7.50 (m, 3H), 2.54 (s, 3H); 13C NMR (100MHz, CDCl3) δ 164.9, 159.7, 150.7,
150.0, 145.5, 138.0, 137.9, 136.4, 130.6, 129.2, 128.6, 128.5, 124.6, 124.4, 121.2,
22.0; HRMS (m/z) [M + H]+ calcd for C20H16N3, 298.1339, found 298.1337.
6ꢀMethylꢀ2ꢀphenylꢀ4ꢀpropylquinazoline (2p). 1.5 h; eluent: EtOAc/PE 1:99; yield:
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62 mg, 59%; brown solid, mp 100ꢀ101 °C; H NMR (400MHz, CDCl3) δ 8.63ꢀ8.60
(m, 2H), 7.96 (d, J = 8.4 Hz, 1H), 7.85 (s, 1H), 7.67 (dd, J = 8.8, 1.6 Hz, 1H),
7.54ꢀ7.47 (m, 3H), 3.28 (t, J = 7.6 Hz, 2H), 2.57 (s, 3H), 2.05ꢀ2.00 (sext, J = 7.6 Hz,
2H), 1.12 (t, J = 7.6 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 170.5, 159.4, 149.2,
138.6, 136.8, 135.5, 130.1, 129.1, 128.5, 128.4, 123.5, 122.5, 36.5, 22.0, 21.8, 14.3;
HRMS (m/z) [M + H]+ calcd for C18H19N2, 263.1543, found 263.1549.
4ꢀIsopropylꢀ6ꢀmethylꢀ2ꢀphenylquinazoline (2q). 5.5 h; eluent: EtOAc/PE 1:99;
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yield: 39 mg, 37%; white solid, mp 102ꢀ103 °C (lit25 120 °C); H NMR (400 MHz,
CDCl3) δ 8.67ꢀ8.65 (m, 2H), 7.98 (d, J = 8.4 Hz, 1H), 7.90 (s, 1H), 7.67 (dd, J = 8.4,
1.6 Hz, 1H), 7.54ꢀ7.45 (m, 3H), 3.93 (hept, J = 6.8 Hz, 1H), 2.57 (s, 3H), 1.50 (d, J =
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6.8 Hz, 6H); 13C NMR (100 MHz, CDCl3) δ 174.7, 159.4, 149.5, 138.8, 136.6, 135.3,
130.1, 129.3, 128.5, 123.0, 121.6, 31.1, 29.7, 22.0, 21.8; HRMS (m/z) [M + H]+ calcd
for C18H19N2, 263.1543, found 263.1543.
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6ꢀMethylꢀ4ꢀphenylꢀ2ꢀ(pꢀtolyl)quinazoline (2r).26 5 h; eluent: EtOAc/PE 1:99; yield:
123 mg, 99%; white solid, mp 174ꢀ175 °C; 1H NMR (400MHz, CDCl3) δ 8.56 (d, J =
8.0 Hz, 2H), 8.01 (d, J = 8.4 Hz, 1H), 7.87ꢀ7.84 (m, 3H), 7.67 (dd, J = 8.8, 2.0 Hz,
1H), 7.60ꢀ7.56 (m, 3H), 7.31 (d, J = 8.0 Hz, 2H), 2.48 (s, 3H), 2.42 (s, 3H); 13C NMR
(100 MHz, CDCl3) δ 167.5, 159.7, 150.6, 140.5, 138.0, 136.9, 135.7, 135.6, 130.2,
129.7, 129.3, 128.8, 128.5, 125.6, 121.6, 21.9, 21.6; HRMS (m/z) [M + H]+ calcd for
C22H19N2, 311.1543, found 311.1556.
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2ꢀ(4ꢀChlorophenyl)ꢀ6ꢀmethylꢀ4ꢀphenylquinazoline (2s).[12e] 5 h; eluent: EtOAc/PE
1:99; yield: 131 mg, 99%; white solid, mp 182ꢀ183 °C; 1H NMR (400 MHz, CDCl3) δ
8.64ꢀ8.60 (m, 2H), 8.04 (d, J = 8.8 Hz, 1H), 7.87ꢀ7.85 (m, 3H), 7.73 (dd, J = 8.8, 2.0
Hz, 1H), 7.62ꢀ7.59 (m, 3H), 7.50ꢀ7.47 (m, 2H), 2.52 (s, 3H); 13C NMR (100 MHz,
CDCl3) δ 167.7, 158.6, 150.5, 137.8, 137.4, 136.9, 136.5, 135.9, 130.1, 129.9, 128.8,
128.7, 128.6, 125.7, 121.7, 21.9; HRMS (m/z) [M + H]+ calcd for C21H16ClN2,
331.0997, found 331.1008.
6ꢀMethylꢀ4ꢀphenylꢀ2ꢀ(3ꢀ(trifluoromethyl)phenyl)quinazoline (2t). 5 h; eluent:
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EtOAc/PE 1:99; yield: 134 mg, 92%; white solid, mp 175ꢀ176 °C; H NMR (400
MHz, CDCl3) δ 8.96 (s, 1H), 8.87 (d, J = 8.0 Hz, 1H), 8.06 (d, J = 8.4 Hz, 1H),
7.88ꢀ7.85 (m, 3H), 7.75ꢀ7.72 (m, 2H), 7.64ꢀ7.60 (m, 4H), 2.52 (s, 3H); 13C NMR
(100MHz, CDCl3) δ 167.8, 158.1, 150.5, 139.2, 137.8, 137.6, 136.1, 131.7, 131.1 (q,
J = 32.1 Hz), 130.1, 129.96, 128.9, 128.6, 126.7 (q, J = 3.7 Hz), 125.7, 125.4 (q, J =
3.9 Hz), 123.0 (q, J = 270.6 Hz, partially overlapped with other peaks), 121.9, 21.9;
HRMS (m/z) [M+H]+ calcd for C22H16F3N2, 365.1260, found 365.1260.
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6ꢀMethylꢀ2ꢀ(naphthalenꢀ1ꢀyl)ꢀ4ꢀphenylquinazoline (2u). 7.5 h; eluent: EtOAc/PE
3:97; yield: 121 mg, 87%; white solid, mp 164ꢀ165 °C; 1H NMR (400 MHz, CDCl3) δ
9.21 (s, 1H), 8.79 (dd, J = 8.8, 1.2 Hz, 1H), 8.10 (d, J = 8.4 Hz, 1H), 8.04ꢀ8.02 (m,
1H), 7.97 (d, J = 8.8 Hz, 1H), 7.93ꢀ7.88 (m, 4H), 7.73 (dd, J = 8.4, 1.2 Hz, 1H),
7.66ꢀ7.61 (m, 3H), 7.54ꢀ7.49 (m, 2H), 2.52 (s, 3H); 13C NMR (100 MHz, CDCl3) δ
167.7, 159.6, 150.6, 137.9, 137.2, 135.9, 135.7, 134.6, 133.5, 130.2, 129.8, 129.3,
128.9, 128.8, 128.6, 128.1, 127.7, 126.9, 126.1, 125.7, 125.6, 121.7, 21.9; HRMS
(m/z) [M + H]+ calcd for C25H19N2, 347.1543, found 347.1552.
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2ꢀ(Furanꢀ2ꢀyl)ꢀ6ꢀmethylꢀ4ꢀphenylquinazoline (2v). 5 h; eluent: EtOAc/PE 10:90;
1
yield: 94 mg, 82%; white solid, mp 191ꢀ192 °C; H NMR (400 MHz, CDCl3) δ 8.06
(d, J = 8.8 Hz, 1H), 7.83ꢀ7.79 (m, 3H), 7.71ꢀ7.68 (m, 2H), 7.60ꢀ7.57 (m, 3H),
7.47ꢀ7.45 (m, 1H), 6.58 (q, J = 1.6 Hz, 1H), 2.49 (s, 3H); 13C NMR (100 MHz, CDCl3)
δ 168.1, 153.0, 152.9, 150.1, 145.0, 137.4, 137.2, 136.1, 130.0, 129.9, 128.64, 128.56,
125.8, 121.6, 113.7, 112.1, 21.9; HRMS (m/z) [M + H]+ calcd for C19H15N2O,
287.1179, found 287.1179.
2ꢀ(tertꢀButyl)ꢀ6ꢀmethylꢀ4ꢀphenylquinazoline (2w). 5 h; eluent: EtOAc/PE 1:99;
1
yield: 94 mg, 85%; white solid, mp 60ꢀ61 °C; H NMR (400 MHz, CDCl3) δ 7.95 (d,
J = 8.4 Hz, 1H), 7.82ꢀ7.79 (m, 3H), 7.64 (dd, J = 8.4, 1.6 Hz, 1H), 7.58ꢀ7.52 (m, 3H),
2.47 (s, 3H), 1.54 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 172.1, 166.7, 150.0, 138.2,
136.4, 135.1, 130.2, 129.5, 128.7, 128.4, 125.3, 120.9, 39.6, 29.8, 21.8; HRMS (m/z)
[M+H]+ calcd for C19H21N2, 277.1699, found 277.1714.
■ASSOCIATED CONTENT
Supporting Information
Schemes for the preparation of substrates 1, and copies of 1H and 13C NMR spectra of
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compounds 1 and 2. This material is available free of charge via the Internet at
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■ AUTHOR INFORMATION
Corresponding Authors
*Eꢀmail: wenquan_yu@zzu.edu.cn
*Eꢀmail: changjunbiao@zzu.edu.cn
Notes
The authors declare no competing financial interest.
■ ACKNOWLEDGMENTS
We thank the National Natural Science Foundation of China (nos. 81302637 and
81330075) and Outstanding Young Talent Research Fund of Zhengzhou University
(no. 1521316004) for financial support.
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