Palladium-Catalyzed Synthesis of 4-Aminoquinazolines from Amide Oxime Ethers and 2-Iodobenzonitrile

Article abstract of DOI:10.1134/S1070363219040054

4-Substituted O-benzyl benzamide oximes reacted with 2-iodobenzonitrile in the presence of 0.1 mol % of [Pd₂(dba)₃], 0.2 mol % of XantPhos, and 1.5 equiv of Cs₂CO₃ in dioxane under argon to give 2-arylquinazolin

Full text of DOI:10.1134/S1070363219040054

ISSN 1070-3632, Russian Journal of General Chemistry, 2019, Vol. 89, No. 4, pp. 668–672. © Pleiades Publishing, Ltd., 2019.
Russian Text © The Authors(s), 2019, published in Zhurnal Obshchei Khimii, 2019, Vol. 89, No. 4, pp. 528–533.
Palladium-Catalyzed Synthesis of 4-Aminoquinazolines
from Amide Oxime Ethers and 2-Iodobenzonitrile
M. Ya. Demakovaa*, R. M. Islamovaa, and V. V. Suslonovb
a St. Petersburg State University, Universitetskaya nab. 7–9, St. Petersburg, 199034 Russia
*e-mail: st008217@spbu.ru
b Center for X-Ray Diffraction Studies, St. Petersburg State University, St. Petersburg, Russia
Received January 19, 2019; revised January 19, 2019; accepted January 24, 2019
Abstract—4-Substituted O-benzyl benzamide oximes reacted with 2-iodobenzonitrile in the presence of
0.1 mol % of [Pd2(dba)3], 0.2 mol % of XantPhos, and 1.5 equiv of Cs2CO3 in dioxane under argon to give
2-arylquinazolin-4-amines. The described reaction is a new type of cascade processes, which affords 4-amino-
quinazoline derivatives without using highly reactive chlorinating agents.
Keywords: oximes, palladium, 4-aminoquinazolines, cross-coupling reactions, metal complex catalysis
DOI: 10.1134/S1070363219040054
4-Aminoquinazolines constitute a pharmacologically
important class of heterocyclic amines; efficient
anticancer agents have been developed on the basis of
4-aminoquinazolines, many of which have already
been introduced into clinical practice [1] or are now
under preclinical trials [2-–5]. In particular, such drugs
as Gefitinib, Erlotinib, Lapatinib, and Vandetanib that
are efficient against a broad spectrum of cancer types
are used in current medical practice [1].
chlorinating agents, e.g., POCl3 or SOCl2 (Scheme 1,
a), followed by nucleophilic aromatic substitution of
chlorine by amino group (b). The use of toxic chlorinat-
ing agents can be avoided when 4-aminoquinazolines
are obtained via reaction of 2-iodobenzonitriles with
primary amidines [6–8] (Scheme 2). However, such
amidines are most often prepared by the Pinner
reaction which is inconvenient due to difficulties
related to the use of anhydrous solvents and dry
gaseous hydrogen chloride and hydrolytic instability of
the products. Furthermore, dry gaseous hydrogen
chloride is no less hazardous and environmentally
undesirable than POCl3 and SOCl2.
Methods of synthesis of 4-aminoquinazolines have
been reviewed in [1]. The main methods are based on
cyclocondensations of 2-aminobenzoic derivatives and
oxidation of quinazoline [1], and most of these
reactions involve intermediate synthesis of quinazolin-
4(3H)-ones which are then treated with highly reactive
In view of the above stated, other synthetic ap-
proaches to 4-aminoquinazolines are being developed
Scheme 1.
O
N
Cl
NR2
NH
a
N
N
b
N
N
Scheme 2.
NR2
N
CuI
NH
N
+
H2N
R
I
N
R
668

PALLADIUM-CATALYZED SYNTHESIS OF 4-AMINOQUINAZOLINES
669
Scheme 3.
NH2
a
0.1 mol % [Pd2(dba)3],
0.2 mol % XantPhos,
1.5 eq. Cs2CO3,
OBn
NH2
N
N
N
dioxane, 100°C, 18 h
N
+
R
I
R
1−5
6
7−11
Reduction
PdII
−BnO−
Pd0
−"HI"
e
b
Η+
OBn
PdII
PdII
BnO
N
OBn
N
N
N
c
d
N
N
N
H
H
H
Pd0
R
R
R
N
N
with the use of more stable and easy-to-handle
substrates than primary amidines, whose preparation
procedures do not require toxic reagents. For example,
it was proposed to obtain 4-aminoquinazolines from
aldehydes using sodium azide and copper(I) salts
[9, 10]. These reactions were characterized by
moderate yields but involved formation of explosive
heavy metal azides. Therefore, development of
preparatively convenient and safe procedures for the
synthesis of 4-aminoquinazolines still remains an
important problem.
required the use of reactive chlorinating agents, which
does not conform to the goal of the present work and
modern trends in the development of organic chemistry.
Unlike amidines, amide oximes can be stored for an
unlimited time under normal conditions without
appreciable decomposition [13]; they can be reduced
in situ to amidines in the presence of low-oxidation-
state metals [14–17]. Furthermore, the synthesis of
amidoximes requires neither anhydrous solvents nor
volatile toxic reagents, and it can be carried out in
ethanol or water [13]. Thus, in this study we set
ourselves at developing a method for the preparation of
4-aminoquinazolines from amide oximes as convenient
synthetic equivalents of amidines.
The goal of the present work was to develop a
procedure for the synthesis of 4-aminoquinazoline
derivatives without using volatile toxic substrates and
unstable under normal conditions (atmospheric air,
room temperature) organic reagents.
It is known that O-substituted amide oximes
undergo arylation with aryl iodides at the amide
nitrogen atom in the presence of [Pd2(dba)3]–XantPhos–
Cs2CO3 catalytic system [18, 19]. This procedure was
adapted to the synthesis of 4-aminoquinazolines from
amide oximes with the use of 2-iodobenzonitrile as
aryl iodide. 4-Substituted O-benzyl benzamide oximes
1–5 reacted with 2-iodobenzonitrile 6 in dioxane in the
presence of 0.1 mol % of [Pd2(dba)3], 0.2 mol % of
XantPhos, and 1.5 equiv of Cs2CO3 under argon at
100°C (18 h) to produce 2-arylquinazolin-4-amines
7–11 (Scheme 3, a).
It was shown in [11] that oximes are convenient
substrates for the synthesis of a broad spectrum of
nitrogen heterocycles. Most of such reactions are metal-
promoted, and they often involve cleavage of the
oxime N–O bond. Thus, in a number of cases oximes
act as synthetic equivalents of imines, and amide
oximes, as synthetic equivalents of amidines. It should
be noted that, prior to our studies, Patil et al. [12]
described the synthesis of 4-aminoquinazolines from
2-aminobenzonitrile derivatives and chloro oximes in
the presence of tin(II). The products were obtained
with high yields, but the synthesis of chloro oximes
The most probable mechanism of this reaction
includes initial Buchwald–Hartwig amination of 1–5
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670
DEMAKOVA et al.
from similarity in their chromatographic mobility and
Yields of 4-aminoquinazolines 7–11
the mobility of unidentified by-products. The reaction
conditions were optimized by varying the temperature
(50–115°C), amount of the catalytic system {up to 5
mol % of [Pd2(dba)3] and 10 mol % of XantPhos),
solvent (chloroform, acetonitrile, dioxane, toluene),
base (Et3N, K2CO3, Cs2CO3, NaH), and reaction time
(1 to 24 h). The best yields were obtained under the
conditions indicated above. Attempted isolation of
compounds 7–11 from the reaction mixtures by
crystallization via slow evaporation of the solvent or
cooling to 10°C (dioxane crystallized below that
temperature) was not successful since the products
were strongly contaminated by unidentified impurities.
Yield, %
1H NMR
Comp. no.
R
isolated
17
7
8
MeO
Me
H
32
47
44
38
25
24
9
21
10
11
F
28
NO2
13
(Scheme 3, b) [18, 19], oxidative insertion of
palladium(0) into the N–O bond (c) [11], ring closure
via nucleophilic addition to the C≡N carbon atom (d),
and subsequent protonation and tautomerization to
give 4-aminoquinazoline and palladium(II) (e); the
latter is likely to be reduced under the reaction
conditions to catalytically active palladium(0). We also
made an attempt to obtain 4-aminoquinazolines 7–11
from O-benzyl amide oximes 1–5 and (2-cyanophenyl)
boronic acid via Cu(OAc)2-catalyzed Chan–Lam
coupling in dioxane on exposure to air. Heterocycles 7
–11 were detected in the reaction mixtures by mass
spectrometry, but we failed to isolate them. Thus, the
Buchwald–Hartwig reaction proved to be more
efficient for N-arylation of amide oxime ethers than
the Chan–Lam coupling.
All compounds 7–11 were reported previously, and
1
their melting points and H and 13C–{1H} NMR and
mass spectra were consistent with the data given in
[20]. The molecular and crystal structures of 2-(4-
fluorophenyl)quinazolin-4-amine (10) were deter-
mined by X-ray analysis (see the figure). A unit cell of
10 contains two crystallographically independent
molecules. The C–C bond lengths in the benzene ring
range from 1.364(3) to 1.420(2) Å, indicating complete
electron density delocalization over the π-system [21].
The N2–C1 and N3–C8 bonds in the pyrimidine ring are
closer to double bonds [1.314(2)–1.340(2) Å], whereas
the N2–C8 and N3–C7 bonds [1.364(2)–1.380(2) Å], as
well as C1–C2 [1.437 and 1.441 Å], are closer to single
bonds [21]. The N1–C1 bond length [1.346(2) and
1.348(2) Å] is intermediate between single and double
bonds [21]. The torsion angle N2C8C9C14 is 4.17 and
9.64° for the two independent molecules.
1
According to the H NMR data, the yields of 7–11
in the palladium-catalyzed reaction were 25–47%,
whereas the isolated yields were as low as 13–28%
(see the table). No obvious relation between the nature
of the R substituent in 1–5 and yield of 7–11 (1H
NMR) was observed. Significant losses of 7–11 ensued
In summary, we have developed a convenient
procedure for the synthesis 4-aminoquinazolines from
stable initial compounds without using highly reactive
chlorinating agents. Furthermore, the reaction is
catalyzed by only 0.1 % of palladium–phosphine
catalyst, which also makes the procedure less toxic. A
drawback of the proposed method is difficult isolation
of the final products; however, it could be promising in
cases where 4-aminoquinazolines are not target
products but are planned to be subjected to further
modification without intermediate isolation.
EXPERIMENTAL
The H and 13C–{1H} NMR spectra were recorded
on a Bruker Avance spectrometer (400 MHz for H)
using CDCl3 as solvent. The mass spectra were
obtained on a Bruker microTOF instrument (samples
1
Structure of the molecule of 2-(4-fluorophenyl)quinazolin-
4-amine (10) according to the X-ray diffraction data. Non-
hydrogen atoms are shown as thermal vibration ellipsoids
with a probability of 50%.
1
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PALLADIUM-CATALYZED SYNTHESIS OF 4-AMINOQUINAZOLINES
671
were introduces as solutions in methanol). The melting
points were measured on a Stuart SMP30 melting
point apparatus.
2.41 s (3H, CH3), 5.99 br.s (2H, NH2), 7.32 d (2H, CH,
J = 8.2 Hz), 7.45–7.50 m (1H, CH), 7.75–7.85 m (4H,
CH), 8.30 d (1H, CH, J = 8.2 Hz). 13C–{1H} NMR
spectrum, δC, ppm: 20.40, 113.37, 123.14, 124.85,
128.08, 128.47, 129.03, 133.13, 135.99, 138.94,
151.02, 160.41, 162.88. Mass spectrum (ESI+): m/z
236.1176 [M + H]+. Calculated: M + H 236.1182.
X-Ray analysis of compound 10. Single crystals
of 10 suitable for X-ray analysis were obtained by
slow evaporation of its solution in ethyl acetate at
room temperature on exposure to air. The X-ray diffrac-
tion data were acquired with a Rigaku Supernova
diffractometer equipped with a micro focus X-ray tube
2-Phenylquinazolin-4-amine (9). Yield 21% (23.2 mg),
1
mp 135°C. H NMR spectrum, δ, ppm: 5.77 br.s (2H,
and
a
HyPix-3000 X-ray detector (100 K,
NH2), 7.40–7.55 m (4H, CH), 7.70–7.80 m (2H, CH),
7.95 d (1H, CH, J = 8.2 Hz), 8.48 s (1H, CH).
13C–{1H} NMR spectrum, δC, ppm: 113.14, 121.85,
125.79, 128.54, 128.60, 128.78, 130.32, 133.45,
138.61, 150.93, 160.88, 161.67. Mass spectrum (ESI+):
m/z 236.1176 [M + H]+. Calculated: M + H 236.1182.
monochromatized CuKα radiation). The structure was
solved by the intrinsic phasing method and was refined
using SHELXL [22] implemented in OLEX2 [23]. A
correction for absorption was applied using
CrysAlisPro [24]. The positions of hydrogen atoms
were calculated according to the algorithms included
in OLEX2; Uiso(H) = 1.2Ueq(C), C–H 0.95 Å for CH
groups; Uiso(H) = 1.2Ueq(N), N–H 0.88 Å for NH2
group; Uiso(H) = 1.5Ueq(O), O–H 0.85 Å for water
molecule. The complete set of X-ray diffraction data
for compound 10 was deposited to the Cambridge
Crystallographic Data Centre (CCDC entry no.
1891327).
2-(4-Fluorophenyl)quinazolin-4-amine (10). Yield
28% (33.5 mg), mp 143°C. 1H NMR spectrum, δ, ppm:
5.72 br.s (2H, NH2), 7.18 t (2H, CH, J = 8.7 Hz), 7.48 t
(1H, CH, J = 7.6 Hz), 7.76 d (1H, CH, J = 8.3 Hz),
7.81 d (1H, CH, J = 8.3 Hz), 7.96 d (1H, CH, J =
8.3 Hz), 8.52 d (1H, CH, J = 5.7 Hz), 8.54 d (1H, CH,
J = 5.7 Hz). 13C–{1H} NMR spectrum, δC, ppm:
112.92, 115.22 d (J = 21.5 Hz), 121.57, 125.76,
128.81, 130.41 d (J = 8.5 Hz), 133.32, 134.65, 151.00,
159.89, 161.38, 164.43 d (J = 249.5 Hz). Mass
spectrum (ESI+): m/z 240.0929 [M + H]+. Calculated:
M + H 240.0932.
General procedure for the synthesis of compound
7–11. A mixture of amide oxime ether 1–5 (0.5 mmol),
2-iodobenzonitrile (6, 0.5 mmol), and Cs2CO3
(0.75 mmol) in 2 mL of anhydrous dioxane was purged
with argon, and a mixture of [Pd2(dba)3] (0.5 μmol)
and XantPhos (1 μmol) in 2 mL of dioxane (pre-
liminarily purged with argon) was added. The mixture
was heated for 18 h at 100°C and cooled to room
temperature, the solvent was distilled off, and the
residue was dissolved in ethyl acetate (2 mL). The
solution was filtered through zeolite and washed with
water (2×1 mL) and with a solution of NaCl (2×1 mL).
The product was isolated by column chromatography
on silica gel (70–230 mesh, Merck) using hexane–
ethyl acetate (15:1 by volume) as eluent.
2-(4-Nitrophenyl)quinazolin-4-amine (11). Yield
13% (17.3 mg), mp 208°C. 1H NMR spectrum, δ, ppm:
6.01 br.s (2H, NH2), 7.64 m (1H, CH), 7.90–7.85 m
(2H, CH), 8.39 d (1H, CH, J = 8.3 Hz), 8.46 d (2H,
CH, J = 8.2 Hz), 8.80 d (2H, CH, J = 8.2 Hz). 13C–
{1H} NMR spectrum was not recorded because of the
poor solubility of 11 in CDCl3. Mass spectrum (ESI+):
m/z 267.0880 [M + H]+. Calculated: M + H 267.0877.
FUNDING
2-(4-Methoxyphenyl)quinazolin-4-amine (7). Yield
17% (21.4 mg), mp 169°C. 1H NMR spectrum, δ, ppm:
3.89 s (3H, CH3), 5.64 br.s (2H, NH2), 7.12 d (2H, CH,
J = 8.8 Hz), 7.35–7.40 m (1H, CH), 7.65–7.85 m (4H,
CH), 8.28 d (1H, CH, J = 8.8 Hz). 13C–{1H} NMR
spectrum, δC, ppm: 57.18, 113.42, 113.71, 123.66,
125.11, 127.48, 129.56, 131.04, 133.59, 149.87,
159.69, 161.01, 161.95. Mass spectrum (ESI+): m/z
252.1138 [M + H]+. Calculated: M + H 252.1132.
This study was performed under financial support
by the Russian Science Foundation (project no. 18-73-
00036, synthesis and study of compounds) and by the
Russian Foundation for Basic Research (project no. 18-
33-20062, X-ray analysis)
This study was performed using the equipment of
the Magnetic Resonance Research Center, Chemical
Analysis and Materials Research Center, and Center
for X-Ray Diffraction Studies at the St. Petersburg
State University.
2-(4-Methylphenyl)quinazolin-4-amine (8). Yield
24% (28.2 mg), mp 131°C. 1H NMR spectrum, δ, ppm:
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DEMAKOVA et al.
11. Bolotin, D.S., Bokach, N.A., Demakova, M.Ya., and
CONFLICT OF INTEREST
Kukushkin, V.Yu., Chem. Rev., 2017, vol. 117, no. 21,
p. 13039. doi 10.1021/acs.chemrev.7b00264
No conflict of interest was declared by the authors.
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