Copper(I)/Bpy-Catalyzed C-2-H Benzylation of Quinazolin-4(3H)-ones with N-Tosylhydrazones

Article abstract of DOI:10.1002/ejoc.202000244

A general and efficient copper-catalyzed C–H benzylation reaction of quinazolin-4(3H)-ones with N-tosylhydrazones is reported. The formation of new C(sp³)–C(sp²) bonds through cross-coupling occurs at the electron-poor C-2 position of quinazolin-4(3H)-one and represents an exceedingly practical method to afford 2-benzylated quinazolin-4(3H)-ones in moderate to good yields under mild reaction conditions. A possible reaction mechanism for this transformation was proposed. This catalytic transformation has the potential to be an important synthetic application for the late-stage functionalization of advanced synthetic intermediates.

Full text of DOI:10.1002/ejoc.202000244

European Journal of Organic Chemistry
Accepted Article
Accepted Article
Title: Copper(I)/Bpy-catalyzed C-2-H benzylation of quinazolin-4(3H)-
ones with N-tosylhydrazones
Authors: Fei Li, Xiao-Juan Gu, Chang-E Zeng, Xia Li, Bo Liu, and Guoli
Huang
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.202000244
Link to VoR: https://doi.org/10.1002/ejoc.202000244
01/2020

10.1002/ejoc.202000244
European Journal of Organic Chemistry
FULL PAPER
Copper(I)/Bpy-catalyzed C-2-H benzylation of quinazolin-4(3H)-
ones with N-tosylhydrazones
Fei Li,[a] Xiao-Juan Gu,[a] Chang-E Zeng,[a] Xia Li,[b] Bo Liu,[a] and Guo-Li Huang*[a]
[a]
Dr. G.-L. Huang
School of Chemistry and Chemical Engineering
Yunnan Normal University
Kunming 650500, China
E-mail: hgli2005@126.com
X. Li
[b]
Department of Library
Yunnan Normal University
Kunming 650500, China
Supporting information for this article is given via a link at the end of the document.
of quinazolin-4-one with nonactivated alkanes to carry out 2-
alkylation of quinazolinones.[19] Unfortunately, some of these
methods suffer from expensive metal catalyst, stoichiometric
amount of oxidant or photocatalyst, highly toxic carbon
monoxide, excess of the radical precursor or high temperature.
Abstract:
A
general and efficient copper-catalyzed C-H
benzylation
reaction of quinazolin-4(3H)-ones with N-
tosylhydrazones is reported. The formation of new C(sp3)-C(sp2)
bonds through cross-coupling occurres at the electron-poor C-2
position of quinazolin-4(3H)-one, and represents an exceedingly
practical method to afford 2-benzylated quinazolin-4(3H)-ones in
moderate to good yields under mild reaction conditions. A possible
reaction mechanism for this transformation was proposed. This
catalytic transformation has the potential to be an important synthetic
applications for the late-stage functionalization of advanced synthetic
intermediates.
Thus,
development
of
efficient
and
economical
functionalization methodologies of 2-alkylquinazolinones is
required and C-2 alkylation remains a challenging goal for
organic
chemists.
Directive
late-stage
modificated
functionalization of quinazolinones is of great value and
significance for rapid synthesis of selective 2-alkylquinazolin-4-
ones under mild reaction conditions.[20] Following our effort in
developing efficient Cu-catalyzated C-H bond functionalization
strategies,[21] herein we decided to investigate the direct
benzylation of quinazolin-4-ones with N-tosylhydrazones.
Introduction
N-tosylhydrazones, which can be easily prepared from
carbonyl compounds, have been widely used as the synthetic
intermediates of diazo compounds or carbenes through the
transition metal-catalyzed or metal-free reactions.[1] N-
tosylhydrazone chemistry has widespread application in the
construction of different types of C-X (X = C,[2] N,[3] O,[4] S,[5] P,[6]
Sn,[7] and B[8]) bonds in organic synthesis and various useful
transformations. Recently, direct methods of Csp3-Csp2 bonds
formation by copper-catalyzed benzylation of arenes and
heteroarenes with N-tosylhydrazones have been developed as a
Results and Discussion
To optimize the reaction conditions, we evaluated various
reaction conditions for the direct benzylation of 3-
phenylquinazolin-4(3H)-one (1a) with acetophenone-derived N-
tosylhydrazone (2a). To our delight, the reaction of 1a with 2a in
the presence of catalytic amount of CuI (10 mol%) with t-BuOLi
(2.5 equiv.) as the base in toluene for 6 hours under nitrogen
atmosphere afforded the C-2 benzylated product 3a selectively
in 26% yield (Table 1, entry 1). To our surprise, the moderate
yield (42% of 3a) was achieved with 0.1 equiv. 1,10-
phenanthroline (Phen) as the ligand (Table 1, entry 2). However,
the various forms of Cu-containing catalysts, such as CuCl,
CuBr, CuCN, Cu(acac)2, CuCl2, and Cu(OAc)2 exhibited a very
low catalytic activity, and validated the crucial role of CuI in the
reaction (Table 1, entries 3-8). Next, we examined the various
ligands, such as Bpy, PPh3, DMEDA, TED, TMEDA, L-proline,
benzil, and Dbm (Table 1, entries 9-13). Pleasingly, the use of
Bpy as a ligand significantly improved the catalytic efficiency and
gave a good yield (72%). The influence of different base and
solvent were also conducted. Various base substituents failed
the reaction, using t-BuONa, t-BuOK, and Cs2CO3 as the base
gave very poor yield, (Table 1, entries 14-16), K3PO4 and K2CO3
provided moderate yield (entries 17, 18), while KOH gave a
slightly lower yield (entry 19), necessitating the usage of t-BuOLi.
In addition, switching the solvent to xylene gave comparative
yield (Table 1, entry 20), other solvent such as dioxane, THF,
DMF, and DCE were found to show less activity. Gratifyingly,
when 0.2 equiv. of CuI and Bpy were used, the yield of the C-2
benzylated product in this reaction could noteworthy increase
from 72 to 90% (Table 1, entry 21).
versatile and efficient technique for C-H bond functionalization.[2b,
2f, 9]
2-Alkylquinazolin-4-ones are a highly significant class of
heteroaromatic compounds that are widely found in bioactive
molecules, natural products, synthetic drugs, pharmaceuticals,
and agrochemicals (Figure 1).[10] Thus, the development of
straightforward access to functionalized quinazolin-4-ones has
become an attractive area of research. The reported literatures
mainly consist of five types of strategies: a) ring-closure
condensation of anthranilic acid derivatives or C-H amidation,[11]
b) palladium-catalyzed carbonylation of 2-halogenoaniline
derivatives or N-arylamidines,[12] c) copper-catalyzed coupling
reactions of 2-halogenobenzoic acid derivatives with
amidines,[13] d) rearrangement or cyclization of other
heterocycles,[14] e) the Minisci reaction, radical approaches have
been recently developed as a strategy to assemble late-stage
alkylation of quinazolinones using carboxylic acids,[15] boronic
acids[16]
,
aldehydes,[17] and alkyltrifluoroborates[18] as alkyl
radical precursors. Recently, Zhang and colleagues developed
PhI(O2CCF3)2/NaN3-promoted cross-dehydrogenative coupling
With the optimized reaction conditions in hand, we
investigated the scope of this copper(I)/bpy-catalyzed C-2
benzylation of quinazolin-4(3H)-ones with N-tosylhydrazones.
First of all, as shown in Table 2, the variation in the quinazolin-
Figure 1. Selected representatives of bioactive 2-alkylquinazolin-4-ones.
1
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10.1002/ejoc.202000244
European Journal of Organic Chemistry
FULL PAPER
Table 1. Optimization of reaction conditions.[a]
Table 2. Substrate scope of quinazolin-4(3H)-ones.[a,b]
Entry
Cat.
Ligand[b]
Base
Yield[c]
1
CuI
-
t-BuOLi
t-BuOLi
t-BuOLi
t-BuOLi
t-BuOLi
t-BuOLi
t-BuOLi
t-BuOLi
t-BuOLi
t-BuOLi
t-BuOLi
t-BuOLi
t-BuOLi
t-BuONa
t-BuOK
Cs2CO3
K3PO4
26
2
CuI
Phen
Phen
Phen
Phen
Phen
Phen
Phen
BPy
42
3
CuCl
CuBr
CuCN
Cu(acac)2
CuCl2
Cu(OAc)2
CuI
trace
25
4
5
10
6
7
7
trace
trace
72
8
9
10
11
12
13
14
15
16
17
18
19
20[d]
21[e]
CuI
PPh3
DMEDA
TED
TMEDA
BPy
32
CuI
13
CuI
trace
10
CuI
CuI
15
CuI
BPy
5
CuI
BPy
trace
31
CuI
BPy
CuI
BPy
K2CO3
44
CuI
BPy
KOH
26
CuI
BPy
t-BuOLi
t-BuOLi
71
[a] Reaction conditions: 1 (0.20 mmol), 2a (0.40 mmol), CuI (20 mol%), Bpy
(20 mol%), and t-BuOLi (0.50 mmol) in tulene (3.0 mL) at 110 oC for 6 h.
[b] Isolated yield.
CuI
BPy
90
[a] Reaction conditions: 1a (0.20 mmol), 2a (0.40 mmol), catalyst (10 mol%),
ligand (10 mol%), and base (2.50 mmol) in 2.0 mL of solvent at 110 oC for 6 h.
substituted quinazolin-4(3H)-ones. However, the corresponding
product 3q was not detected when the benzylation of 1q bearing
NO2 group with 2a was carried out.
[b] Phen
= 1,10-phenanthroline; Bpy = 2,2'-bipyridine; DMEDA = N,N'-
dimethylethylene diamine; TED = triethylene diamine; TMEDA = N,N,N,N'-
tetramethylethylene diamine.
After studying the scope of quinazolin-4(3H)-ones, we turned
our attention toward direct C-2 benzylation of 3-
phenylquinazolin-4(3H)-one 1a to investigate the scope of
substituted N-tosylhydrazones. As shown in Table 3, the
reaction was found to work well with a wide range of N-
tosylhydrazones, affording the desired products (4a-f) in
moderate to good yields. N-tosylhydrazones with electron-
donating alkyl and alkoxy groups were well-tolerated, as
evidenced by the formation of 4a, 4b, 4d, and 4e in good yields,
ranging from 40% to 78%. Halogen-substituted N-
tosylhydrazones were also found compatible for this reaction (4c
and 4f). Conversely, we found that the N-tosylhydrazones
derived from benzaldehyde (4g), acetone (4h) and
benzophenone (4i) were not tolerated by this transformation.
On the basis of the experimental results and previously
reported copper(I)-catalyzed C-H benzylation,[1,2b,9] a proposed
reaction mechanism is described in Scheme 1. Firstly, the
reaction was initiated by deprotonation-metallation of the C-H
bond at C-2 position of quinazolin-4(3H)-one 1 in presence of
[c] Unless specified, the yield was estimated by 1H NMR.
[d] The solvent was xylene.
[e] The catalyst loading and ligand were 20 mol%
4(3H)-ones part of the reaction was studied. We were pleased to
observe that a wide range of N3-arylated quinazolin-4(3H)-ones
undergo the reaction successfully, affording the desired products
(3a-c, 3f, 3g) in good to excellent yields. It is noteworthy that
compound 3f was obtained in 87% yield from the large steric
effects reaction. To further investigate the functional group
tolerance, alkylated substituted substrates on N3-positions of
quinazolin-4-ones all reacted smoothly to afford the
corresponding C-2 benzylated compounds (3h-k) in good yields.
Additionally, quinazolin-4(3H)-ones bearing either electron-
donating or electron-withdrawing groups, such as F, Cl, Br, Me,
OMe, and OBn, at C6- or C7-positions of the aromatic nucleus
were well-tolerated in the reaction system to give the
corresponding products (3d, 3e, 3l-p) in moderate to good yields
and provided the possibility for further functionalization of the
2
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10.1002/ejoc.202000244
European Journal of Organic Chemistry
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discovery can be easily used for the modular synthesis of
bioactive quinazolin-4-one libraries.
Table 3. Substrate scope of N-tosylhydrazones.[a,b]
Experimental Section
General Information: All chemicals were purchased from the Wencai
New Material Technology and Merck in high purity and were used directly
without any purification. Solvents were freshly distilled prior to use. All
reactions were carried out under nitrogen atmosphere unless noted. 1H
NMR and 13C NMR spectra were recorded with a Bruker Avance III 500
MHz spectrometer in CDCl3 or DMSO-d6 solution. High resolution mass
(HRMS) spectra were measured with
spectrometer. Melting points (mp) were determined with
a
VG Auto Spec-3000
digital
a
electrothermal apparatus without further correction. TLC analyses were
performed on commercial glass plates bearing a 0.25 mm layer of Merck
silica gel 60 F254. Silica gel (200-300 mesh) was used for column
chromatography.
General experimental procedure for benzylation of quinazolin-4(3H)-
ones with N-tosylhydrazones: In
a 10 mL round bottom flask
quinazolin-4(3H)-ones 1 (0.20 mmol), N-tosylhydrazones 2 (0.40 mmol,
2.0 equiv), CuI (7.8 mg, 0.04 mmol, 0.2 equiv.), Bpy (6.2 mg, 0.04 mmol,
0.2 equiv.), and t-BuOLi (40.0 mg, 2.5 equiv.) in toluene (3.0 mL) were
taken. The reaction mixture was stirred at 110 oC for 6 h. The progress of
the reaction was monitored by TLC. After the consumption of the starting
materials, the reaction mixture was allowed to cool, and subsequently
extracted with CH2Cl2 (2×10 mL). The combined organic extracts were
dried over anhydrous MgSO4. Concentration of the material in vacuo
followed by flash chromatography on silica gel column afforded a pure
benzylated product.
[a] Reaction conditions: 1 (0.20 mmol), 2 (0.40 mmol), CuI (20 mol%), Bpy (20
mol%), and t-BuOLi (0.50 mmol) in tulene (3.0 mL) at 110 oC for 6 h.
[b] Isolated yield.
Bpy-stabilized copper(I) complex (CuLn) and base (t-BuOLi) to
generate the intermediate A. Sequently A possibly would
undergo the diazo compound
B
derived from the N-
3-Phenyl-2-(1-phenylethyl)quinazolin-4(3H)-one (3a): White solid, yield:
85%, m.p. 128 oC. 1H NMR (500 MHz, CDCl3) δ = 8.16 (dd, J = 7.8, 1.4 Hz,
1H), 7.62-7.56 (m, 2H), 7.53-7.48 (m, 3H), 7.47-7.39 (m, 4H), 7.32 (dd, J =
tosylhydrazone 2 by t-BuOLi, to form a Cu(I) carbene species C.
The latter was then converted into D by 1,2-migration insertion
of alkenyl group to the carbenic carbon. Finally by protonation
liberated the benzylated product 3 along with regeneration of the
copper catalyst.
16.3, 7.7 Hz, 3H), 7.25 (t, J = 7.6 Hz, 1H), 4.20 (s, 1H), 1.58 (s, 3H) ppm. 13
C
NMR (125 MHz, CDCl3) δ = 159.9, 145.7, 141.1, 139.4, 133.7, 129.3, 128.7,
127.5, 127.1, 126.1, 126.1, 125.1, 125.1, 122.7, 63.4, 43.1, 12.0 ppm. HRMS
(ESI): Calcd for C22H19N2O [M+H+]: 327.1492, Found 327.1495.
3-(4-Methoxyphenyl)-2-(1-phenylethyl)quinazolin-4(3H)-one (3b): White
solid, yield: 68%, m.p. 162 oC. 1H NMR (500 MHz, CDCl3) δ = 8.13 (dd, J = 7.8,
1.5 Hz, 1H), 7.56 (dd, J = 8.3, 1.2 Hz, 2H), 7.49 (td, J = 7.7, 1.6 Hz, 1H), 7.40
(dd, J = 10.5, 8.2 Hz, 4H), 7.33-7.27 (m, 2H), 7.24 (td, J = 7.7, 1.1 Hz, 1H),
6.99-6.94 (m, 2H), 4.17 (s, 1H), 3.82 (s, 3H), 1.56 (s, 3H) ppm. 13C NMR (125
MHz, CDCl3) δ = 160.1, 158.5, 145.7, 141.2, 133.6, 132.2, 128.6, 128.5, 127.4,
126.7, 126.2, 126.1, 125.0, 122.7, 114.6, 63.7, 55.5, 43.0, 12.1 ppm. HRMS
(ESI): Calcd for C23H21N2O2 [M+H+]: 357.1598, Found 357.1603.
2-(1-Phenylethyl)-3-(p-tolyl)quinazolin-4(3H)-one (3c): White solid, yield:
70%, m.p. 162-164 oC. 1H NMR (500 MHz, CDCl3) δ = 8.14 (d, J = 7.8 Hz, 1H),
7.57 (d, J = 7.7 Hz, 2H), 7.52-7.47 (m, 1H), 7.42-7.35 (m, 4H), 7.30 (dd, J =
15.0, 7.6 Hz, 2H), 7.26-7.21 (m, 3H), 4.18 (s, 1H), 2.37 (s, 3H), 1.56 (s, 3H)
ppm. 13C NMR (125 MHz, CDCl3) δ = 160.0, 145.7, 141.2, 137.0, 136.8, 133.6,
129.9, 128.6, 127.4, 126.2, 126.1, 125.1, 125.0, 122.7, 63.5, 43.0, 21.1, 12.1
ppm. HRMS (ESI): Calcd for C23H21N2O [M+H+]: 341.1648, Found 341.1645.
6-Bromo-3-phenyl-2-(1-phenylethyl)quinazolin-4(3H)-one (3d): White solid,
yield: 70%, m.p. 128-129 oC. 1H NMR (500 MHz, CDCl3) δ = 8.28 (d, J = 2.3
Hz, 1H), 7.60 (dd, J = 8.4, 2.3 Hz, 1H), 7.56 (d, J = 7.7 Hz, 2H), 7.49-7.40 (m,
6H), 7.33 (dd, J = 13.9, 7.0 Hz, 2H), 7.18 (d, J = 8.4 Hz, 1H), 4.19 (s, 1H), 1.58
(s, 3H) ppm. 13C NMR (125 MHz, CDCl3) δ = 158.7, 144.7, 140.7, 139.1, 136.6,
131.4, 129.4, 128.7, 127.9, 127.7, 127.3, 126.1, 125.0, 124.3, 118.2, 63.5,
43.6, 12.0 ppm. HRMS (ESI): Calcd for C22H18BrN2O [M+H+]: 405.0597, Found
405.0603.
6-Bromo-2-(1-phenylethyl)-3-(p-tolyl)quinazolin-4(3H)-one (3e): White solid,
yield: 64%. m.p. 172-174 oC. 1H NMR (500 MHz, CDCl3) δ = 8.25 (d, J = 2.3
Hz, 1H), 7.59 (dd, J = 8.4, 2.4 Hz, 1H), 7.54 (dd, J = 8.3, 1.0 Hz, 2H), 7.42-
7.39 (m, 2H), 7.35-7.30 (m, 3H), 7.25 (d, J = 8.4 Hz, 2H), 7.17 (d, J = 8.4 Hz,
1H), 4.17 (s, 1H), 2.37 (s, 3H), 1.57 (s, 3H) ppm. 13C NMR (125 MHz, CDCl3) δ
= 158.7, 144.8, 140.8, 137.3, 136.5, 136.4, 131.4, 130.0, 128.7, 127.9, 127.6,
126.1, 125.0, 124.3, 118.2, 63.6, 43.5, 21.1, 12.1 ppm. HRMS (ESI): Calcd for
C23H20BrN2O [M+H+]: 419.0754, Found 419.0760.
Scheme 1. Proposed reaction mechanism.
Conclusion
In summary, an efficient copper(I)-catalyzed system for the
direct
benzylation
of
quinazolin-4(3H)-ones
with
N-
tosylhydrazones was developed. A variety of C-2-benzylated
quinazolin-4(3H)-one derivatives have been successfully
synthesized in moderate to good yields. This reaction provides
an exceedingly effective, practical, and economical strategy to
access C-H bond functionalization of biologically important
quinazolin-4-ones by challenging the secondary benzyl group.
This methodology features a highly efficient synthetic process,
wide substrate scope, and high functional-group tolerance. This
3-(Naphthalen-1-yl)-2-(1-phenylethyl)quinazolin-4(3H)-one (3f): Colorless
oil, yield: 87%. 1H NMR (500 MHz, CDCl3) δ = 8.30 (d, J = 2.2 Hz, 1H), 7.94 (d,
J = 7.7 Hz, 3H), 7.66 (dd, J = 8.4, 2.3 Hz, 1H), 7.59-7.53 (m, 4H), 7.49-7.46 (m,
3
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10.1002/ejoc.202000244
European Journal of Organic Chemistry
FULL PAPER
3H), 7.34 (t, J = 7.6 Hz, 2H), 7.27-7.25 (m, 2H), 4.26 (s, 1H), 1.76 (s, 3H) ppm.
13C NMR (125 MHz, CDCl3) δ = 159.4, 145.4, 140.8, 136.7, 135.7, 134.9,
131.5, 129.6, 129.2, 128.8, 128.6, 128.2, 127.5, 127.5, 126.8, 126.2, 125.8,
125.5, 124.1, 122.3, 118.3, 64.2, 43.8, 12.8 ppm. HRMS (ESI): Calcd for
C26H21N2O [M+H+]: 377.1648, Found 377.1650.
N-(4-(4-oxo-2-(1-phenylethyl)quinazolin-3(4H)-yl)phenyl)acetamide (3g):
Yellow solid, yield: 90%. m.p. 169-171 oC. 1H NMR (500 MHz, CDCl3) δ = 8.16
(dd, J = 7.8, 1.4 Hz, 1H), 8.03 (d, J = 8.7 Hz, 2H), 7.68 (d, J = 8.7 Hz, 2H),
7.61 (d, J = 8.0 Hz, 2H), 7.53 (td, J = 7.8, 1.5 Hz, 1H), 7.44 (t, J = 7.7 Hz, 2H),
7.35 (t, J = 7.4 Hz, 1H), 7.30 (d, J = 7.9 Hz, 1H), 7.28-7.25 (m, 1H), 4.17 (s,
1H), 2.60 (s, 3H), 1.53 (s, 3H) ppm. 13C NMR (125 MHz, CDCl3) δ = 196.9,
160.0, 145.4, 143.6, 140.7, 134.9, 134.1, 129.3, 128.8, 128.8, 127.7, 126.1,
126.0, 125.2, 123.8, 122.3, 62.9, 43.5, 26.6, 11.7 ppm. HRMS (ESI): Calcd for
C24H22N3O2 [M+H+]: 384.1707, Found 384.1702.
3-Benzyl-2-(1-phenylethyl)quinazolin-4(3H)-one (3h): Colorless oil, yield:
78%. 1H NMR (500 MHz, CDCl3) δ = 8.10 (dd, J = 7.8, 1.4 Hz, 1H), 7.46-7.41
(m, 1H), 7.40-7.31 (m, 7H), 7.29-7.26 (m, 1H), 7.24 (dt, J = 5.9, 2.1 Hz, 2H),
7.22-7.17 (m, 2H), 5.49 (d, J = 14.3 Hz, 1H), 4.18 (d, J = 14.3 Hz, 1H), 3.89 (s,
1H), 0.89 (s, 3H) ppm. 13C NMR (125 MHz, CDCl3) δ = 160.1, 145.6, 141.3,
136.2, 133.4, 129.4, 128.7, 128.4, 128.2, 127.2, 126.2, 126.0, 124.9, 122.2,
61.9, 48.7, 43.0, 12.1 ppm. HRMS (ESI): Calcd for C23H21N2O [M+H+]:
341.1648, Found 341.1652.
3-Ethyl-2-(1-phenylethyl)quinazolin-4(3H)-one (3i): Colorless oil, yield: 72%.
1H NMR (500 MHz, CDCl3) δ = 8.05 (d, J = 7.8 Hz, 1H), 7.55 (d, J = 7.9 Hz,
2H), 7.45-7.39 (m, 3H), 7.32 (t, J = 7.3 Hz, 1H), 7.20 (dd, J = 15.1, 7.9 Hz, 2H),
4.16 (dq, J = 14.5, 7.3 Hz, 1H), 3.89 (s, 1H), 3.26 (dq, J = 14.2, 7.2 Hz, 1H),
1.37 (s, 3H), 1.26 (t, J = 7.2 Hz, 3H) ppm. 13C NMR (125 MHz, CDCl3) δ =
160.0, 145.5, 141.6, 133.2, 128.6, 128.1, 127.3, 126.1, 126.0, 124.9, 122.4,
61.8, 42.4, 39.8, 12.6, 12.2 ppm. HRMS (ESI): Calcd for C18H19N2O [M+H+]:
279.1492, Found 279.1490.
3-(Tert-butyl)-2-(1-phenylethyl)quinazolin-4(3H)-one (3j): White solid, yield:
86%, m.p. 120-122 oC. 1H NMR (500 MHz, CDCl3) δ = 7.96 (dd, J = 7.8, 1.2
Hz, 1H), 7.53 (d, J = 7.2 Hz, 2H), 7.39 (dt, J = 9.4, 4.5 Hz, 3H), 7.31 (t, J = 7.3
Hz, 1H), 7.12 (m, 2H), 4.00 (s, 1H), 1.54 (s, 9H), 1.47 (s, 3H) ppm. 13C NMR
(126 MHz, CDCl3) δ = 161.5, 144.7, 141.3, 133.0, 128.6, 128.0, 127.2, 125.9,
124.4, 124.3, 123.6, 60.4, 57.3, 42.5, 28.2, 12.4 ppm. HRMS (ESI): Calcd for
C20H23N2O [M+H+]: 307.1805, Found 307.1809.
2-(1-Phenylethyl)-3-propylquinazolin-4(3H)-one (3k): Colorless oil, yield:
80%. 1H NMR (500 MHz, CDCl3) δ = 8.05 (dd, J = 7.7, 1.2 Hz, 1H), 7.54 (d, J
= 7.2 Hz, 2H), 7.46-7.39 (m, 3H), 7.32 (t, J = 7.3 Hz, 1H), 7.23-7.17 (m, 2H),
4.01 (m, 1H), 3.89 (s, 1H), 3.18 (m, 1H), 1.67 (m, 2H), 1.37 (s, 3H), 1.00 (t, J =
7.4 Hz, 3H) ppm. 13C NMR (125 MHz, CDCl3) δ = 160.2, 145.5, 141.6, 133.2,
128.6, 128.2, 127.3, 126.1, 126.0, 124.9, 122.4, 62.3, 47.0, 42. 4, 20.9, 12.2,
11.6 ppm. HRMS (ESI): Calcd for C19H21N2O [M+H+]: 293.1648, Found
293.1652.
6-Methyl-3-phenyl-2-(1-phenylethyl)quinazolin-4(3H)-one (3l): Yellow oil,
yield: 92%. 1H NMR (500 MHz, CDCl3) δ = 7.96 (d, J = 1.2 Hz, 1H), 7.61-7.55
(m, 2H), 7.49 (d, J = 8.2 Hz, 2H), 7.47-7.38 (m, 4H), 7.31 (q, J = 7.6 Hz, 3H),
7.19 (d, J = 8.0 Hz, 1H), 4.17 (s, 1H), 2.39 (s, 3H), 1.55 (s, 3H) ppm. 13C NMR
(125 MHz, CDCl3) δ = 160.1, 142.9, 141.3, 139.5, 134.9, 134.6, 129.2, 128.8,
128.6, 127.4, 127.0, 126.2,126.1, 125.1, 122.2, 63.4, 42.6, 21.0, 11.9 ppm.
HRMS (ESI): Calcd for C23H21N2O [M+H+]: 341.1648, Found 341.1654.
7-Fluoro-3-phenyl-2-(1-phenylethyl)quinazolin-4(3H)-one (3m): Colorless
oil, yield: 60%. 1H NMR (500 MHz, CDCl3) δ = 8.15 (dd, J = 8.7, 6.3 Hz, 1H),
7.55 (d, J = 7.3 Hz, 2H), 7.49-7.39 (m, 6H), 7.36-7.29 (m, 2H), 6.99 (m, 1H),
6.94 (m, 1H), 4.20 (s, 1H), 1.60 (s, 3H) ppm. 13C NMR (125 MHz, CDCl3) δ =
167.1, 165.1, 159.3, 148.1 (JCF = 12.1 Hz), 140.6, 139.1, 131.2 (JCF = 10.5 Hz),
129.3, 128.7, 127.7, 127.3, 126.1, 125.1, 119.1, 113.0, 112.8 (JCF = 12.6 Hz),
112.7, 63.8, 44.0, 12.1 ppm. HRMS (ESI): Calcd for C22H18FN2O [M+H+]:
345.1398, Found 345.1404.
6-(Benzyloxy)-3-phenyl-2-(1-phenylethyl)quinazolin-4(3H)-one
(3p):
Yellow oil, yield: 79%. 1H NMR (500 MHz, CDCl3) δ = 7.75 (d, J = 2.9 Hz, 1H),
7.57 (d, J = 7.9 Hz, 2H), 7.50-7.45 (m, 6H), 7.43-7.39 (m, 4H), 7.34-7.30 (m,
3H), 7.24 (d, J = 8.7 Hz, 1H), 7.16-7.13 (m, 1H), 5.11 (s, 2H), 4.16 (s, 1H),
1.55 (s, 3H) ppm. 13C NMR (125 MHz, CDCl3) δ = 159.9, 156.2, 141.2, 139.4,
138.7, 136.6, 129.4, 129.3, 129.2, 128.7, 128.4, 128.2, 127.7, 127.5, 127.4,
127.1, 126.1, 125.1, 123.2, 122.2, 112.2, 70.5, 63.5, 42.1, 11.8 ppm. HRMS
(ESI): C29H25N2O2 [M+H+]: 433.1911, Found 433.1919.
3-Phenyl-2-(1-(o-tolyl)ethyl)quinazolin-4(3H)-one (4a): Colorless oil, yield:
40%. 1H NMR (500 MHz, CDCl3) δ = 8.14 (d, J = 7.7 Hz, 1H), 7.57-7.51 (m,
3H), 7.50-7.45 (m, 4H), 7.42 (t, J = 7.4 Hz, 1H), 7.25 (d, J = 7.9 Hz, 1H), 7.19
(t, J = 9.6 Hz, 2H), 7.11 (d, J = 6.7 Hz, 1H), 4.47 (s, 1H), 2.16 (s, 3H), 1.48 (s,
3H) ppm. 13C NMR (125 MHz, CDCl3) δ = 160.5, 145.7, 139.7, 139.6, 135.7,
133.7, 130.7, 129.8, 128.7, 128.2, 128.2, 127.8, 127.4, 126.2, 126.1, 125.1,
122.5, 62.9, 44.3, 19.2, 13.6 ppm. HRMS (ESI): C23H21N2O [M+H+]: 341.1648,
Found 341.1652.
2-(1-(3-Methoxyphenyl)ethyl)-3-phenylquinazolin-4(3H)-one
(4b):
Colorless oil, yield: 78%. 1H NMR (500 MHz, CDCl3) δ = 8.15 (d, J = 7.8 Hz,
1H), 7.53-7.47 (m, 3H), 7.44 (t, J = 7.8 Hz, 2H), 7.31 (dd, J = 17.0, 8.4 Hz, 3H),
7.24 (d, J = 7.6 Hz, 1H), 7.18-7.12 (m, 2H), 6.86 (d, J = 8.2 Hz, 1H), 4.18 (s,
1H), 3.85 (s, 3H), 1.55 (s, 3H) ppm. 13C NMR (125 MHz, CDCl3) δ = 160.0,
145.6, 142.8, 139.4, 133.7, 129.7, 129.3, 128.7, 127.1, 126.1, 125.1, 125.0,
122.6, 118.5, 112.5, 112.2, 63.4, 55.3, 43.0, 11.9 ppm. HRMS (ESI):
C23H21N2O2 [M+H+]: 357.1598, Found 357.1600.
2-(1-(4-Bromophenyl)ethyl)-3-phenylquinazolin-4(3H)-one (4c): White solid,
yield: 86%. m.p. 144-146 oC .1H NMR (500 MHz, CDCl3) δ = 8.15 (d, J = 8.1
Hz, 1H), 7.54-7.48 (m, 3H), 7.44 (m, 6H), 7.30 (t, J = 6.8 Hz, 1H), 7.28-7.25 (s,
1H), 4.13 (s, 1H), 1.54 (s, 3H) ppm. 13C NMR (125 MHz, CDCl3) δ = 159.8,
145.2, 140.2, 139.3, 133.8, 131.8 129.3, 128.7, 127.9, 127.2, 126.1, 125.3,
125.0, 122.6, 121.5, 63.4, 42.6, 11.7 ppm. HRMS (ESI): C22H18BrN2O [M+H+]:
405.0597, Found 405.0607.
2-(1-(3-Ethoxyphenyl)ethyl)-3-phenylquinazolin-4(3H)-one (4d): Colorless
oil, yield: 54%. 1H NMR (500 MHz, CDCl3) δ = 8.15 (d, J = 7.8 Hz, 1H), 7.52-
7.47 (m, 3H), 7.46-7.41 (m, 2H), 7.31 (dd, J = 17.4, 8.4 Hz, 3H), 7.24 (d, J =
7.7 Hz, 1H), 7.17-7.13 (m, 2H), 6.87-6.81 (m, 1H), 4.18 (s, 1H), 4.08 (q, J =
7.0 Hz, 2H), 1.55 (s, 3H), 1.44 (t, J = 7.0 Hz, 3H) ppm. 13C NMR (125 MHz,
CDCl3) δ = 159.9, 159.3, 145.6, 142.8, 139.4, 133.7, 129.7, 129.3, 128.7,
127.1, 126.1, 125.1, 125.0, 122.6, 118.4, 112.9, 63.5, 63.4, 43.0, 14.9, 11.9
ppm. HRMS (ESI): C24H23N2O2 [M+H+]: 371.1754, Found 371.1758.
2-(1-(3-(Benzyloxy)phenyl)ethyl)-3-phenylquinazolin-4(3H)-one
(4e):
Colorless oil, yield: 46%. 1H NMR (500 MHz, CDCl3) δ = 8.14 (d, J = 7.8 Hz,
1H), 7.52-7.37 (m, 9H), 7.37-7.29 (m, 3H), 7.28-7.25 (m, 2H), 7.24-7.21 (m,
1H), 7.18 (d, J = 7.8 Hz, 1H), 6.93 (dd, J = 8.1, 2.4 Hz, 1H), 5.10 (s, 2H), 4.17
(s, 1H), 1.54 (s, 3H) ppm. 13C NMR (125 MHz, CDCl3) δ = 159.9, 159.1, 145.5,
142.8, 139.3, 136.8, 133.7, 129.7, 129.3, 128.7, 128.1, 127.6, 127.1, 126.1,
125.1, 125.1, 122.6, 118.7, 113.3, 113.2, 70.1, 63.4, 42.9, 11.9 ppm. HRMS
(ESI): C29H25N2O2 [M+H+]: 433.1911, Found 433.1918.
2-(1-(4-Fluorophenyl)ethyl)-3-phenylquinazolin-4(3H)-one (4f): Colorless
oil, yield: 59%.1H NMR (500 MHz, CDCl3) δ = 8.15 (d, J = 7.7 Hz, 1H), 7.56-
7.50 (m, 3H), 7.50-7.43 (m, 4H), 7.32 (d, J = 6.9 Hz, 1H), 7.30-7.26 (m, 2H),
7.09 (t, J = 8.6 Hz, 2H), 4.15 (s, 1H), 1.55 (s, 3H) ppm. 13C NMR (125 MHz,
CDCl3) δ = 163.1, 161.1, 159.9, 145.4, 139.3, 136.9, 133.8, 129.3, 128.7,
127.8 (JCF = 8.1 Hz), 127.2, 126.1, 125.2 (JCF = 6.2 Hz), 122.5, 115.5 (JCF
=
8.1 Hz) , 63.4, 42.5, 12.1 ppm. HRMS (ESI): C22H18FN2O [M+H+]: 345.1398,
Found 345.1405.
Acknowledgements
7-Chloro-3-phenyl-2-(1-phenylethyl)quinazolin-4(3H)-one (3n): White solid,
yield: 52%, m.p. 120-122 oC. 1H NMR (500 MHz, CDCl3) δ = 8.07 (d, J = 8.4
Hz, 1H), 7.55 (d, J = 7.3 Hz, 2H), 7.45 (m, 6H), 7.35-7.29 (m, 3H), 7.22 (dd, J
= 8.4, 2.0 Hz, 1H), 4.20 (s, 1H), 1.60 (s, 3H) ppm. 13C NMR (125 MHz, CDCl3)
δ = 159.3, 147.0, 140.5, 139.8, 139.1, 130.0, 129.4, 128.7, 127.7, 127.3, 126.1,
125.6, 125.1, 121.2, 63.7, 44.0, 12.1 ppm. HRMS (ESI): Calcd for
C22H18ClN2O [M+H+]: 361.1102, Found 361.1105.
We are thankful for the Natural Science Foundation of China
(21861043), the Basic Research Projects of Yunnan Province
(2019FB016), and the Science Research Foundation Teacher
Projects of Yunnan Education Department (2018JS145) for
partial support of this work.
6-Methoxy-3-phenyl-2-(1-phenylethyl)quinazolin-4(3H)-one (3o): Colorless
oil, yield: 63%. 1H NMR (500 MHz, CDCl3) δ = 7.65 (d, J = 2.9 Hz, 1H), 7.57 (d,
J = 8.1 Hz, 2H), 7.49 (d, J = 7.8 Hz, 2H), 7.44 (t, J = 7.3 Hz, 2H), 7.41 (t, J =
7.4 Hz, 2H), 7.31 (td, J = 7.5, 0.9 Hz, 2H), 7.23 (d, J = 8.6 Hz, 1H), 7.08 (dd, J
= 8.7, 3.0 Hz, 1H), 4.16 (s, 1H), 3.86 (s, 3H), 1.54 (s, 3H) ppm. 13C NMR (125
MHz, CDCl3) δ = 160.0, 157.1, 141.3, 139.4, 138.4, 129.3, 128.6, 127.4, 127.3,
127.1, 126.1, 125.1, 123.2, 121.5, 111.1, 63.5, 55.7, 42.0, 11.7 ppm. HRMS
(ESI): C23H21N2O2 [M+H+]: 357.1598, Found 357.1592.
Disclosure statement
We confirm that none of the authors have any conflict of
interest in the context of this article.
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10.1002/ejoc.202000244
European Journal of Organic Chemistry
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Copper(I)/Bpy-catalyzed C-2-H benzylation of quinazolin-4(3H)-ones with N-tosylhydrazones
The regioselective C-2-H benzylation of quinazolin-4(3H)-ones with N-tosylhydrazones in ligand dependent copper system was
studied. Under the optimized conditions, an array of substituted quinazolin-4(3H)-ones could couple effectively with a wide variety of
N-tosylhydrazones derived from aryl ketones toafford the alkylated products in moderate to good yields. This useful and scalable
procedure promotes the construction of C(sp2)-C(sp3) bonds from quinazolin-4(3H)-ones and N-tosylhydrazones in a time-efficient
strategy.
6
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