Visible-Light-Induced Benzylic C-H Functionalization for the Synthesis of 2-Arylquinazolines

Article abstract of DOI:10.1002/ejoc.201900996

This work reports a mild and efficient approach for the synthesis of substituted quinazolines using 1-(2-aminoaryl)ethan-1-ones in conjunction with arylmethanamines as starting materials via visible-light-induced benzylic C–H functionalization. The reaction proceeded at room temperature with low catalyst loading and the reaction system was clean from beginning to end. Significantly, this method exhibited good tolerance even to free hydroxyl group and amino group contained in substrates.

Full text of DOI:10.1002/ejoc.201900996

A Journal of
Accepted Article
Title: Visible-light induced benzylic C-H functionalization for the
synthesis of 2-arylquinazolines
Authors: Jingchang Zhang, Qibao Wang, Yongen Guo, Lin Ding,
Maocai Yan, Yinglin Gu, and Jiajia Shi
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201900996
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10.1002/ejoc.201900996
European Journal of Organic Chemistry
COMMUNICATION
Visible-light induced benzylic C-H functionalization for the
synthesis of 2-arylquinazolines
Jingchang Zhang,* Qibao Wang,* Yongen Guo, Lin Ding, Maocai Yan, Yinglin Gu, Jiajia Shi
effect of lowering the bond dissociation energy of the C−H bonds
at amine α-positions[7]. A good hydrogen atom acceptor present
in the reaction could abstract a hydrogen atom from α-position of
amine, converting the aminium radical cation to the iminium ion
(Scheme 1, Path A). At same time, aminium radical cation had
lower pKa value of the protons at α-positions[8] that might be
deprotonated to yield an α-amino radical and then converted to
iminium ion via a second single-electron oxidation[9] (Scheme 1 ,
Path B). These processes usually proceeded at room
temperature under visible light irradiation, and the catalytically
generated iminium ions could undergo cycloaddition with 2-
aminobenzoketones to yield 1, 2-dihydroquinazolines which
were subsequently oxidized to generate corresponding
quinazoline products (Scheme 2). Herein, we aimed to develop
a mild and efficient approach with higher substrates tolerance for
the synthesis of 2-arylquinazolines via visible light induced
benzylic C-H functionalization at room temperature using 1-(2-
aminoaryl)ethan-1-ones in conjunction with arylmethanamines
as starting materials.
Abstract: This work reports a mild and efficient approach for
the synthesis of substituted quinazolines using 1-(2-
aminoaryl)ethan-1-ones in conjunction with arylmethanamines
as starting materials via visible light induced benzylic C-H
functionalization. The reaction proceeded at room temperature
with low catalyst loading and the reaction system was clean
from beginning to end. Significantly, this method exhibited
good tolerance even to free hydroxyl group and amino group
contained in substrates.
Introduction
The C-H activation catalyzed by photoredox catalysts
including organic photoredox catalysts and transition metal
complexes has been widely used in the organic synthesis
because of its efficiency and mildness[1]. These reactions usually
proceeded at room temperature with low catalyst loading.
Quinazolines were a kind of six-membered natural products with
medicinal value[2] and a lot of methods for the construction of
quinazolines have been developed from diffrent substrates such
as 2-(aminomethyl)arylamines[3], 2-aminoarylamides[4], etc[5].
Although synthesis of quinazoline derivates using 2-
Results and Discussion
Table 1.Optimization of the Reaction Conditionsa
aminobenzoketones
or
2-aminobenzaldehydes
and
arylmethanamines as starting materials have been developed,
high temperature was usually needed and substrates tolerance
was limited in these methods[6]. These methods all involved a
benzylic C-H activation of arylmethanamines.
As we knew, amines were very good electron donors, readily
undergoing
single-electron
oxidation
by
excited-state
photocatalyst to yield an aminium radical cation which had the
Scheme 1. Pathways of Amine Oxidation to Iminium Ions[1a]
Scheme 2. Cycloaddition between 2-aminobenzoketones and
arylmethaniminium ions
School of Pharmacy, Jining Medical University, 669 Xueyuan
Road, Rizhao, Shandong, China
Email: zhangjingchang84@outlook.com
http://yxy.jnmc.edu.cn/2017/0530/c160a862/page.htm
Supporting information for this article is given via a link at the end
of the document.
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European Journal of Organic Chemistry
COMMUNICATION
We started our research by treating 1-(2-aminophenyl)ethan-
oxidant and blue leds irradiation respectively, there was no
product observed which indicated catalyst, oxidant and blue leds
irradiation were all necessary for the reaction (Table 1, Entry 15-
17). After a series of reaction conditions optimization, we finally
got the optimal reaction condition: the mixture of 1-(2-
aminophenyl)ethan-1-one (1a), 2 eq phenylmethanamine (2a), 1
1-one (1a) with
2 eq phenylmethanamine (2a), 2 mol %
Ru(bpy)3Cl2 and 4eq tert-butyl peroxybenzoate (TBPB) in DMSO
and got the desired product 3aa in 55% yield (Table 1, Entry 1).
With this good result in hand, we sequentially optimized a series
of reaction conditions including catalysts, oxidants, additives,
and solvents. Compared to Ru(bpy)3Cl2, Ir(ppy)3 was cheaper
and obviously improved the yield while Eosin Y decreased the
yield (Table 1, Entry 2-3). The oxidative efficiency of TBHP and
DTBP were all inferior to TBPB (Table 1, Entry 4-5). Addition of
Li2CO3 improved the yield to 69% smoothly while K2CO3 and
Na2CO3 all decreased the yield (Table 1, Entry 6-8). Various
solvents, such as MeCN, PhCF3 and a series of mixed solvents,
were sequentially examined, among which the mixed solvent of
DMSO and PhCF3 (1:4, v/v) gave the best result (Table 1, Entry
9-13). Reducing catalyst loading did not decrease the reaction
yield (Table 1, Entry 14). Moreover, in the absence of catalyst,
mol% Ir(ppy)3,
(PhCF3:DMSO=4:1, v/v) were stirred for 12
4
eq TBPB,
3
eq Li2CO3 and solvent
under N2
h
atmosphere with blue leds irradiation (Table 1, Entry 14).
We subsequently investigated the reaction scope of
substrates and prepared a series of substituted quinazolines as
shown in Table 2. For the 1-(2-aminoaryl)ethan-1-ones, it was
interesting that the anilino ring bearing whether electron-
donating groups or electron-withdrawing groups all decreased
the reaction yield at different level. Electron-donating groups had
more adverse effects than electron-withdrawing groups on this
reaction. 2-aminobenzaldehydes or 2-aminobenzoketones could
also participate in the reaction smoothly and give the
corresponding products in good to excellent yield. For the 2-
aminobenzoketones, the introduction of electron-withdrawing
groups to the para position of the free phenyl ring could
obviously improve the yield (Table 2, 3ha, 3ia). The reaction
scope of arylmethanamines were also examined. A series of
arylmethanamines participated in the reaction smoothly and
gave the corresponding products in good to excellent yield. The
introduction of whether electron-donating groups or electron-
withdrawing groups to phenyl ring of arylmethanamines all
decreased the yield at different level, especially the electron-
donating groups. It was noteworthy that free hydroxyl group
borne on the phenyl ring of arylmethanamines or free amino
group borne on the anilino ring of 2-aminobenzaldehydes could
also be tolerated perfectly in the reaction which was rarely
reported in the related field of transition metal catalyzed C-H
functionalization (Table 2, 3ag, 3ja, 3ch). We also examined the
applicability of alkanamines for this method. Unfortunately, there
were no products observed when alkanamines participated in
the reaction. The results may due to unstability of alkaniminium
ions.
Table 2.Preparation of 2-aryl quinazolines a
A
proposed mechanism was shown in Scheme 3. The
photocatalyst Ir(ppy)3 absorbed visible light to give the strongly
IV/*III
reducing excited-state *Ir(ppy)3 (E1/2
which was oxidized by TBPB to generate benzoate anion, tert-
= −1.73 V vs SCE)[10]
IV/III
butoxy radical and Ir(IV) intermediate (E1/2
= +0.77 V vs SCE).
This Ir(IV) intermediate accepted an electron from
phenylmethanamine to generate intermediate I. tert-Butoxy
radical might then abstract a hydrogen atom from the benzylic
Scheme 3. Proposed mechanism
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10.1002/ejoc.201900996
European Journal of Organic Chemistry
COMMUNICATION
position of intermediate
intermediate II underwent
I
to give intermediate II. The
cycloaddition with 1-(2-
was removed under reduced pressure. The residue was purified by flash
chromatography on silica gel (petroleum ether/EtOAc as an eluent) to
afford 2-arylquinazolines.
aminoaryl)ethan-1-ones to give intermediate III which was
subsequently oxidized to generate corresponding quinazoline
product. Abstracting a hydrogen atom from the benzylic position
of phenylmethanamine by tert-butoxy radical initially, followed by
oxidation by Ir(IV) intermediate to generate intermediate II was
also plausible.
Keywords: photocatalyst • room temperature• quinazolines
1.
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Conclusion
In conclusion, we successfully developed a mild and efficient
approach for synthesis of quinazolines via photo-induced C-H
functionalization
using
1-(2-aminoaryl)ethan-1-ones
in
2.
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conjunction with arylmethanamines as starting materials and
Ir(ppy)3 as photocatalyst. The reaction proceeded at room
temperature with low catalyst loading and the reaction system
was clean from beginning to end. A series of substituted groups
contained in substrates even including free hydroxyl group and
amino group were well-suited for this process. A plausible
mechanism was proposed based on the reported theories. The
application of this new method for the preparation of other useful
heterocycles is underway in our laboratory.
4.
5.
6.
Experimental Section
Genaral
Procedure:
1-(2-aminoaryl)ethan-1-ones
or
2-
aminobenzaldehydes or 2-aminobenzoketones (0.2 mmol), Ir(ppy)3
(0.002 mmol, 13 mg) and Li2CO3 (0.6 mmol, 44.3 mg) were added to a
Schlenk tube. The tube was degassed and refilled with N2 for three times.
Then arylmethanamines (0.4 mmol), TBPB (0.8 mmol, 155.4 mg) and
solvent (PhCF3:DMSO=4:1, V/V, 1ml) was added by syringe. The
reaction mixture was stirred at room temperature for 12h under the
irradiation of a 36 W blue LEDs (distance app. 3.0 cm from the bulb).
Then the reaction mixture was extracted with EtOAc (3 × 5 ml)and water.
The combined organic extracts were dried over Na2SO4 and the solvent
7.
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10.1002/ejoc.201900996
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Entry for the Table of Contents (Please choose one layout)
COMMUNICATION
Photochemistry*
Jingchang Zhang,*
Wang,* Yongen Guo, Lin Ding,
Maocai Yan, Yinglin Gu, Jiajia
Shi
Visible-light induced synthesis
of substituted quinazolines
using1-(2-aminoaryl)ethan-1-
ones in conjunction with
arylmethanamines as starting
materials
Qibao
Page No. – Page No.
Visible-light
benzylic
induced
C-H
functionalization
synthesis
for
the
2-
of
arylquinazolines
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