Preparation of 4-arylquinazolines with: O-(N-alkyl, N-p-tosyl)aminobenzonitriles, aryllithiums, and NIS

Article abstract of DOI:10.1039/d0ob01223h

The treatment of o-(N-alkyl,N-p-tosyl)aminobenzonitriles with aryllithiums, followed by the reaction with water, NIS under irradiation with a fluorescent lamp, and then tBuOK gave 2-alkyl-4-arylquinazolines or 4-arylquinazolines in good to moderate yields. The present reaction proceeds through the formation of N-iodoimines from imines with NIS, the generation of iminyl radicals, the 1,6-H shift by iminyl radicals, the cyclization via 6-exo-tet mode, and finally the elimination of p-toluenesulfinate to generate 2-alkyl-4-arylquinazolines or 4-arylquinazolines.

Full text of DOI:10.1039/d0ob01223h

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Preparation of 4-arylquinazolines with o-(N-alkyl,
N-p-tosyl)aminobenzonitriles, aryllithiums, and
NIS†
Cite this: DOI: 10.1039/d0ob01223h
Hiroki Naruto and Hideo Togo
*
The treatment of o-(N-alkyl,N-p-tosyl)aminobenzonitriles with aryllithiums, followed by the reaction with
t
water, NIS under irradiation with a fluorescent lamp, and then BuOK gave 2-alkyl-4-arylquinazolines or
Received 15th June 2020,
Accepted 6th July 2020
4-arylquinazolines in good to moderate yields. The present reaction proceeds through the formation of
N-iodoimines from imines with NIS, the generation of iminyl radicals, the 1,6-H shift by iminyl radicals,
the cyclization via 6-exo-tet mode, and finally the elimination of p-toluenesulfinate to generate 2-alkyl-
4-arylquinazolines or 4-arylquinazolines.
DOI: 10.1039/d0ob01223h
rsc.li/obc
ones in the presence of [RhCp*Cl2]2 and Zn(NTf2)2;2f the prepa-
ration of 2,4-diarylquinazolines with o-aminobenzonitriles,
Introduction
Quinazolines are one of the most important and attractive arylboronic acids, and aromatic aldehydes in the presence of
nitrogen-containing bicyclic heteroaromatics because some Pd(acac)2 and 5,5′-dimethyl-2,2′-bipyridyl;2g and the prepa-
quinazoline derivatives show biological activities, such as anti- ration of 2-aryl-4-methylquinazolines with o-aminoacetophe-
viral and anticancer activities.1 For example, Prazosin and nones, benzylamines, and tert-butyl perbenzoate (TBPB) in the
Erlotinib are drugs for high blood pressure and pancreatic presence of Ir(ppy)3 under blue LED irradiation.2h Moreover,
cancer, respectively, and Quazodine has the neuromuscular recent synthetic studies of quinazolines under transition-
blocking activity of tubocurarine, as shown in Fig. 1.1a
metal-free conditions are as follows:3 the preparation of 4-aryl-
with o-aminophenyl aryl ketones,
Active synthetic studies of the quinazoline core have been quinazolines
carried out. Recent synthetic studies of the quinazoline core N-iodosuccinimide (NIS), TBHP, and NH3 in N,N-dimethyl-
using transition metals are as follows:2 the preparation of acetamide;3a the preparation of 2-arylquinazolines with
2-substituted and 2,4-disubstituted quinazolines with o-bro- N-arylbenzimidates and paraformaldehyde in the presence of
mobenzaldehydes or o-bromophenyl ketones and amidine BF3·Et2O;3b the preparation of 2-arylquinazolines with o-ami-
hydrochlorides in the presence of CuI, L-proline, and
Cs2CO3;2a the microwave-assisted preparation of 2,5-di-
substituted quinazolines with (o-aminoaryl)alkanone O-phenyl
oximes and aldehydes in the presence of ZnCl2;2b the prepa-
ration of 2-arylquinazolines with o-nitrobenzaldehyde
O-methyl oximes and benzylic alcohols in the presence of Pd
(OAc)2 and dppf;2c the preparation of 2-aryl- and 2-alkylquina-
zolines with (o-aminobenzyl)amines, primary alcohols, and
tert-butyl hydrogen peroxide (TBHP) in the presence of
α-MnO2-150;2d the preparation of 4-methoxy-2-arylquinazolines
with benzimidates and 1,4,2-dioxazol-5-ones in the presence of
[RhCp*Cl2]2 and AgBF4;2e the preparation of quinazoline
N-oxides with alkyl phenyl ketone oximes and 1,4,2-dioxazol-5-
Graduate School of Science, Chiba University, Yayoi-cho 1-33, Inage-ku, Chiba 263-
8522, Japan
†Electronic supplementary information (ESI) available: 1H-NMR and 13C-NMR
charts of all starting material 1, intermediate 3a-A, and all 4-arylquinazolines 4
and 5. See DOI: 10.1039/d0ob01223h
Fig. 1 Drugs containing quinazoline core.
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nobenzylamines, benzylamines, and I2;3c the preparation of
2-arylquinazolines with o-aminobenzylamines, aromatic alde-
hydes, and PhI(OAc)2;3d and the preparation of 2-(N-aryl)
amino-4-phenylquinazolines with o-aminobenzophenones, iso-
thiocyanates, and I2.3e The photochemical preparation of
2-arylquinazolines with o-aminobenzylamines and aromatic
aldehydes in the presence of MgI2 under O2 atmosphere and
visible light irradiation,4a and in the presence of Eosin Y
under O2 atmosphere and green LED irradiation4b was also
reported.
Table 1 Optimization of reaction conditions
On the other hand, the synthetic uses of imino-nitrogen-
centered radical (iminyl radicals) for the preparation of nitro-
gen-containing heterocycles, such as dihydropyrroles and phe-
nanthridines, have attracted much attention recently.5
Previously, we reported the preparation of 6-aryl- or 6-alkylphe-
nanthridines from the reactions of o-cyanobiaryls and aryl-
lithiums or alkyllithiums, followed by the reaction with water
and then with I2 at 60 °C;6a the preparation of 6-arylphenan-
thridines from the reaction of aryl o-biaryl ketones, TMS2NH,
and Sc(OTf)3, followed by the reaction with I2 at 60 °C;6b and
the preparation of 2-arylquinolines from the reactions of
β-arylpropionitriles and aryllithiums, followed by the reaction
with water and then with NIS under irradiation with a tungsten
lamp.6c All those reactions proceed through the formation of
N-iodoimines, their homolytic N–I bond cleavage to form
iminyl radicals, and the cyclization onto the aromatic rings by
the iminyl radicals.
As part of our synthetic studies of iminyl radicals formed
from N-iodoimines for the construction of nitrogen-containing
heteroaromatics, we would like to report herein the prepa-
ration of 2-alkyl-4-arylquinazolines and 4-arylquinazolines
from the reaction of o-(N-alkyl,N-p-tosyl)aminobenzonitriles
with aryllithiums, followed by the reaction with water and then
NIS under warming conditions.
(2nd step)
Entry Reagent
Conditions
Time (h) Yield (%)
1a
2b
3
NIS
NIS
NIS
NIS
NIS
300 W W-hv
300 W W-hv
300 W W-hv
40 W W-hv
40 W W-hv
3
3
3
3
6
3
3
3
3
3
3
3
3
8
8
8
8
8
8
44
56
60
68
66
62
66
57
0
55
0
60
61
72
45
0
4
5
6c
NIS, K2CO3 40 W W-hv
NIS
NIS
NIS
DIH
I2, K2CO3
NIS
NIS
NIS
7d
8e
40 W W-hv
40 W W-hv
40 W W-hv
40 W W-hv
9f
10g
11h
12
13
14
15
16
17
18i
19j
40 W W-hv
40 °C, fluorescent lighting
60 °C, fluorescent lighting
60 °C, fluorescent lighting
60 °C, dark
60 °C, fluorescent lighting
60 °C, fluorescent lighting
60 °C, fluorescent lighting
60 °C, fluorescent lighting
NIS
NBS
NCS
NIS
0
0
0
NIS
a 1st reaction step was carried out at 0 °C. b 1st reaction step was carried
out at −30 °C. c K2CO3 (1.5 equiv.) was added. d Instead of N-Ts-p group
in 1a, N-SO2C6H5 group was used. e Instead of N-Ts-p group in 1a,
N-SO2C6H4Cl-p group was used. f Instead of N-Ts-p group in 1a,
N-SO2C2H5 group was used. g Instead of NIS, DIH (1.5 equiv.) was used.
h Instead of NIS, I2 (3.0 equiv.) and K2CO3 (1.5 equiv.) were used. i In
2nd reaction step, BHT (1.5 equiv.) was added. j In 2nd reaction step,
TEMPO (1.5 equiv.) was added.
Results and discussion
First, treatment of o-(N-ethyl,N-p-tosyl)aminobenzonitrile 1a
(1.0 mmol) with PhLi (A, 2.0 equiv.) in THF (5.0 mL) at 0 °C
for 1.5 h (1st step), followed by the reaction with water gave
phenyl imine 2a-A in 90% yield. Here, 2.0 equiv. of PhLi was 300 W tungsten lamp under the same procedure and con-
required because the nucleophilic reactivity of PhLi toward ditions as those of entry 3, 1,2-dihydroquinazoline 3a-A was
aromatic nitrile 1a at 0 °C is not sufficiently high. Based on obtained in 68% and 66% yields, respectively (entries 4 and 5).
this result, further treatment of phenyl imine 2a-A with NIS When the 2nd reaction step was conducted in the presence of
(3.0 equiv.) in 1,2-dichloroethane (DCE, 5.0 mL) under K2CO3 (1.5 equiv.) under the same procedure and conditions
irradiation with a 300 W tungsten lamp in the temperature as those of entry 4, the yield of 1,2-dihydroquinazoline 3a-A
range of 35 °C–38 °C for 3 h (2nd step) gave 2-methyl-4-phenyl- was slightly decreased to 62% (entry 6). On the other hand,
1-p-tosyl-1,2-dihydroquinazoline 3a-A in 44% yield, as shown when 1a derivatives bearing other N-protecting groups, such as
in Table 1 (entry 1). Treatment of nitrile 1a with PhLi at −30 °C N-benzenesulfonyl group, N-p-chlorobenzenesulfonyl group,
and at −50 °C for 1.5 h, followed by the reaction with water and N-ethanesulfonyl group, instead of N-p-tosyl group, were
and then with NIS under the same procedure and conditions treated under the same procedure and conditions as those of
as those of entry 1 gave 1,2-dihydroquinazoline 3a-A in 56% entry 4, 1,2-dihydroquinazoline 3a-A was obtained in 66%,
and 60% yields, respectively (entries 2 and 3). When the 2nd 57%, and 0% yields, respectively (entries 7–9). Thus, the N-p-
reaction step was carried out for 3 h and 6 h at room tempera- tosyl group in compound 1a was the best among those
ture under irradiation with a 40 W tungsten lamp instead of a N-protecting groups. When 1,3-diiodo-5,5-dimethylhydantoin
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Scheme 1 (Contd).
(DIH, 1.5 equiv.) was used instead of NIS in the 2nd reaction
step, yield of 1,2-dihydroquinazoline 3a-A was decreased to
55% (entry 10). Moreover, when a mixture of I2 (3.0 equiv.) and
K2CO3 (1.5 equiv.) was used instead of NIS in the 2nd reaction
step, 1,2-dihydroquinazoline 3a-A was not obtained at all
(entry 11). Then, the 2nd reaction step with 1a and PhLi was
carried out at 40 °C and 60 °C for 3 h under irradiation with a
fluorescent lamp (32 W) without using a tungsten lamp, and
1,2-dihydroquinazoline 3a-A was obtained in 60% and 61%
yields, respectively (entries 12 and 13). Moreover, the same 2nd
reaction step with 1a was conducted at 60 °C for 8 h under
irradiation with a fluorescent lamp (32 W), and 1,2-dihydroqui-
nazoline 3a-A was obtained in 72% yield (entry 14). On the
other hand, when the same 2nd reaction step was carried out at
60 °C for 8 h under dark conditions, the yield of 1,2-dihydroqui-
nazoline 3a-A was decreased to 45% (entry 15). Thus, treatment
of o-(N-ethyl,N-p-tosyl)aminobenzonitrile 1a (1.0 mmol) with
PhLi (2.0 equiv.) in THF (5.0 mL) at −50 °C for 1.5 h (1st step),
followed by the reaction with water, and then with NIS (3.0
equiv.) in DCE (5.0 mL) at 60 °C for 8 h under irradiation with a
fluorescent lamp (2nd step) gave 2-methyl-4-phenyl-1-p-tosyl-1,2-
dihydroquinazoline 3a-A in the highest yield (entry 14).
Scheme 1 Transformation of compounds 1 into 4-arylquinazolines 4.
a Compound 1a (4.0 mmol) was used. b In 1st reaction step, ArLi (3.0
equiv.) was used. c In 2nd reaction step, the reaction mixture was irra-
diated with
methylbenzonitrile as compound 1 was used.
When N-bromosuccinimide (NBS) and N-chlorosuccinimide
(NCS) instead of NIS were used in the 2nd reaction step under
the same conditions as those of entry 14, 1,2-dihydroquinazo-
a 40 W
tungsten lamp. d 2-(N-Alkyl,N-tosyl)amino-4-
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line 3a-A was not formed at all (entries 16 and 17). Thus, with o-(N-benzyl,N-p-tosyl)aminobenzonitrile
1 with PhLi
iodine of NIS plays an important role in the formation of 1,2- under the same procedure and conditions generated phenyl
dihydroquinazoline 3a-A. In addition, when the 2nd reaction p-tolyl sulfone and o-(N-benzyl)aminobenzonitrile in high
step was carried out in the presence of 2,6-di-tert-butyl-p-cresol yields, because of steric hindrance in addition reaction to the
(BHT, 1.5 equiv.) and 2,2,6,6-tetramethylpiperidine 1-oxyl cyano group by PhLi probably.
(TEMPO, 1.5 equiv.) under the same conditions as those of
To understand the reaction pathway for the formation of
entry 14, 1,2-dihydroquinazoline 3a-A was not obtained at all 4-aryl-2-alkylquinazolines 4 from o-(N-alkyl,N-p-tosyl)amino-
(entries 18 and 19). Together, those results suggest that the benzonitriles 1, an isotope-effect experiment for the formation
2nd reaction step for the formation of 1,2-dihydroquinazoline of
3a-A is a radical-mediated reaction.
4-phenyl-1-p-tosyl-1,2-dihydroquinazoline
4-phenyl-1-p-tosyl-1,2-dihydroquinazoline-2d2 3b-A′ from
of o-(N-methyl,N-p-tosyl)aminobenzonitrile
3b-A
and
a
1b
Once
2-methyl-4-phenyl-1-p-tosyl-1,2-dihydroquinazoline mixture
t
(3a-A) was formed, treatment of 3a-A (1.0 mmol) with BuOK (0.5 mmol) and o-(N-methyl-d3,N-p-tosyl)aminobenzonitrile 1b′
(3.5 equiv.) in THF (15.0 mL) at room temperature for 12 h pro- (0.5 mmol) with PhLi (2.0 equiv.), H2O, and then NIS (3.0
vided 2-methyl-4-phenylquinazoline 4a-A in >99% yield.
equiv.) was carried out, as shown in Scheme 2 (eqn (1)), and
Based on those results, treatment of o-(N-ethyl,N-p-tosyl) estimated kH/kD based on the yields of 3b-A and 3b-A′ was 4.7.
aminobenzonitrile 1a (1.0 mmol) with various ArLi (2.0 Thus, the hydrogen-atom abstraction from the N-methyl group
equiv.), such as PhLi (A), o-MeC6H4Li (B), m-MeC6H4Li (C), of compound 1b by the formed iminyl radical through 1,6-H
p-MeC6H4Li (D), p-tBuC6H4Li (E), 3,5-Me2C6H3Li (F), shift would probably be the rate-determining step. Another
m-MeOC6H4Li (G), p-MeOC6H4Li (H), p-FC6H4Li (I), isotope-effect experiment for the formation of 4-phenylquina-
p-ClC6H4Li (J), p-BrC6H4Li (K), 2-naphthyllithium (L), zoline 4b-A and 4-phenylquinazoline-2d1 4b-A′ from a mixture
p-PhOC6H4Li (M), and benzothiophen-2-yllithium (N), in THF of 4-phenyl-1-p-tosyl-1,2-dihydroquinazoline 3b-A (0.5 mmol)
(5.0 mL) at −50 °C for 1.5 h (1st step), followed by the reaction and
with water, NIS (3.0 equiv.) in DCE (5.0 mL) at 60 °C for 8 h (0.5 mmol) with BuOK (3.5 equiv.) was carried out, and esti-
under irradiation with a fluorescent lamp (2nd step), and then mated kH/kD based on the yields of 4b-A and 4b-A′ was 3.7
tBuOK (3.5 equiv.) in THF (15.0 mL) at room temperature for (eqn (2)). Thus, proton abstraction from the N-methylene group
4-phenyl-1-p-tosyl-1,2-dihydroquinazoline-2d2
3b-A′
t
t
8 h gave 4a-A–4a-N in good to moderate yields, respectively, as of compound 3b-A by BuOK would be the rate-determining
shown in Scheme 1. As a gram-scale experiment, treatment of step, and probably, the reaction proceeds via E2 reaction.
o-(N-ethyl,N-p-tosyl)aminobenzonitrile 1a (4.0 mmol) with
Based on those results, a possible reaction pathway is
PhLi (A, 2.0 equiv.) under the same procedure and conditions shown in Scheme 3. Treatment of o-(N-alkyl,N-p-tosyl)amino-
gave 2-methyl-4-phenylquinazoline 4a-A in 75% yield. The
same treatment of o-(N-methyl,N-p-tosyl)aminobenzonitrile 1b
t
with ArLi (A, C–N), water, NIS, and then BuOK under the
same procedure and conditions gave also 4-arylquinazolines
4b-A and 4b-C–4b-N in good to moderate yields, respectively.
Similarly, treatment of o-(N-propyl,N-p-tosyl)aminobenzonitrile
1c with ArLi, such as PhLi (A), p-MeC6H4Li (D), and
t
p-ClC6H4Li (J), water, NIS, and then BuOK under the same
procedure and conditions gave also 4-aryl-2-ethylquinazolines
4c-A, 4c-D, and 4c-J in moderate yields, respectively. In
addition, treatment of 2-(N-ethyl,N-p-tosyl)amino-4-methyl-
benzonitrile
(1d),
2-(N-methyl,N-p-tosyl)amino-4-methyl-
benzonitrile (1e), and 2-(N-propyl,N-p-tosyl)amino-4-methyl-
benzonitrile (1f) bearing a methyl group on the aromatic ring
with ArLi, such as PhLi (A), p-MeC6H4Li (D) and p-ClC6H4 (J),
t
water, NIS, and then BuOK under the same procedure and
conditions gave also 4-aryl-7-methylquinazolines 5d-A, 5e-A,
5e-D, 5e-J, and 5f-A in good to moderate yields, respectively.
However, successive treatment of 4-chloro-2-(N-ethyl,N-p-tosyl)
aminobenzonitrile (1g) with PhLi (A), water, NIS, and then
tBuOK under the same procedure and conditions gave
7-chloro-2-methyl-4-phenylquinazoline in low yield (35%).
Finally, when o-(N-ethyl,N-p-tosyl)aminobenzonitrile 1a
(1.0 mmol) was treated with MeLi under the same procedure
and conditions, 2,4-dimethylquinazoline was not obtained due
to the formation of enamine from methyl imine and its iodina-
tion by NIS at 2nd reaction step. In addition, the same reaction Scheme 2 Isotope effects.
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zolines and 4-arylquinazolines, and would be a useful reaction
for the preparation of quinazoline derivatives.
Experimental section
General
1H NMR and 13C NMR spectra were obtained with
JEOL-JNM-ECX400 and JEOL-JNM-ECS400 spectrometers.
Chemical shifts were recorded as follows: chemical shift in
ppm from internal tetramethylsilane (TMS) on the δ scale,
multiplicity (s = singlet; d = doublet; t = triplet; q = quartet;
m = multiplet; b = broad), coupling constant (Hz) and inte-
gration. High-resolution mass spectra (HRMS) were recorded
by a Thermo Fisher Scientific Exactive Orbitrap mass spectro-
meter. IR spectra were measured with a JASCO FT/IR-4100
spectrometer. Melting points were determined with a Yamato
Melting Point Apparatus Model MP-21. Silica gel 60F254(Merck)
was used for TLC and Silica gel 60N (63–210 mesh, Kanto
Kagaku Co.) was used for short column chromatography.
Scheme 3 Possible reaction pathway.
Typical procedure for preparation of o-(N-alkyl,N-p-tosyl)
aminobenzonitrile 1
benzonitrile 1 with ArLi and then water generates imine 2 (1st
step). Further treatment of imine 2 with NIS at 60 °C furnishes
2-alkyl-4-aryl-1-p-tosyl-1,2-dihydroquinazoline 3 through the
formation of N-iodoimine I, the homolytic N–I bond cleavage
of N-iodoimine I to form iminyl radical II, the 1,6-hydrogen
atom transfer (1,6-H shift)7 of iminyl radical II via 7-membered
cyclic transition state to form carbon-centered radical III, the
reaction of carbon-centered radical III with iodine to form
δ-iodo imine IV, and its 6-exo-tet cyclization (2nd step). Final
treatment of formed 2-alkyl-4-aryl-1-p-tosyl-1,2-dihydroquina-
To a solution of o-aminobenzonitrile (15.0 mmol, 1772.0 mg)
in dichloromethane (7.5 mL) and pyridine (7.5 mL) was added
p-toluenesulfonyl chloride (16.5 mmol, 3145.0 mg) at 0 °C. The
obtained mixture was stirred for 12 h at room temperature
under argon atmosphere. H2O (5.0 mL) was added to the
mixture, and the product was extracted with CHCl3 (15.0 mL ×
3). The organic layer was dried over Na2SO4 and filtered. After
removal of the solvent under reduced pressure, NaH
(16.5 mmol, 55%, dispersion in Paraffin Liquid, 720.0 mg) was
added to the solution in DMF (15.0 mL) at 0 °C. After 15 min,
iodoethane (22.5 mmol, 3824.0 mg) was added to the mixture
at 0 °C. The obtained mixture was stirred for 12 h at room
temperature under argon atmosphere. Sat. NH4Cl aq. solution
(15.0 mL) was added to the reaction mixture and the product
was extracted with CHCl3 (15.0 mL × 3). The organic layer was
dried over Na2SO4 and filtered. After removal of the solvent
under reduced pressure, the residue was recrystallized (from
MeOH/n-hexane) to give o-(N-ethyl,N-p-tosyl)aminobenzonitrile
1a in 65% yield (2929.0 mg).
t
zoline 3 with BuOK generates 2-alkyl-4-arylquinazoline 4 (3rd
step). From the isotope-effect experiment (1) in Scheme 2, the
1,6-H shift of intermediate II would be the rate-determining
step for the formation of 2-alkyl-4-aryl-1-p-tosyl-1,2-dihydroqui-
nazoline 3 in the 2nd reaction step, probably due to the low
concentration of iminyl radical II. Elimination of 2-alkyl-4-aryl-
t
1-p-tosyl-1,2-dihydroquinazoline 3 with BuOK would proceed
via E2 reaction in the 3rd reaction step.
Other o-(N-alkyl,N-p-tosyl)aminobenzonitriles 1a–1f were
obtained in 60–80% yields by the same procedure.
Conclusions
2-Alkyl-4-arylquinazolines and 4-arylquinazolines could be
o-(N-Ethyl,N-p-tosyl)aminobenzonitrile (1a)
obtained by the successive treatment of o-(N-alkyl,N-p-tosyl)
aminobenzonitrile with ArLi, water, and then NIS at 60 °C White solid; mp: 123 °C; IR (neat): 2310, 1340, 1165 cm−1
;
under fluorescent lighting condition, through the formation of 1H-NMR (400 MHz, CDCl3): δ = 1.10 (t, 3H, J = 7.3 Hz), 2.44 (s,
N-iodoimines, the homolytic N–I bond cleavage of 3H), 3.67 (q, 2H, J = 7.3 Hz), 7.27 (d, 2H, J = 7.3 Hz), 7.31 (d,
N-iodoimines to form iminyl radicals, the 1,6-H shift of the 1H J = 7.9 Hz), 7.45 (td, 1H, J = 7.7, 1.1 Hz), 7.59 (td, 1H, J =
iminyl radicals, the formation of δ-iodo imine, its 6-exo-tet 7.7, 1.8 Hz), 7.57–7.70 (m, 3H); 13C-NMR (100 MHz, CDCl3): δ =
cyclization, and β-elimination of the formed 2-alkyl-4-aryl-1-p- 13.8, 21.5, 46.2, 115.6, 116.4, 1127.9, 128.7, 129.6, 130.3, 133.3,
t
tosyl-1,2-dihydroquinazolines by BuOK. The present method 133.8, 135.0, 141.3, 144.1; HRMS (ESI): calcd for C16H17O2N2S
is a novel approach for the preparation of 2-alkyl-4-arylquina- [M + H]+ = 301.1005, found = 301.1004.
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o-(N-Methyl,N-p-tosyl)aminobenzonitrile (1b)
(2.0 mmol, 1.1 M in cyclohexane and diethyl ether, 1.8 mL) at
−50 °C. The obtained mixture was stirred for 90 min at −50 °C
under argon atmosphere. H2O (5.0 mL) was added to the
mixture, and the product was extracted with CHCl3 (15.0 mL ×
3). The organic layer was dried over Na2SO4 and filtered. After
removal of the solvent under reduced pressure, NIS (3.0 mmol,
675.0 mg) was added to the solution of 1,2-dichloroethane
(5.0 mL) at room temperature and the mixture was stirred
under fluorescent lighting condition for 8 h at 60 °C. Sat.
Na2SO3 aq. solution (15.0 mL) was added to the reaction
mixture and the product was extracted with CHCl3 (15.0 mL ×
3). Then, the organic layer was dried over Na2SO4 and filtered.
After removal of the solvent under reduced pressure, the
residue was purified by silica-gel column chromatography
(eluent: n-hexane : EtOAc = 3 : 1) to give 2-methyl-4-phenyl-1-p-
tosyl-1,2-dihydroquinazoline 3a-A (272.1 mg 72%). To
2-methyl-4-phenyl-1-p-tosyl-1,2-dihydroquinazoline 3a-A in
THF (15.0 mL) was added tBuOK (3.5 mmol, 392.7 mg) at room
temperature. The mixture was stirred for 8 h at room tempera-
ture. H2O (15.0 mL) was added to the reaction mixture and the
product was extracted with CHCl3 (15.0 mL × 3). The organic
layer was dried over Na2SO4 and filtered. After removal of the
solvent under reduced pressure, the residue was purified by
silica-gel column chromatography (eluent: n-hexane : EtOAc =
2 : 1) to give 2-methyl-4-phenylquinazoline 4a-A (152.4 mg
69%).
White solid; mp: 136 °C; IR (neat): 2232, 1343, 1186 cm−1
1H-NMR (400 MHz, CDCl3): δ = 2.45 (s, 3H), 3.25 (s, 3H), 7.31 (d,
1H, J = 7.4 Hz), 7.32 (d, 2H, J = 7.7 Hz), 7.43 (td, 1H, J = 7.5, 1.1
Hz), 7.58 (td, 1H, J = 7.9, 1.6 Hz), 7.64–7.68 (m, 3H); 13C-NMR
(100 MHz, CDCl3): δ = 21.6, 38.5, 113.8, 116.3, 128.1, 128.5, 129.3,
129.7, 133.4, 133.8, 133.9, 143.8, 144.3; HRMS (ESI): calcd for
C15H15O2N2S [M + H]+ = 287.0849, found = 287.0848.
;
o-(N-Propyl,N-p-tosyl)aminobenzonitrile (1c)
White solid; mp: 88 °C; IR (neat): 2232, 1389, 1115 cm−1
;
1H-NMR (400 MHz, CDCl3): δ = 0.90 (t, 3H, J = 7.3 Hz), 1.47
(sext, 2H, J = 7.5 Hz), 2.44 (s, 3H), 3.56 (t, 2H, J = 7.3 Hz), 7.25
(d, 1H, J = 8.8 Hz), 7.30 (d, 2H, J = 7.9 Hz), 7.43 (td, 1H, J = 7.6,
1.1 Hz), 7.58 (td, 1H, J = 7.9, 1.6 Hz), 7.63 (d, 2H, J = 8.2 Hz),
7.68 (dd, 1H, J = 7.7, 1.4 Hz); 13C-NMR (100 MHz, CDCl3): δ =
11.0, 21.6, 21.8, 52.9, 115.4, 116.4, 128.0, 128.6, 130.0, 130.4,
133.3, 133.9, 134.9, 141.8, 144.1; HRMS (ESI): calcd for
C17H19O2N2S [M + H]+ = 315.1162, found = 315.1162.
2-(N-Ethyl,N-p-tosyl)-4-methylaminobenzonitrile (1d)
White solid; mp: 94–95 °C; IR (neat): 2234, 1378, 1182 cm−1
;
1H-NMR (400 MHz, CDCl3): δ = 1.09 (t, 3H, J = 7.0 Hz), 2.41 (s,
3H), 2.45 (s, 3H), 3.64 (q, 2H, J = 7.0 Hz), 7.13 (s, 1H), 7.24 (d,
1H, J = 8.6 Hz), 7.31 (d, 2H, J = 7.9 Hz), 7.55 (d, 1H, J = 7.7 Hz),
7.70 (d, 2H, J = 8.4 Hz); 13C-NMR (100 MHz, CDCl3): δ = 13.9,
21.6, 21.7, 46.1, 112.1, 116.6, 128.0, 129.5, 129.6, 131.6, 133.5,
135.2, 141.2, 144.1, 144.7; HRMS (ESI): calcd for C17H19O2N2S
[M + H]+ = 315.1162, found = 315.1162.
Typical procedure for transformation of o-(N-alkyl,N-p-tosyl)
aminobenzonitriles 1 into 2-alkyl-4-arylquinazolines (2)
nBuLi (2.0 mmol, 1.6 M in hexane, 1.3 mL) was added drop-
wise to a solution of p-bromotoluene (2.1 mmol, 342.1 mg) in
THF (2.0 mL) at −50 °C under argon atmosphere. After
30 min, a solution of o-(N-ethyl,N-p-tosyl)aminobenzonitrile 1a
(1.0 mmol, 435.62 mg) in THF (4.0 mL) was added to the
mixture at −50 °C. The obtained mixture was stirred for
90 min at −50 °C under argon atmosphere. H2O (5.0 mL) was
added to the mixture, and the product was extracted with
CHCl3 (15.0 mL × 3). The organic layer was dried over Na2SO4
and filtered. After removal of the solvent under reduced
pressure, NIS (3.0 mmol, 670.0 mg) was added to the solution
of 1,2-dichloroethane (5.0 mL) at room temperature, and the
mixture was stirred under fluorescent lighting condition for
8 h at 60 °C. Sat. Na2SO3 aq. solution (15.0 mL) was added to
the reaction mixture and the product was extracted with CHCl3
(15.0 mL × 3). The organic layer was dried over Na2SO4 and fil-
tered. After removal of the solvent under reduced pressure, the
residue was purified by silica-gel column chromatography
(eluent: n-hexane : EtOAc = 3 : 1) to give 2-methyl-4-(4′-methyl-
phenyl)-1-p-tosyl-1,2-dihydroquinazoline 3a-D (262.4 mg 67%).
tBuOK (3.5 mmol, 392.7 mg) was added to 2-methyl-4-(4′-
methylphenyl)-1-p-tosyl-1,2-dihydroquinazoline 3a-D in THF
(15.0 mL) at room temperature, and the mixture was stirred for
8 h at room temperature. H2O (15.0 mL) was added to the reac-
tion mixture and the product was extracted with CHCl3
2-(N-Methyl,N-p-tosyl)-4-methylaminobenzonitrile (1e)
White solid; mp: 114 °C; IR (neat): 2227, 1342, 1159 cm−1
;
1H-NMR (400 MHz, CDCl3): δ = 2.40 (s, 3H), 2.45 (s, 3H), 3.22
(s, 3H), 7.17 (s, 1H), 7.22 (d, 1H, J = 7.9 Hz), 7.33 (d, 2H, J = 7.9
Hz), 7.53 (d, 1H, J = 7.7 Hz), 7.68 (d, 2H, J = 6.7 Hz); 13C-NMR
(100 MHz, CDCl3): δ = 21.6, 21.7, 38.4, 110.4, 116.5, 128.1,
129.3, 129.6, 130.2, 133.6, 134.0, 143.6, 144.3, 144.8; HRMS
(ESI): calcd for C16H17O2N2S [M + H]+ = 301.1005, found =
301.1005.
4-Methyl-2-(N-propyl,N-p-tosyl)aminobenzonitrile (1f)
White solid; mp: 117 °C; IR (neat): 2232, 1389, 1115 cm−1
;
1H-NMR (400 MHz, CDCl3): δ = 0.89 (t, 3H, J = 7.5 Hz), 1.46
(sext, 2H, J = 7.3 Hz), 2.40 (s, 3H), 2.45 (s, 3H), 3.54 (t, 2H, J =
7.5 Hz), 7.10 (s, 1H), 7.23 (d, 1H, J = 7.9 Hz), 7.31 (d, 1H, J = 7.9
Hz), 7.54 (d, 1H, J = 7.9 Hz), 7.66 (d, 2H, J = 8.2 Hz); 13C-NMR
(100 MHz, CDCl3): δ = 10.9, 21.5, 21.6, 21.7, 52.8, 112.0, 116.6,
127.9, 129.4, 129.5, 131.0, 133.5, 134.9, 141.5, 144.0, 144.6;
HRMS (ESI): calcd for C18H21O2N2S [M + H]+ = 329.1318, found
= 329.1319.
Typical procedure for transformation of o-(N-Alkyl,N-p-tosyl)
aminobenzonitriles 1 into 2-alkyl-4-phenylquinazolines (1)
To a solution of o-(N-ethyl,N-p-tosyl)aminobenzonitrile 1a (15.0 mL × 3). The organic layer was dried over Na2SO4 and fil-
(1.0 mmol, 300.4 mg) in THF (5.0 mL) was added PhLi tered. After removal of the solvent under reduced pressure, the
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residue was purified by silica-gel column chromatography 2-Methyl-4-(4′-tert-butylphenyl)quinazoline (4a-E)
(eluent: n-hexane : EtOAc = 2 : 1) to give 2-methyl-4-(4′-methyl-
Yield: 146.2 mg (53%); yellow oil; IR (neat): 2961, 2906, 1652,
1636 cm−1; 1H-NMR (400 MHz, CDCl3): δ = 1.40 (s, 9H), 2.94 (s,
3H), 7.53 (td, 1H, J = 7.6 Hz), 7.59 (d, 2H, J = 8.4 Hz), 7.71 (d,
2H, J = 8.6 Hz) 7.87 (td, 1H, J = 7.7, 1.4 Hz), 8.01 (d, 1H, J = 8.2
Hz), 8.12 (dd, 1H, J = 8.4, 0.7 Hz); 13C-NMR (100 MHz, CDCl3):
δ = 26.6, 31.2, 34.8, 121.0, 125.6, 126.5, 127.2, 128.0, 129.6,
133.5, 134.4, 151.3, 153.1, 163.8, 168.6; HRMS (ESI): calcd for
C19H21N2 [M + H]+ = 277.1699, found = 277.1694.
phenyl)quinazoline 4a-D (150.1 mg 64%).
2-Methyl-4-phenyl-1-p-tosyl-1,2-dihydroquinazoline (3a-A)
Yield: 272.1 mg (72%); white solid; mp: 175–176 °C; IR (neat):
1613, 1330, 1163 cm−1; 1H-NMR (400 MHz, CDCl3): δ = 1.27 (d,
3H, J = 6.6 Hz), 2.21 (s, 3H), 6.44 (q, 1H, J = 6.6 Hz), 6.95–6.98
(m, 4H), 7.08 (dd, 1H, J = 7.7, 1.4 Hz), 7.23 (td, 1H, J = 8.3, 1.1
Hz), 7.29–7.40 (m, 5H), 7.57 (td, 1H, J = 7.9, 1.6 Hz), 7.86 (d,
1H, J = 7.6 Hz); 13CNMR (100 MHz, CDCl3): δ = 18.1, 21.2, 68.4,
124.2, 126.4, 127.5, 127.6, 127.8, 128.3, 128.4, 129.1, 129.5,
132.1, 135.0, 135.1, 136.6, 143.6, 162.7; HRMS (ESI): calcd for
C22H21O2N2S [M + H]+ = 377.1318, found = 377.1312.
4-(3′,5′-Dimethylphenyl)-2-methylquinazoline (4a-F)
Yield: 144.5 mg (58%); white solid; mp: 106–107 °C; IR (neat):
1
2987, 2901, 1602, 1551 cm−1; H-NMR (400 MHz, CDCl3): δ =
2.43 (s, 6H), 2.95 (s, 3H), 7.19 (s, 1H), 7.34 (s, 2H), 7.53 (t, 1H,
J = 7.0 Hz), 7.86 (t, 1H, J = 7.3 Hz), 8.00 (d, 1H, J = 8.4 Hz), 8.06
(d, 1H, J = 8.2 Hz); 13C-NMR (100 MHz, CDCl3): δ = 21.3, 26.6,
121.1, 126.5, 127.2, 127.5, 128.0, 131.4, 133.5, 137.1, 138.2,
151.3, 163.7, 169.0; HRMS (ESI): calcd for C17H17N2 [M + H]+ =
249.1386, found = 249.1382.
2-Methyl-4-phenylquinazoline (4a-A)
Yield: 152.4 mg (69%); white solid; mp: 54 °C; IR (neat): 3006,
1
2976, 1616, 1563 cm−1; H-NMR (400 MHz, CDCl3): δ = 2.96 (s,
3H), 7.53 (td, 1H, J = 7.6, 1.1 Hz), 7.56–7.59 (m, 3H), 7.75–7.77
(m, 2H), 7.87 (td, 1H, J = 7.7, 1.4 Hz), 8.02 (d, 1H, J = 8.4 Hz),
8.05 (d, 1H, J = 8.4 Hz); 13C-NMR (100 MHz, CDCl3): δ = 26.6,
120.9, 126.6, 126.9, 128.0, 128.5, 129.5, 129.8, 133.6, 137.2,
151.3, 163.7, 168.5; HRMS (ESI): calcd for C15H13N2 [M + H]+ =
221.1073, found = 221.1017.
2-Methyl-4-(3′-methoxyphenyl)quinazoline (4a-G)
Yield: 155.9 mg (62%); white solid; mp: 108–109 °C; IR (neat):
3060, 2995, 1599, 1551, 1040 cm−1 1H-NMR (400 MHz,
;
2-Methyl-4-(2′-methylphenyl)quinazoline (4a-B)
CDCl3): δ = 2.96 (s, 3H), 3.90 (s, 3H), 7.10 (dd, 1H, J = 8.3, 2.5
Hz), 7.28–7.32 (m, 2H), 7.48 (t, 1H, J = 7.9 Hz), 7.53 (td, 1H, J =
7.6, 1.1 Hz), 7.87 (td, 1H, J = 7.7, 1.4 Hz), 8.02 (d, 1H, J = 8.4
Hz), 8.07 (d, 1H, J = 7.7 Hz); 13C-NMR (100 MHz, CDCl3): δ =
26.6, 55.4, 114.9, 115.7, 120.9, 122.2, 126.7, 127.0, 128.0, 129.6,
133.6, 138.4, 151.3, 159.7, 163.7, 168.4; HRMS (ESI): calcd for
C16H15ON2 [M + H]+ = 251.1179, found = 251.1174.
Yield: 93.7 mg (40%); white solid; mp: 123 °C; IR (neat): 2986,
1
2906, 1596 cm−1; H-NMR (400 MHz, CDCl3): δ = 2.13 (s, 3H),
2.96 (s, 3H), 7.33–7.37 (m, 3H), 7.41–7.50 (m, 2H), 7.62 (d, 1H,
J = 7.5 Hz), 8.02 (d, 1H, J = 8.4 Hz), 8.06 (d, 1H, J = 7.7 Hz);
13C-NMR (100 MHz, CDCl3): δ = 19.8, 26.6, 121.9, 125.8, 126.8,
127.0, 128.0, 129.1, 129.2, 130.6, 133.9, 136.0, 136.6, 150.9,
163.8, 169.9; HRMS (ESI): calcd for C16H15N2 [M + H]+
235.1230, found = 235.1229.
=
2-Methyl-4-(4′-methoxyphenyl)quinazoline (4a-H)
2-Methyl-4-(3′-methylphenyl)quinazoline (4a-C)
Yield: 112.9 mg (45%); white solid; mp: 66–67 °C; IR (neat):
2996, 2901, 1608, 1577, 1033 cm−1 1H-NMR (400 MHz,
;
Yield: 180.9 mg (77%); white solid; mp: 86–87 °C; IR (neat):
1
2987, 2920, 1613, 1547 cm−1; H-NMR (400 MHz, CDCl3): δ =
CDCl3): δ = 2.94 (s, 3H), 3.91 (s, 3H), 7.09 (d, 2H, J = 8.8 Hz),
7.53 (td, 1H, J = 7.6, 1.1 Hz), 7.76 (d, 2H, J = 8.8 Hz), 7.85 (td,
1H, J = 7.7, 1.4 Hz), 8.00 (d, 1H, J = 8.4 Hz), 8.10 (d, 1H, J = 7.7
Hz); 13C-NMR (100 MHz, CDCl3): δ = 26.6, 55.4, 114.1, 120.9,
126.5, 127.0, 128.1, 129.7, 131.5, 133.4, 151.4, 161.1, 163.7,
168.6; HRMS (ESI): calcd for C16H15ON2 [M + H]+ = 251.1179,
found = 251.1175.
2.48 (s, 3H), 2.95 (s, 3H), 7.37 (d, 1H, J = 7.7 Hz), 7.45 (t, 1H, J
= 7.5 Hz), 7.51–7.54 (m, 2H), 7.57 (s, 1H), 7.87 (t, 1H, J = 7.0
Hz), 8.01 (d, 1H, J = 8.6 Hz), 8.05 (d, 1H, J = 8.4 Hz); 13C-NMR
(100 MHz, CDCl3): δ = 21.4, 26.6, 121.0, 126.6, 126.9, 127.1,
128.0, 128.3, 130.2, 130.5, 133.5, 137.1, 138.4, 151.3, 163.7,
168.7; HRMS (ESI): calcd for C16H15N2 [M + H]+ = 235.1230,
found = 235.1226.
2-Methyl-4-(4′-methylphenyl)quinazoline (4a-D)
4-(4′-Fluorophenyl)-2-methylquinazoline (4a-I)
Yield: 150.1 mg (64%); white solid; mp: 86–88 °C; IR (neat): Yield: 115.1 mg (48%); white solid; mp: 108–110 °C; IR (neat):
1
1
3029, 2928, 1613, 1561 cm−1; H-NMR (400 MHz, CDCl3): δ = 3065, 2986, 1604, 1567 cm−1; H-NMR (400 MHz, CDCl3): δ =
2.48 (s, 3H), 2.94 (s, 3H), 7.38 (d, 2H, J = 7.7 Hz), 7.52 (td, 1H, J 2.95 (s, 3H), 7.25–7.29 (m, 2H), 7.55 (td, 1H, J = 7.7, 0.9 Hz),
= 7.7, 1.2 Hz), 7.67 (d, 2H, J = 8.0 Hz) 7.86 (t, 1H, J = 7.6 Hz), 7.76–7.80 (m, 2H), 7.88 (td, 1H, J = 7.6, 1.6 Hz), 8.03 (d, 2H, J =
8.01 (d, 1H, J = 8.3 Hz), 8.08 (d, 1H, J = 8.0 Hz); 13C-NMR 9.1 Hz); 13C-NMR (100 MHz, CDCl3): δ = 26.6, 115.7 (d, JC–F
=
(100 MHz, CDCl3): δ = 21.4, 26.6, 121.0, 126.5, 127.0, 128.0, 21.6 Hz), 120.9, 126.7, 126.9, 128.2, 131.9 (d, JC–F = 8.5 Hz),
129.2, 129.8, 133.4, 134.4, 140.0, 151.3, 163.7, 168.5; HRMS 133.3 (d, JC–F = 2.6 Hz), 133.7, 151.4, 163.8, 163.8 (d, JC–F
(ESI): calcd for C16H15N2 [M + H]+ = 235.1230, found = 250.9 Hz), 167.4; HRMS (ESI): calcd for C15H12N2F [M + H]+ =
=
235.1230.
239.0979, found = 239.0975.
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4-(4′-Chlorophenyl)-2-methylquinazoline (4a-J)
2H), 7.93 (td, 1H, J = 7.6, 1.4 Hz), 8.12–8.16 (m, 2H), 9.39 (s,
1H); 13C-NMR (100 MHz, CDCl3): δ = 123.0, 127.0, 127.6, 128.5,
128.8, 129.8, 130.0, 133.6, 137.0, 151.0, 154.6, 168.3, 168.3;
HRMS (ESI): calcd for C14H11N2 [M + H]+ = 207.0917, found =
207.0915.
Yield: 148.5 mg (58%); white solid; mp: 108–110 °C; IR (neat):
1
2987, 2901, 1545 cm−1; H-NMR (400 MHz, CDCl3): δ = 2.95 (s,
3H), 7.55–7.57 (m, 3H), 7.77 (d, 2H, J = 6.6, 2.0 Hz), 7.89 (td,
1H, J = 7.9, 1.4 Hz), 8.00–8.04 (m, 2H); 13C-NMR (100 MHz,
CDCl3): δ = 26.5, 120.7, 126.5, 126.9, 128.2, 128.9, 131.2, 133.8,
135.6, 136.2, 151.4, 163.8, 167.2; HRMS (ESI): calcd for
C15H12N235Cl [M + H]+ = 255.0684, found = 255.0679.
4-(3′-Methylphenyl)quinazoline (4b-C)
Yield: 139.4 mg (63%); yellow oil; IR (neat): 2987, 2920, 1613,
1
1547 cm−1; H-NMR (400 MHz, CDCl3): δ = 2.49 (s, 3H), 7.39
4-(4′-Bromophenyl)-2-methylquinazoline (4a-K)
(d, 1H, J = 7.7 Hz), 7.47 (t, 1H, J = 7.5 Hz), 7.57 (d, 1H, J = 7.5
Hz), 7.60–7.64 (m, 2H), 7.93 (td, 1H, J = 7.7, 1.4 Hz), 8.12 (d,
1H, J = 8.6 Hz), 8.15 (dd, 1H, J = 8.4, 1.4 Hz), 9.38 (s, 1H);
13C-NMR (100 MHz, CDCl3): δ = 21.4, 123.1, 127.0, 127.1,
127.6, 128.3, 128.7, 130.3, 130.7, 133.6, 136.9, 138.5, 151.0,
Yield: 152.9 mg (51%); white solid; mp: 118–119 °C; IR (neat):
1
2987, 2965, 1592, 1522 cm−1; H-NMR (400 MHz, CDCl3): δ =
2.95 (s, 3H), 7.55 (t, 1H, J = 6.8 Hz), 7.65 (d, 2H, J = 8.6 Hz),
7.72 (d, 2H, J = 8.6 Hz), 7.89 (td, 1H, J = 7.7, 1.4 Hz), 7.99–8.07
(m, 2H); 13C-NMR (100 MHz, CDCl3): δ = 26.5, 120.7, 124.5,
126.5, 126.9, 128.2, 131.4, 131.8, 133.8, 136.0, 151.4, 163.8,
154.5, 168.5; HRMS (ESI): calcd for C15H13N2 [M + H]+
221.1073, found = 221.1069.
=
167.3; HRMS (ESI): calcd for C15H12N279Br [M + H]+
=
4-(4′-Methylphenyl)quinazoline (4b-D)
299.0178, found = 299.0174, calcd for C15H12N281Br [M + H]+ =
301.0158, found = 301.0153.
Yield: 150.1 mg (68%); white solid; mp: 47 °C; IR (neat): 2971,
1
2901, 1612, 1562 cm−1; H-NMR (400 MHz, CDCl3): δ = 2.49 (s,
2-Methyl-4-(naphthalen-2′-yl)quinazoline (4a-L)
3H), 7.39 (d, 2H, J = 7.9 Hz), 7.61 (t, 1H, J = 7.2 Hz), 7.70 (d,
2H, J = 8.2 Hz), 7.92 (td, 1H, J = 7.7, 1.4 Hz), 8.11 (d, 1H, J = 8.6
Hz), 8.17 (d, 1H, J = 8.4 Hz), 9.37 (s, 1H); 13C-NMR (100 MHz,
CDCl3): δ = 21.4, 123.1, 127.1, 127.5, 128.8, 129.3, 129.9, 130.5,
134.2, 140.2, 151.0, 154.6, 168.3; HRMS (ESI): calcd for
C15H13N2 [M + H]+ = 221.1073, found = 221.1069.
Yield: 133.3 mg (49%); white solid; mp: 117–118 °C; IR (neat):
1
2902, 2972, 1598, 1564 cm−1; H-NMR (400 MHz, CDCl3): δ =
2.99 (s, 3H), 7.53–7.62 (m, 3H), 7.86–7.91 (m, 2H), 7.95–7.99
(m, 2H), 8.04–8.06 (m, 2H), 8.13 (d, 1H, J = 7.7 Hz), 8.26 (s,
1H); 13C-NMR (100 MHz, CDCl3): δ = 26.7, 121.1, 126.6, 126.8
(2C), 127.1, 127.2, 127.8, 128.1, 128.4, 128.6, 130.0, 132.9,
133.6, 133.8, 134.6, 151.4, 163.8, 168.5; HRMS (ESI): calcd for
C19H15N2 [M + H]+ = 271.1230, found = 271.1226.
4-(4′-tert-Butylphenyl)quinazoline (4b-E)
Yield: 134.1 mg (51%); white solid; mp: 122–124 °C; IR (neat):
1
2971, 2901, 1608, 1560 cm−1; H-NMR (400 MHz, CDCl3): δ =
2-Methyl-4-(4′-phenoxyphenyl)quinazoline (4a-M)
1.41 (s, 9H), 7.59–7.64 (m, 3H), 7.75 (d, 2H, J = 8.6 Hz), 7.92
(td, 1H, J = 7.7, 1.4 Hz), 8.12 (d, 1H, J = 8.6 Hz), 8.21 (d, 1H, J =
8.6 Hz), 9.37 (s, 1H); 13C-NMR (100 MHz, CDCl3): δ = 31.2,
34.9, 123.1, 125.6, 127.2, 127.5, 128.8, 129.8, 133.6, 134.2,
151.0, 153.4, 154.7, 168.4; HRMS (ESI): calcd for C18H19N2
[M + H]+ = 263.1543, found = 263.1539.
Yield: 237.4 mg (76%); yellow oil; IR (neat): 3064, 2926, 1581,
1
1553 cm−1; H-NMR (400 MHz, CDCl3): δ = 2.95 (s, 3H), 7.12
(dd, 2H, J = 8.6, 1.1 Hz), 7.17–7.20 (m, 3H), 7.40 (t, 2H, J = 7.9
Hz), 7.55 (t, 1H, J = 7.0 Hz), 7.77 (d, 2H, J = 8.8 Hz), 7.88 (td,
1H, J = 7.7, 1.4 Hz), 8.02 (d, 1H, J = 8.4 Hz), 8.10 (d, 1H, J = 7.5
Hz); 13C-NMR (100 MHz, CDCl3): δ = 26.6, 118.4, 119.6, 120.9,
124.0, 126.7, 126.9, 128.1, 129.9, 131.6, 131.9, 133.6, 151.4,
156.3, 159.2, 163.8, 167.8; HRMS (ESI): calcd for C21H17ON2 [M
+ H]+ = 313.1335 found = 313.1330.
4-(3′,5′-Dimethylphenyl)quinazoline (4b-F)
Yield: 117.6 mg (50%); white solid; mp: 92–93 °C; IR (neat):
1
3045, 2917, 1604, 1567 cm−1; H-NMR (400 MHz, CDCl3): δ =
2.44 (s, 6H), 7.21 (s, 1H), 7.39 (s, 2H), 7.62 (t, 1H, J = 8.2 Hz),
7.92 (t, 1H, J = 7.0 Hz), 8.11 (d, 1H, J = 8.4 Hz), 8.16 (d, 1H, J =
8.4 Hz) 9.37 (s, 1H); 13C-NMR (100 MHz, CDCl3): δ = 21.3,
123.2, 127.3, 127.5, 127.6, 128.8, 131.6, 133.6, 136.9, 138.3,
151.0, 154.6, 168.8; HRMS (ESI): calcd for C16H15N2 [M + H]+ =
235.1230, found = 235.1226.
4-(Benzo[b]thiophen-2′-yl)-2-methylquinazoline (4a-N)
Yield: 138.5 mg (50%); yellow solid; mp: 106–107 °C; IR (neat):
1
3057, 2930, 1613, 1547 cm−1; H-NMR (400 MHz, CDCl3): δ =
2.95 (s, 3H), 7.44–7.48 (m, 2H), 7.65 (td, 1H, J = 7.7, 1.4 Hz),
7.89–7.96 (m, 3H), 8.03 (d, 1H, J = 8.6 Hz), 8.06 (s, 1H), 8.55 (d,
1H, J = 8.6 Hz); 13C-NMR (100 MHz, CDCl3): δ = 26.4, 120.3,
122.4, 124.7, 126.0 (2C), 127.3, 128.1, 128.5, 133.7 (2C), 139.9,
140.8, 141.2, 151.8, 160.9, 163.7; HRMS (ESI): calcd for
C17H13N2S [M + H]+ = 277.0794, found = 277.0790.
4-(3′-Methoxyphenyl)quinazoline (4b-G)
Yield: 133.3 mg (56%); yellow oil; IR (neat): 2999, 2937, 1568,
1
1547, 1041 cm−1; H-NMR (400 MHz, CDCl3): δ = 3.90 (s, 3H),
7.13 (dd, 1H, J = 8.4, 2.5 Hz), 7.32–7.35 (m, 2H), 7.49 (t, 1H, J =
7.7 Hz), 7.63 (td, 1H, J = 7.6, 1.1 Hz), 7.93 (td, 1H, J = 7.7,
4-Phenylquinazoline (4b-A)
Yield: 165.2 mg (80%); white solid; mp: 96–97 °C; IR (neat): 1.4 Hz), 8.13 (d, 1H, J = 8.4 Hz), 8.17 (d, 1H, J = 8.6 Hz), 9.39 (s,
1
2972, 2901, 1607, 1566 cm−1; H-NMR (400 MHz, CDCl3): δ = 1H); 13C-NMR (100 MHz, CDCl3): δ = 55.4, 115.0, 116.0, 122.4,
7.57–7.60 (m, 3H), 7.63 (td, 1H, J = 7.7, 1.1 Hz), 7.78–7.80 (m, 123.1, 127.1, 127.7, 128.8, 129.6, 133.7, 138.3, 151.0, 154.6,
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159.7, 168.2; HRMS (ESI): calcd for C15H13ON2 [M + H]+
237.1022, found = 237.1020.
=
4-(4′-Phenoxyphenyl)quinazoline (4b-M)
Yield: 147.1 mg (49%); white solid; mp: 84–85 °C; IR (neat):
1
3065, 2927, 1610, 1585 cm−1; H-NMR (400 MHz, CDCl3): δ =
4-(4′-Methoxyphenyl)quinazoline (4b-H)
7.12–7.14 (m, 2H), 7.17–7.22 (m, 3H), 7.41 (t, 2H, J = 8.0 Hz),
7.64 (td, 1H, J = 7.6, 1.1 Hz), 7.80 (d, 2H, J = 8.8 Hz), 7.93 (td,
1H, J = 7.7, 1.4 Hz), 8.12 (d, 1H, J = 8.4 Hz), 8.19 (d, 1H, J = 8.5
Hz), 9.37 (s, 1H); 13C-NMR (100 MHz, CDCl3): δ = 118.2, 119.6,
123.0, 124.0, 126.9, 127.6, 128.8, 129.9, 131.6, 131.7, 133.6,
151.0, 154.5, 156.1, 159.4, 167.5; HRMS (ESI): calcd for
C20H15ON2 [M + H]+ = 299.1179, found = 299.1174.
Yield: 104.9 mg (44%); white solid; mp: 61–63 °C; IR (neat):
3050, 2939, 1606, 1562, 1025 cm−1 1H-NMR (400 MHz,
;
CDCl3): δ = 3.92 (s, 3H), 7.11 (d, 2H, J = 8.4 Hz), 7.62 (t, 1H, J =
7.5 Hz), 7.79 (d, 2H, J = 8.4 Hz), 7.91 (t, 1H, J = 7.9 Hz), 8.10 (d,
1H, J = 8.4 Hz), 8.19 (d, 1H, J = 8.6 Hz) 9.35 (s, 1H); 13C-NMR
(100 MHz, CDCl3): δ = 55.4, 114.0, 123.0, 127.1, 127.5, 128.8,
129.4, 131.6, 133.4, 151.0, 154.5, 161.2, 167.7; HRMS (ESI):
calcd for C15H13ON2 [M + H]+ = 237.1022, found = 237.1020.
4-(Benzo[b]thiophen-2′-yl)quinazoline (4b-N)
Yield: 124.1 mg (47%); yellow solid; mp: 119 °C; IR (neat):
1
4-(4′-Fluorophenyl)quinazoline (4b-I)
3042, 2932, 1610, 1557 cm−1; H-NMR (400 MHz, CDCl3): δ =
7.43–7.50 (m, 2H), 7.74 (td, 1H, J = 7.7, 1.4 Hz), 7.92–7.99 (m,
3H), 8.10 (s, 1H), 8.14 (d, 1H, J = 8.4 Hz), 8.63 (d, 1H, J = 8.5
Hz), 9.36 (s, 1H); 13C-NMR (100 MHz, CDCl3): δ = 122.4, 122.5,
124.8 (2C), 126.0, 126.2, 128.4, 128.5, 129.2, 133.8, 139.9,
140.7, 141.2, 151.4, 154.4, 160.8; HRMS (ESI): calcd for
C16H11N2S [M + H]+ = 263.0637, found = 263.0633.
Yield: 139.7 mg (62%); white solid; mp: 81–82 °C; IR (neat):
1
2972, 2901, 1606, 1566 cm−1; H-NMR (400 MHz, CDCl3): δ =
7.29 (t, 2H, J = 8.6 Hz), 7.64 (td, 1H, J = 7.6, 1.1 Hz), 7.79–7.84
(m, 2H), 7.94 (td, 1H, J = 7.7, 1.4 Hz), 8.10–8.15 (m, 2H), 9.38
(s, 1H); 13C-NMR (100 MHz, CDCl3): δ = 115.8 (d, JC–F = 22.6
Hz), 123.0, 126.7, 127.8, 129.0, 131.9 (d, JC–F = 8.5 Hz), 133.1
(d, JC–F = 3.8 Hz), 133.7, 151.1, 154.5, 163.9 (d, JC–F = 250.9 Hz),
167.1; HRMS (ESI): calcd for C14H10N2F [M + H]+ = 225.0823,
found = 225.0821.
2-Ethyl-4-phenylquinazoline (4c-A)
Yield: 134.3 mg (57%); white solid; mp: 82 °C; IR (neat): 3060,
1
2969, 1614, 1548 cm−1; H-NMR (400 MHz, CDCl3): δ = 1.50 (t,
3H, J = 7.6 Hz), 3.20 (q, 2H, J = 7.6 Hz), 7.53 (td, 1H, J = 7.0, 1.4
Hz), 7.56–7.60 (m, 3H), 7.76–7.78 (m, 2H), 7.87 (td, 1H, J = 7.9,
1.4 Hz), 8.04–8.07 (m, 2H); 13C-NMR (100 MHz, CDCl3): δ =
13.1, 33.2, 121.2, 126.6, 126.9, 128.3, 128.5, 129.7, 129.8, 133.4,
137.4, 151.4, 167.9, 168.5; HRMS (ESI): calcd for C16H15N2
[M + H]+ = 235.1230, found = 235.1225.
4-(4′-Chlorophenyl)quinazoline (4b-J)
Yield: 144.9 mg (60%); white solid; mp: 119–120 °C; IR (neat):
1
2987, 2901, 1615, 1594 cm−1; H-NMR (400 MHz, CDCl3): δ =
7.57 (d, 2H, J = 8.4 Hz), 7.64 (td, 1H, J = 7.0, 1.4 Hz), 7.75 (d,
2H, J = 8.4 Hz), 7.95 (td, 1H, J = 7.7, 1.4 Hz), 8.10 (d, 1H, J = 8.6
Hz), 8.14 (d, 1H, J = 8.6 Hz), 9.38 (s, 1H); 13C-NMR (100 MHz,
CDCl3): δ = 122.9, 126.6, 127.9, 128.9, 129.0, 131.3, 133.8,
135.5, 136.4, 151.1, 154.6, 167.1; HRMS (ESI): calcd for
C14H10N235Cl [M + H]+ = 241.0527, found = 241.0525.
2-Ethyl-4-(4′-methylphenyl)quinazoline (4c-D)
Yield: 107.5 mg (43%); white solid; mp: 62–63 °C; IR (neat):
1
2967, 1611, 1561 cm−1; H-NMR (400 MHz, CDCl3): δ = 1.50 (t,
3H, J = 7.7 Hz), 2.48 (s, 3H), 3.19 (q, 2H, J = 7.5 Hz), 7.38 (d,
2H, J = 7.9 Hz) 7.52 (td, 1H, J = 7.7, 0.9 Hz), 7.68 (d, 2H, J = 7.9
Hz), 7.85 (td, 1H, J = 7.7, 1.4 Hz), 8.03 (d, 1H, J = 8.4 Hz), 8.09
(d, 1H, J = 8.0 Hz); 13C-NMR (100 MHz, CDCl3): δ = 13.1, 21.4,
33.2, 121.2, 126.5, 127.0, 128.2, 129.2, 129.9, 133.3, 134.6,
140.0, 151.4, 167.9, 168.5; HRMS (ESI): calcd for C17H17N2
[M + H]+ = 249.1386, found = 249.1383.
4-(4′-Bromophenyl)quinazoline (4b-K)
Yield: 173.3 mg (61%); white solid; mp: 150–151 °C; IR (neat):
1
2965, 2922, 1614, 1589 cm−1; H-NMR (400 MHz, CDCl3): δ =
7.64 (t, 1H, J = 7.0 Hz), 7.68–7.75 (m, 4H), 7.95 (td, 1H, J = 7.7,
1.5 Hz), 8.09 (d, 1H, J = 8.4 Hz), 8.14 (d, 1H, J = 8.4 Hz), 9.38 (s,
1H); 13C-NMR (100 MHz, CDCl3): δ = 122.9, 124.8, 126.6, 127.9,
129.0, 131.5, 131.9, 133.9, 135.9, 151.1, 154.6, 167.1; HRMS
(ESI): calcd for C14H10N279Br [M + H]+ = 285.0022, found =
4-(4′-Chlorophenyl)-2-ethylquinazoline (4c-J)
285.0017, C14H10N281Br [M
286.9997.
+ = 287.0001, found =
H]+
Yield: 140.5 mg (52%); white solid; mp: 97 °C; IR (neat): 3062,
1
2976, 1614, 1576 cm−1; H-NMR (400 MHz, CDCl3): δ = 1.50 (t,
3H, J = 7.7 Hz), 3.19 (q, 2H, J = 7.5 Hz), 7.53–7.57 (m, 3H), 7.73
(d, 2H, J = 8.6 Hz), 7.88 (td, 1H, J = 7.7, 1.4 Hz), 8.01 (d, 1H, J =
8.6 Hz), 8.05 (d, 1H, J = 8.4 Hz); 13C-NMR (100 MHz, CDCl3): δ
= 13.1, 33.2, 121.0, 126.5, 126.9, 128.5, 128.9, 131.3, 133.6,
135.8, 136.1, 151.5, 167.2, 168.0; HRMS (ESI): calcd for
C16H14N235Cl [M + H]+ = 269.0840, found = 269.0836.
4-(Naphthalen-2′-yl)quinazoline (4b-L)
Yield: 154.5 mg (60%); white solid; mp: 129–130 °C; IR (neat):
1
3032, 2930, 1610, 1561 cm−1; H-NMR (400 MHz, CDCl3): δ =
7.59–7.67 (m, 3H), 7.90–7.99 (m, 4H), 8.06 (d, 1H, J = 8.6 Hz),
8.16 (d, 1H, J = 8.4 Hz), 8.23 (d, 1H, J = 7.7 Hz), 8.29 (s, 1H),
9.44 (s, 1H); 13C-NMR (100 MHz, CDCl3): δ = 123.3, 126.7 (2C),
126.8, 127.1, 127.3, 127.8, 128.4, 128.6, 128.9, 130.2, 132.8,
2,7-Dimethyl-4-phenylquinazoline (5d-A)
133.7, 133.8, 134.4, 151.1, 154.6, 168.3; HRMS (ESI): calcd for Yield: 166.8 mg (71%); white solid; mp: 73 °C; IR (neat): 3052,
1
C18H13N2 [M + H]+ = 257.1073, found = 257.1069.
2920, 1625, 1550 cm−1; H-NMR (400 MHz, CDCl3): δ = 2.58 (s,
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3H), 2.93 (s, 3H), 7.35 (d, 1H, J = 8.6 Hz), 7.55–7.59 (m, 3H), 4-Phenylquinazoline-2-d (4b′-A)
7.73–7.75 (m, 2H), 7.79 (s, 1H), 7.93 (d, 1H, J = 8.6 Hz);
Yield: 163.8 mg (79%); white solid; mp: 73–74 °C; IR (neat):
13C-NMR (100 MHz, CDCl3): δ = 22.1, 26.6, 119.1, 126.6, 127.0,
128.5, 128.9, 129.7 (2C), 137.3, 144.6, 151.6, 163.8, 167.9;
HRMS (ESI): calcd for C16H15N2 [M + H]+ = 235.1230, found =
235.1227.
1
3062, 2923, 1613, 1566 cm−1; H-NMR (400 MHz, CDCl3): δ =
7.57–7.65 (m, 4H), 7.78–7.82 (m, 2H), 7.93 (td, 1H, J = 7.6, 1.6
Hz), 8.14 (t, 2H, J = 8.2 Hz); 13C-NMR (100 MHz, CDCl3): δ =
123.0, 127.0, 127.6, 128.5, 128.8, 129.8, 130.0, 133.6, 137.0,
151.0, 154.2, 168.3; HRMS (ESI): calcd for C14H10DN2 [M + H]+
= 208.0980, found = 208.0978.
7-Methyl-4-phenylquinazoline (5e-A)
Yield: 181.1 mg (82%); white solid; mp: 93 °C; IR (neat): 3052,
1
2920, 1625, 1550 cm−1; H-NMR (400 MHz, CDCl3): δ = 2.62 (s,
3H), 7.44 (dd, 1H, J = 8.6, 1.8 Hz), 7.57–7.59 (m, 3H), 7.77–7.79
(m, 2H), 7.89 (s, 1H), 8.02 (d, 1H, J = 8.6 Hz), 9.33 (s, 1H);
13C-NMR (100 MHz, CDCl3): δ = 22.1, 121.3, 126.8, 127.7,
128.6, 129.9, 130.0 (2C), 137.2, 144.8, 151.3, 154.7, 167.8;
HRMS (ESI): calcd for C15H13N2 [M + H]+ = 221.1073, found =
221.1070.
Conflicts of interest
There are no conflicts of interest to declare.
Acknowledgements
7-Methyl-4-(4′-methylphenyl)quinazoline (5e-D)
Financial support in the form of a Grant-in-Aid for Scientific
Research (No. 18K05118) from the Ministry of Education,
Culture, Sports, Science, and Technology in Japan is gratefully
acknowledged.
Yield: 169.2 mg (72%); white solid; mp: 108–109 °C; IR (neat):
1
3034, 2916, 1621, 1542 cm−1; H-NMR (400 MHz, CDCl3): δ =
2.48 (s, 3H), 2.61 (s, 3H), 7.38 (d, 2H, J = 8.2 Hz), 7.43 (d, 1H, J
= 7.3 Hz), 7.69 (d, 2H, J = 8.6 Hz), 7.87 (s, 1H), 8.04 (d, 1H, J =
8.6 Hz), 9.31 (s, 1H); 13C-NMR (100 MHz, CDCl3): δ = 21.4,
22.1, 121.3, 126.8, 127.7, 129.3, 129.8, 129.9, 134.4, 140.2,
144.6, 151.3, 154.8, 167.8; HRMS (ESI): calcd for C16H15N2 [M
+ H]+ = 235.1230, found = 235.1226.
Notes and references
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4-(4′-Chlorophenyl)-7-methylquinazoline (5e-J)
Yield: 152.8 mg (60%); white solid; mp: 146 °C; IR (neat): 3051,
1
2917, 1624, 1593 cm−1; H-NMR (400 MHz, CDCl3): δ = 2.62 (s,
3H), 7.46 (dd, 1H, J = 8.6, 1.6 Hz), 7.56 (d, 2H, J = 8.6 Hz), 7.74
(d, 2H, J = 9.9 Hz), 7.90 (s, 1H), 7.97 (d, 1H, J = 8.6 Hz), 9.32 (s,
1H); 13C-NMR (100 MHz, CDCl3): δ = 22.1, 121.1, 126.3, 127.9,
128.9, 130.2, 131.2, 135.6, 136.3, 145.0, 151.4, 154.7, 166.6;
HRMS (ESI): calcd for C15H12N235Cl [M + H]+ = 255.0684, 2 With transition metals: (a) C. Huang, Y. Fu, H. Fu, Y. Jiang
found = 255.0682.
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2-Ethyl-7-methyl-4-phenylquinazoline (5f-A)
Yield: 122.4 mg (49%); white solid; mp: 83 °C; IR (neat): 3059,
2966, 1623, 1586 cm−1; H-NMR (400 MHz, CDCl3): δ = 1.49 (t,
1
3H, J = 7.7 Hz), 2.58 (s, 3H), 3.18 (q, 2H, J = 7.5 Hz) 7.35 (dd,
1H, J = 8.6, 1.6 Hz), 7.54–7.59 (m, 3H), 7.74–7.77 (m, 2H), 7.82
(s, 1H), 7.94 (d, 1H, J = 8.6 Hz); 13C-NMR (100 MHz, CDCl3): δ
= 13.1, 22.0, 33.2, 119.3, 126.6, 127.2, 128.5, 128.8, 129.6,
129.8, 137.5, 144.4, 151.7, 167.9, 168.0; HRMS (ESI): calcd for
C17H17N2 [M + H]+ = 249.1386, found = 249.1381.
2-(N-Methyl-d3,N-p-tosyl)aminobenzonitrile (1b′)
White solid; mp: 130 °C; IR (neat): 2232, 1396, 1186 cm−1
;
1H-NMR (400 MHz, CDCl3): δ = 2.45 (s, 3H), 7.31 (d, 1H, J = 7.4
Hz), 7.32 (d, 2H J = 7.7 Hz), 7.43 (td, 1H, J = 7.5, 1.1 Hz), 7.58
(td, 1H, J = 7.9, 1.6 Hz), 7.64–7.68 (m, 3H); 13C-NMR (100 MHz,
CDCl3): δ = 21.5, 37.7 (sep, J = 21.6 Hz), 113.8, 116.3, 128.0,
128.4, 128.9, 129.7, 133.3, 133.6, 133.8, 143.7, 144.3; HRMS
(ESI): calcd for C15H12D3O2N2S [M + H]+ = 290.1037, found =
290.1037.
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