Scandium-catalyzed Michael addition of quinazolinones and vinylazaarenes

Article abstract of DOI:10.1016/j.tetlet.2020.151926

We described a novel scandium-catalyzed selective Michael addition of quinazolinones and vinylazaarenes. The protocol proceeds smoothly to give diverse quinazolinone derivatives in moderate to excellent yields. The high practicality of this protocol was proved by excellent chemo selectivity and broad substrate and functional group compatibility.

Full text of DOI:10.1016/j.tetlet.2020.151926

Journal Pre-proofs
Scandium-Catalyzed Michael Addition of Quinazolinones and Vinylazaarenes
Zhiguang Zhang, Siwei Dai, Ling Li, Chenyu Jia, Yong Zhang, Hao Li
PII:
S0040-4039(20)30369-5
DOI:
Reference:
https://doi.org/10.1016/j.tetlet.2020.151926
TETL 151926
To appear in:
Tetrahedron Letters
Received Date:
Revised Date:
Accepted Date:
28 February 2020
6 April 2020
8 April 2020
Please cite this article as: Zhang, Z., Dai, S., Li, L., Jia, C., Zhang, Y., Li, H., Scandium-Catalyzed Michael
Addition of Quinazolinones and Vinylazaarenes, Tetrahedron Letters (2020), doi: https://doi.org/10.1016/j.tetlet.
2020.151926
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Scandium-Catalyzed Michael Addition of
Quinazolinones and Vinylazaarenes
Leave this area blank for abstract info.
Zhiguang Zhang, Siwei Dai, Ling Li, Chenyu, Jia, Yong Zhang, Hao Li
OH
O
N
N
N
Sc(OTf)3 (10 mol%)
toluene, 110 oC, N2
N
N
X
R
+
R
X
N
up to 95 % yield
34 examples
X=C, N

1
Tetrahedron Letters
journal homepage: www.elsevier.com
Scandium-Catalyzed Michael Addition of Quinazolinones and Vinylazaarenes
Zhiguang Zhanga, Siwei Daia, Ling Lia, Chenyu Jiaa, Yong Zhanga* and Hao Lib*
a College of Chemical and Pharmaceutical Engineering, Hebei University of Science and Technology, NO. 26 Yuxiang Rd, Shijiazhuang, 050018, PR China
bState Key Laboratory of Bioengineering Reactor, Shanghai Key Laboratory of New Drug Design, and School of Pharmacy, East China University of Science
and Technology, NO.130 Meilong Rd, Shanghai, 200237, PR China
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
We described a novel scandium-catalyzed selective Michael addition of quinazolinones and
vinylazaarenes. The protocol proceeds smoothly to give diverse quinazolinone derivatives in
moderate to excellent yields. The high practicality of this protocol was proved by excellent
chemo selectivity and broad substrate and functional group compatibility.
Available online
2009 Elsevier Ltd. All rights reserved.
Keywords:
Quinazolinones
Scandium
Vinylazaarenes
Michael addition
The N-substituted quinazolinones and related tautomerizable
heterocycles present frequently in natural products, drug
candidates and bioactive molecules.1 For example, Tryptanthrin
is a plant alkaloid displaying anti-inflammatory and anti-cancer
activities. Vasicinone, which was found in Peganum harmala,
was shown to have antianaphylactic activity (Figure 1). Besides,
quinazolinones are also widely used in material science.2
Although various strategies have been established, it’s still highly
important to develop novel and effective protocols to accomplish
diverse functionalization of quinazolinones.
heterocycles with allyl alcohols (Figure 2a).6 N-alkylated product
was obtained in excellent selectivity with high yields. Moreover,
they described oxidative allylic amidation of tautomerizable
heterocycles with allylbenzene through the modified White’s
strategy in 2016 (Figure 2b).7
Figure 2. Synthesis of quinazolinones derivatives
Previous work:
a)
O
N
OH
Pd(PPh3)4 (5 mol%)
DMC, 100 o
N
Ph
N
+
HO
Ph
Ph
C
N
Figure 1. Quinazolinones derivatives with biological
O
activities
b)
c)
OH
H
N
PdCl2 (10 mol%)
DMBQ (1.5 equiv)
N
Ph
N
+
N
O
O
N
N
N
O
N
OH
N
DMSO, 100 o
C
N
N
N
OH
F
OH
O
HN
O
N
N
Pd(dba)2 (10 mol%)
PPh3 (24 mol%)
OH
(-)-Vasicinone
N
N
Ph
+
Ph
Me
3-Cl-C6H4COOH (1 equiv)
(+)-Febrifugine
Albaconazole
N
dioxane, 140 o
C
F
The pursuit of high chemo selectivity is always critical in the
process of functioning tautomerizable heterocycles because these
substrates have multiple nucleophilic centers.3 In some reactions,
O-alkylated product can be dominant.4 Thus, achieving N-
selectivity in related reactions is always a challenging task.
Consequently, much attention has been paid to improving the
selectivity of desired N-alkylation reaction.5 Mechanism of the
reactions was also probed to illustrate the reason for the
production of N- or O- alkylated products.3b To the best of our
knowledge, only a few methods have been developed in the
functioning of theses tautomerizable heterocycles with high
chemo selectivity. In 2015, Cook and coworkers developed Pd-
catalyzed chemo- and regioselective allylation of tautomerizable
This work:
OH
O
N
O
N
N
N
NH
N
X
X
N
N
[Sc]
Meanwhile, Lu and coworkers discovered that the reaction
between tautomerizable heterocycles with simple alkynes could
afford same product (Figure 2c).3c Besides, Breit described the
first rhodium-catalyzed allylic reaction between 4-
hydroxyquinazoline with allylic carbonates, achieving high
chemo-, and regioselectivities.8 While diverse methods have been
developed for synthesizing tautomerizable heterocycle
derivatives, very limited addition reaction examples have been

2
Tetrahedron
reported.9 In 2015, Xuan and coworkers described oxidative
Table 1. Optimization of direct addition of 4-quinazolinone
(1a) with 4-vinylpyridine (2a).a
coupling of 2-aryl-4-quinazolinones with olefins through C-H
activation/aza-Michael reaction strategy.9a Subsequently, Peng
found rhodium could also promote these tandem reactions
successfully.9b Interestingly, Engle reported palladium-catalyzed
directed alkene hydroamination between 2-pyridone derivatives
and olefins in 2017.9c Recently, Hou reported the first aza-
Michael addition of 2-hydroxypyridines with α, β-unsaturated
1,4-dicarbonyl compounds with high N-selectivity in 2019.10
N
O
N
N
OH
O
N
catalyst
N
N
N
+
+
solvent, T
N
N
3b
3a
1a
2a
not observed
entry
1
catalyst
solvent
DMSO
T(℃)
110
110
110
110
110
110
110
110
110
110
110
110
110
110
110
110
80
yield%b
54
43
58
17
55
42
34
56
91
79
19
43
71
23
67
72
56
0
On the other hand, vinylazaarenes have been successfully
employed as novel Michael acceptor by Lam,11 Wang,12
Harutyunyan,13 Terada14 and Jiang15 in recent years. A series of
nucleophiles such as aldehydes, azoles,16 amino acid esters,17 and
alkoxyamine18 have been utilized to react with the novel Michael
acceptor.19 We envisioned whether this methodology could be
smoothly transferred to derivatization of tautomerizable
heterocycles. Herein, we report the first Sc(OTf)3 catalyzed aza-
Michael addition reaction between quinazolinones and
vinylazaarenes.
Sc(OTf)3
Sc(OTf)3
Sc(OTf)3
Sc(OTf)3
Sc(OTf)3
Sc(OTf)3
Sc(OTf)3
Sc(OTf)3
Sc(OTf)3
Cu(OAc)2
FeCl3
2
1,4-dioxane
DMF
3
4
THF
5
EtOAc
DCE
6
7
CH3CN
neat
8
To begin, 4-hydroxyquinazoline (4-quinazolinone) 1a was
selected as a model substrate with two distinct tautomerizable
nucleophilic centers (–OH and –NH) to react with 4-
vinylpyridine 2a (Table 1). To our delight, N-alkylated
quinazolinone product 3a was obtained in 54% yield with 10
9
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
10
11
12
13
14
15
o
mol% Sc(OTf)3 catalyst in 3 mL DMSO at 110 C under an N2
Pd(OAc)2
Pd(PPh)4
ZnBr2
atmosphere without observing any O-alkylated product (Table1,
entry 1). The studies showed that the solvent had a great impact
on this reaction. It proved that only 17% yield was observed
when the reaction was carried out in THF (entry 4). After
screening of solvent, the product 3a was obtained in 91% yield
with toluene as solvent (Table1, entry 9). Next, a series of Lewis
acids were tested for the reaction. Cu(OAc)2, FeCl3, Pd(OAc)2,
Pd(PPh)4 or ZnBr2 could also promote the reaction with relatively
lower yield (entry 10-14). It should be noted that Brφnsted acid
could also promote the transformation (entry 15). Considering
the corrosiveness of HOTf, it was not chosen for catalyzing the
reaction. In the absence of catalyst, no reaction was occurred
(entry 19). A systematic survey of catalysts revealed that
Sc(OTf)3 could promote the reaction most effectively. The yield
decreased apparently when the catalyst loading was lowered to 5
mol%. (entry 16) Decreasing reaction temperature results in
much lower yield (entry 17). Moreover, the reaction could not
proceed at all when the temperature was lowered to 60 ℃. (entry
18) Therefore, the optimal reaction condition was confirmed as
follow: a solution of 1 (1 equiv), 2 (2 equiv), 10 mol% Sc(OTf)3
in toluene was stirred for 12 h at 110 oC with a N2 balloon (entry
9).
HOTf
16c
17
18
19
a
Sc(OTf)3
Sc(OTf)3
Sc(OTf)3
-
60
110
0
Reaction conditions: 1a (0.5 mmol), 2a (1 mmol), 10 mol%
catalyst, in 3 mL solvent at 110 oC for 12 h.
b isolated yield.
c 5 mol% of Sc(OTf)3 was used as the catalyst.
or meta-position could react with 4-hydroxyquinazoline
successfully in 51%-87% yield. It appeared those substrates with
electron-donating groups resulted in lower yields (3l, 3m), which
may be attributed to the lower reactivity of these compounds. We
then explored whether this reaction could be applied for
heterocycles other than pyridine. Gratifyingly, heterocycles such
as pyrimidine and benzoxazole were well tolerated (3n, 3o) with
good yields. But the reaction between 1a and 2-vinylquinoline
afforded product 3p in 26% yield. Next, it was found that the
reaction between 1a and (E)-2-(prop-1-en-1-yl)pyridine couldn’t
occur, probably due to its lower reactivity (3q).
With the optimal condition in hand, the scope of the reaction
between 4-hydroxyquinazoline 1a and various vinylazaarenes
was probed. (Table 2) A wide range of readily accessible
vinylazaarenes underwent this reaction with 1a in excellent
chemo selectivity. Generally, 2-vinylpyridines with electron-
deficient or electron-rich groups afforded products 3a-3f in
moderate to excellent yields (73-89%). In the case of para-
substituted substrate 3f, lower yield was observed compared to
3d and 3e. Additionally, the reaction of 4-hydroxyquinazoline
with 4-vinylpyridine resulted in 91% yield (3g). Next, we
examined the reactions for 4-vinylpyridines with different
functional groups. It turned out that 4-vinylpyridines with
halogen atoms (3h-3k) such as -Cl, -Br, -F on the ortho-position
Subsequently, the scope of 4-hydroxyquinazolines was
examined for the reaction with 4-vinylpyridine as a standard
substrate and the results are shown in Table 3. 4-
hydroxyquinazolines with different substituents could react well
to produce 5 in moderate to high yields with excellent chemo
selectivity. It was found that these 4-hydroxyquinazolines with
electron-deficient groups reacted well to afford the adduct
product in 62-95% yields (Table 3, 5a-5i). Besides, the position
of substituent groups on the phenyl didn’t affect the reaction
apparently (5b-5d). 4-hydroxyquinazolines with electron-rich
groups on the phenyl afforded 55-74% yield (5j, 5k), indicating

3
the electron-rich groups could lower the nucleophilicity of the
Table 2. Range of vinylazaarenes in addition reaction with 4-
quinazolinone 1aa
substrates. However, 2-substituted quinazolinones couldn’t react
with 2a to afford the desired product probably due to the steric
effects (5p). Furthermore, other biologically relevant
tautomerizable heteroarenes were tested to prove the
applicability of this method. To our delight, heterocycles such
O
N
OH
Sc(OTf)3 (10 mol%)
toluene, 110 oC, N2
N
N
X
N
+
X
N
N
1a
3
2
Cl
O
Cl
O
O
as
isoquinolinone
(5l),
phthalazinone
(5m),
N
N
N
N
benzo[d][1,2,3]triazin-4(3H)-one (5n) and 2-benzoxazolinone
(5o) all reacted smoothly with medium to good yields under the
optimal condition. Unfortunately, pyridin-2-ol couldn’t react with
2a under the standard condition (5q).
N
N
N
O
N
N
3b
, 81%
3c
, 80%
3a
, 82%
O
O
The proposed mechanism of this addition reaction was shown
in Figure 3. The nitrogen of 2-vinylpyridine was activated by
Sc(OTf)3 to produce polarized intermediate structure A, which
was converted to intermediate B with positive charge at the
terminal carbon. Then the intermediate C was obtained by the
conjugate addition of 4-hydroxypyridine. Subsequently,
intermediate D was produced through protonation. Finally,
Sc(OTf)3 was recycled to afford the final product 3a.
N
N
N
N
N
N
N
N
N
3d
3f,
Cl
3e
73%
,89%
, 83%
O
N
O
N
N
O
N
N
N
N
Cl
N
N
3h
, 74%
N
3i
, 77%
O
3g
, 91%
O
N
N
O
N
F
N
Figure 3. Proposed mechanism for the reaction.
N
Br
N
N
N
3l
, 71%
3k,
51%
N
3j
, 87%
N
O
N
N
N
O
N
3a
O
N
N
N
O
N
Sc(OTf)3
O
N
O
3m
, 23%
3n
, 73%
3o
, 80%
N
N
O
Sc(OTf)3
O
N
N
Sc(OTf)3
A
N
N
D
N
N
N
N
3q
, 0%
3p
, 26%
OH
N
a
General condition: 1a (0.5 mmol), 2a (1.0 mmol), Sc(OTf)3
(0.05 mol), toluene (3 mL), isolated yields are given.
H+
O
N
N
N
N
N
Sc(OTf)3
Sc(OTf)3
Table 3. Range of quinazolinones in reaction with 4-
vinylpyridine 2aa
B
C
O
N
OH
N
Sc(OTf)3 (10 mol%)
toluene, 110 oC, N2
N
N
In conclusion, we have developed an efficient protocol for the
synthesis of N-substituted quinazolinones. This new strategy may
be a better choice for the synthesis of quinazolinone derivatives
owing to excellent N-selectivity and the relatively broad scopes
of both the tautomerizable heterocycles and vinylazaarenes
substrates. Further investigation of this methodology in the
synthesis of bioactive molecules are undergoing in our
laboratories.
X
X
+
N
N
4
5
2a
O
N
O
N
N
O
N
N
N
F
Cl
N
N
Cl
N
5c
, 83%
N
5a
, 88%
O
5b
, 95%
O
N
N
O
N
Cl
N
Br
I
N
N
N
N
N
Acknowledgments
5e,
83%
5f
, 62%
5d
, 85%
O
O
N
O
N
We thank the Natural Science Foundation of Hebei province
(B2019208137) for financial support.
O2N
N
N
N
N
N
MeOOC
N
CF3
5i
, 84%
5h
, 81%
5g
, 83%
References and notes
O
N
O
N
O
N
N
O
N
N
N
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N
5l
, 71%
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5j
, 55%
, 74%
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N
N
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4
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Supplementary Material
Supplementary material that may be helpful in the review
process should be prepared and provided as a separate electronic
file.

5
Highlights
1. Excellent chemo selectivity.
2. Broad substrate and functional group
compatibility.
3. Readily available starting materials and the
catalyst.