Metal-free visible light driven synthesis of tetrahydroquinoline derivatives utilizing Rose Bengal

Article abstract of DOI:10.1016/j.tet.2017.06.030

The visible-light driven reaction for the synthesis of tetrahydroquinoline derivatives via tandem radical cyclization of N,N-dimethylanilines with 2-benzylidenemalononitriles has been developed. Corresponding products were obtained with yields of up to 74

Full text of DOI:10.1016/j.tet.2017.06.030

Accepted Manuscript
Metal-free visible light driven synthesis of tetrahydroquinoline derivatives utilizing
Rose Bengal
Jing-Rui Xin, Jun-Tao Guo, Dominic Viglitaturo, Yan-Hong He, Zhi Guan
PII:
S0040-4020(17)30663-4
10.1016/j.tet.2017.06.030
TET 28795
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 5 May 2017
Revised Date: 13 June 2017
Accepted Date: 16 June 2017
Please cite this article as: Xin J-R, Guo J-T, Viglitaturo D, He Y-H, Guan Z, Metal-free visible light driven
synthesis of tetrahydroquinoline derivatives utilizing Rose Bengal, Tetrahedron (2017), doi: 10.1016/
j.tet.2017.06.030.
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ACCEPTED MANUSCRIPT
Graphical Abstract

ACCEPTED MANUSCRIPT
Metal-free Visible Light Driven Synthesis of
Tetrahydroquinoline Derivatives Utilizing Rose Bengal
Jing-Rui Xina, Jun-Tao Guoa, Dominic Viglitaturob, Yan-Hong Hea,* and Zhi Guana,*
a Key Laboratory of Applied Chemistry of Chongqing Municipality, School of Chemistry and Chemical Engineering,
Southwest University, Chongqing 400715, PR China
b Chemistry Department, College of Saint Benedict and Saint John’s University, MN 56374, USA
E-mails: heyh@swu.edu.cn (for Y.-H. He); guanzhi@swu.edu.cn (for Z. Guan)
Abstract: The visible-light driven reaction for the synthesis of tetrahydroquinoline derivatives via
tandem radical cyclization of N,N-dimethylanilines with 2-benzylidenemalononitriles has been
developed. Corresponding products were obtained with yields of up to 74% under mild conditions
by using Rose Bengal as a triplet sensitizer, which is inexpensive, environmentally-friendly and
easily acquired. This work demonstrates the potential benefits of Rose Bengal for the production of
tetrahydroquinoline derivatives.
Key words: visible light, photoredox catalysis, Rose Bengal, tetrahydroquinoline, tandem radical
cyclization
1 Introduction
Visible light is an abundant, readily available and renewable clean energy.‐Its application for
organic synthesis has received great attention from the chemical workers.1 However, since most of
organic molecules cannot directly absorb visible light, thereby they require a medium to play this
important role in the reaction system.2 Recently, MacMillan,3 Yoon,4 Stephenson,5 et al. have
demonstrated that metal complexes, such as ruthenium (II) and iridium (III), have good
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photocatalytic properties, which make visible light widely used in the organic synthesis. Although
numerous photocatalysts based on Ru or Ir have been investigated during the past decades, these
complexes are expensive and potentially toxic. Meanwhile, organic dyes possess the distinguishing
qualities of high extinction coefficients in the visible-light range, long excited-state lifetimes, and
low cost, which make these organic photosensitizers desirable for photoredox transformations.
Therefore, more and more organic dyes have been used in photocatalytic reactions.6 For example,
the economical Rose Bengal has been employed in decarboxylative amination,7 alkylation
reaction,8 cycloaddition reaction 9 thiocyanation reaction10 and formylation reaction 11
, . Taking into
consideration of the advantages of Rose Bengal as the photosensitizer, we decided to further explore
the application of Rose Bengal in organic synthesis.
Tetrahydroquinoline derivatives are a class of very important compounds, and the fragments of
tetrahydroquinoline moiety are also vital building blocks generally found in many natural products
and bioactive molecules.12 Due to their ubiquitous distribution in natural products and medicinal
agents, tetrahydroquinolines have become important synthetic targets for chemists.13 The tandem
cyclization of free radical and unsaturated olefin is widely used in organic synthesis.14 The synthesis
of tetrahydroquinoline derivatives by cyclization of benzylidenemalononitriles with α-amino
o
radical has been reported. In 2011, Miura15 et al. used CuCl2/O2 at 60 C to obtain the
corresponding tetrahydroquinolines in moderate yields. In 2013, Rueping group16 reported the
photoinitiated cycloaddition reactions of N-methylanilines with 2-benzylidenemalononitriles for
the synthesis of tetrahydroquinolines using [Ir(ppy)2bpy]PF6 under blue LED, and yields of up to
71% were obtained. In 2016, Bissember17 et al. used [Cu(dap)2]Cl as a photosensitizer under green
LED to obtain the tetrahydroquinolines in moderate yields. However, the catalysts used in these
reports are metals including noble metal and costly ligands, and the photocatalytic methods used
high-intensity monochromatic LEDs as light source. Taking into account the importance of
tetrahydroquinolines, the exploration of more economical, environmentally-friendly and easily
acquired catalysts for the synthesis of tetrahydroquinolines still has greatly practical value. Herein,
we report a metal-free visible light driven synthesis of tetrahydroquinoline derivatives from
2-benzylidenemalononitriles and substituted anilines, in which Rose Bengal was used as a triplet
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sensitizer and the compact fluorescent lamp (CFL) as light source. This process might provide a
promising alternative protocol for the synthesis of tetrahydroquinoline derivatives.
2 Results and discussion
The tandem radical cyclization of N,N-dimethylaniline (1a) with 2-benzylidenemalononitrile (2a)
under air condition was chosen as a model reaction. Firstly, fluorescence experiments with 1a, 2a
and Rose Bengal were performed. 1a and 2a could not absorb light in the visible light region while
Rose Bengal exhibited a strong absorption in the visible light region at λ = 563 nm (ε = 122633 L
mol⁻1cm⁻1) in DMSO (the spectrum shown in the Supporting Information). Then, some control
experiments were conducted. As shown in Table 1, in the presence of Rose Bengal (3 mol%) and
under irradiation of a 23 W household CFL (λ = 400-720 nm) in DMSO for 36 h,18 the model
reaction gave product (3a) in 55% yield (Table 1, entry 1). To verify both visible light and Rose
Bengal are necessary in this catalytic process, control experiments were conducted. In the absence
of both visible light and Rose Bengal, or either one of them, only trace amount of product (3a)
could be observed (Table 1, entries 2-4). Those results indicated that both Rose Bengal and visible
light are indispensable for the model reaction. When the model reaction was conducted under N2
instead of air, the product was only obtained in 7% yield (Table 1, entry 5), showing that O2 was
involved in the reaction process. To get an insight into the reaction mechanism,
2,2,6,6-tetramethyl-1-piperidinyloxy (TEMPO), a well-known radical scavenger, was added to the
reaction system, which completely inhibited the reaction (Table 1, entry 6). This revealed that the
reaction must proceed through a radical process. Taking into consideration of the possibility that
Rose
Bengal
can
generate
singlet
oxygen
through
energy
transfer,11,19
1,4-diazabicyclo[2.2.2]-octane (DABCO) as a quencher of 1O2 was added to the model reaction.
Only trace amount of product was observed in the presence of DABCO (Table 1, entry 7),
indicating that singlet oxygen participated in the reaction process.
Table 1. Control experimentsa
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Entry
Visible light
Rose Bengal
(3 mol%)
TEMPO
DABCO
Yield (%)b
(0.6 mmol)
(0.6 mmol)
1
2
+
-
+
-
-
-
-
-
55
trace
trace
trace
7
3
+
-
-
-
-
4
+
+
+
+
-
-
5c
6
+
+
+
-
-
+
-
-
trace
trace
7
+
a Reaction conditions: a mixture of 1a (0.3 mmol), 2a (0.2 mmol), Rose Bengal (3 mol%) and TFA
(1 eq. relative to 2a) in DMSO (1.0 mL) was irradiated using a 23 W CFL in air for 36 h.
b Yield of the isolated product.
c Under N2.
Next, we optimized the reaction conditions in terms of solvent, molar ratio, catalyst dosage,
wattage of lamp and solvent volume. Since solvent effect also affects the rate of free radical
reaction,20 we firstly screened the solvents. DMSO was found to be the best solvent among DMSO,
MeCN, MeOH, THF, toluene, CHCl3, CH2Cl2, 1-methyl-2-pyrrolidinone and cyclohexane (Table
S1). Then, we investigated other reaction conditions. To conclude, the optimized reaction
conditions for a 0.2 mmol scale reaction were found to consist of the following: 1 mL of DMSO, a
molar ratio of 1a/2a = 3:2, a Rose Bengal dosage of 3 mol%, and a fluorescent lamp wattage of 23
W (For more details, please see the Supporting Information Tables S1-S4).
Some literatures revealed that acid additive could control formation rate of α-amino
radical through affecting the balance between free amine and its corresponding (unreactive)
ammonium salt.17,21 Therefore, the species of acid additive were investigated. Among the tested acid
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additives, TFA could promote the reaction significantly, giving a yield of 52% (Table 2, entry 2).
When formic acid and p-toluenesulfonic acid were used, very low yields were obtained (Table 2,
entries 3 and 4). Moreover, influence of the TFA loading was investigated. When 1 equivalent of
TFA relative to 2a (0.2 mmol) was employed, the best yield of 55% was received (Table 2, entry 6).
Therefore, 1 equivalent of TFA relative to 2a (0.2 mmol) was chosen as optimal conditions for the
reaction.
Table 2. Influence of acidsa
Entry
Acid
Acid equivalents (relative to 2a)
Yield (%)b
1
2
3
4
5
6
7
8
None
TFA
-
2
37
52
34
22
47
55
53
50
HCOOH
TsOH·H2O
TFA
2
2
0.5
1
TFA
TFA
1.5
2.5
TFA
a Reaction conditions: a mixture of 1a (0.3 mmol), 2a (0.2 mmol), Rose Bengal (3 mol%) and acid
in DMSO (1.0 mL) was irradiated using a 23 W CFL in air for 36 h.
b Yield of the isolated product.
With the optimized conditions in hand, the scope of substituted anilines 1 and
benzylidenemalononitriles 2 were examined (Table 3 and Scheme 1). It can be seen that
N,N-dimethylanilines with an electron-donating group (4-Me) give better yields than those with an
electron-withdrawing group (4-F or 4-Cl) (Table 3, entries 2-4). The possible reason is that the
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electron-donating group is beneficial to the stability of α-amino radicals formed in the reaction
process. Benzylidenemalononitriles with either an electron-withdrawing (-CF3, -F, -Cl, -Br) or an
electron-donating group (-OMe, -OEt, -Me, -Ph) could take part in the reaction smoothly (Table 3,
entries 5-17). Generally, electron-rich benzylidenemalononitriles delivered the desired products
with better yields than electron-deficient ones.
A
dditionally
,
o-, m- or p-chloro
benzylidenemalononitrile could be utilized to give the corresponding products 3 (Table 3, entries
12, 14 and 15). The reactions between both electron-rich N,N-dimethylanilines and
benzylidenemalononitriles gave good yields (Table 3, entries 16 and 17). Additionally, besides
N,N-dimethylanilines some other substituted anilines were also evaluated, and to our delight,
N-ethyl-N-methylaniline, N-methyldiphenylamine and 4-phenylmorpholine could participate in the
reaction with 2a giving corresponding products in 34%, 55%, and 25% yields, respectively
(Scheme 1). Eighteen new tetrahydroquinoline derivatives were obtained, and their structures
1
were confirmed by HRMS, H NMR, and 13C NMR. (For details, please see the Supporting
Information).
Table 3. Substrate scopea.
Entry
R1
H
R2
H
Product
3aa
Yield (%)b
1
2
3
4
5
6
7
57
67
52
50
65
63
58
4-Me
4-F
4-Cl
H
H
3ba
H
3ca
H
3da
4-OMe
4-OEt
3-OMe
3ab
H
3ac
H
3ad
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8
H
H
3-Me
4-Ph
4-CF3
4-F
58
45
38
55
54
47
56
47
73
74
3ae
3af
3ag
3ah
3ai
9
10
11
12
13
14
15
16
17
H
H
H
4-Cl
H
4-Br
3aj
3ak
3al
H
3-Cl
H
2-Cl
4-Me
4-Me
4-OEt
4-OMe
3bb
3bc
a Reaction conditions: a mixture of 1 (0.3 mmol), 2 (0.2 mmol), Rose Bengal (3 mol%) and TFA (1
eq. relative to 2) in DMSO (1.0 mL) was irradiated using a 23 W CFL in air for 36 h.
b Yield of the isolated product.
Scheme 1. Reactions of other substituted anilines besides N,N-dimethylanilines
On the basis of our control experiments and previous work,6a,15-18 a plausible reaction pathway
for this visible light induced cyclization reaction was proposed (Scheme 2). Firstly, the triplet
sensitizer Rose Bengal (RB) absorbs a photon to form the excited-state RB*, which interacts with
1
O2 to generate O2 via the energy transfer. Subsequently, the generated 1O2 proceeds a
single-electron transfer (SET) from N,N-dimethylaniline 1 to give the amine cation radical 4.
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Then 4 donates one proton to the dioxygen radical anion and results in formation of the amine
radical 5, which can easily react with 2-benzylidenepropanedinitrile 2 to produce the alkyl radical
6. And intramolecular cyclization generates the corresponding intermediate 7, which is then
readily rearomatized by the second electron transfer/proton elimination leading to the product 3. In
this process, acid additive (TFA) maybe play a role to control the formation rate of α-amino
radicals through affecting the balance between free amine and its corresponding (unreactive)
ammonium salt,17,21 which ensures a higher utilization of the radicals by avoiding the
decomposition caused by free radical accumulation. On the other hand, some reports have
suggested that Brønsted acids have the ability to promote radical additions.21-22
H
N
CH3
CH3
CF3COOH
N
ꢀH+
CH3
CH3
N
N
1
CH3
SET
CH2
4
5
H2O2
1O2
CN
O2
NC
Rose Bengal
Energy Transfer
Rose Bengal *
2
H+
CN
NC
HOO
3O2
H+
e
CH2
N
hv
CH3
6
NC CN
NC CN
ꢀe
ꢀH+
N
N
CH3
CH3
7
3
Scheme 2. Possible mechanism.‐
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3 Conclusion
In summary, we have developed a metal-free visible-light driven method for the synthesis of
tetrahydroquinoline derivatives. The mild conditions enable moderate yields by using cheap and
commercially available Rose Bengal in place of previous transition metal photocatalysts and a
household light bulb instead of a high-intensity monochromatic LED light source. The yields
obtained with this method can match the previously reported yields, and eighteen new
tetrahydroquinoline derivatives were obtained. This work demonstrates that there is a synergistic
benefit of combining TFA with Rose Bengal and might provide a promising protocol for the
synthesis of tetrahydroquinoline derivatives.
4. Experimental section
4.1. General experimental details
Rose bengal was purchased from aladdin industrial corporation Shanghai, China.
R104993-1g, 95%. Unless otherwise noted, all reagents were purchased from commercial
suppliers and used without further purification. Reactions were monitored by thin-layer
chromatography (TLC) with Haiyang GF 254 silica gel plates (Qingdao Haiyang chemical
industry Co Ltd, Qingdao, China) using UV light and vanillic aldehyde as visualizing agents.
Flash column chromatography was performed using 200–300 mesh silica gel at increased
pressure. 1H NMR spectra and 13C NMR spectra were respectively recorded on 600 MHz and
150 MHz NMR spectrometers. Chemical shifts (δ) were expressed in ppm with TMS as the
internal standard, and coupling constants (J) were reported in Hz. High-resolution mass spectra
were obtained by using ESI ionization sources (Varian 7.0 T FTICR-MS) and ESI-TOF. Melting
points were taken on a WPX-4 apparatus and were uncorrected (Yice instrument equipment Co
Ltd, Shanghai).
2.2. General procedure for the preparation of benzylidenemalononitriles (2)23
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Malononitrile (10.0 mmol) was added to a stirred solution of aromatic aldehyde (10.0 mmol)
and piperidine (1.0 mmol) in ethanol (10 mL). The reaction mixture was stirred at room
temperature for 1 h. A precipitate was formed and collected by suction filtration, and then purified
by recrystallization from CH2Cl2 and petroleum ether to afford the products 2.
4.3. General procedure for the synthesis of tetrahydroquinoline derivatives (3)
A round-bottom flask was charged with Rose Bengal (3 mol%), substituted aniline 1 (0.3
mmol, ) and 2-benzylidenemalononitrile 2 (0.2 mmol) in DMSO (1.0 ml), to which TFA (1 eq
relative to 2) was introduced. The resultant mixture was stirred at r.t. under irradiation of 23 W CFL
(Philips) in air for 36 h. Then 10 mL of ethyl acetate was added to the reaction system, followed by
washing with saturated salt water (3×5 mL). The organic layer was dried over Na2SO4, filtered, and
concentrated. The residue was purified by flash column chromatography (petroleum ether/ ethyl
acetate 20:1-8:1, 0.5% NEt3 was present in the eluent) to give the products 3.
4.3.1. 1-methyl-3-phenyl-2,3-dihydroquinoline-4,4(1H)-dicarbonitrile (3aa)17
1
White solid, m.p. 140-142 oC, H NMR (600 MHz, CDCl3) δ 7.51-7.53 (d, J = 7.2 Hz, 1H),
7.40-7.49 (m, 5H), 7.32-7.35 (m, 1H), 6.80-6.83 (m, 1H), 6.73-6.75 (m, 1H), 3.96 (t, J = 11.9 Hz,
1H), 3.60 (dd, J = 11.4, 3.8 Hz, 1H), 3.52 (dd, J = 11.4, 3.8 Hz, 1H), 3.03 (s, 3H). 13C NMR (151
MHz, CDCl3) δ 144.0, 134.8, 131.7, 129.3, 129.2, 128.8, 128.5, 117.6, 115.2, 114.1, 112.9, 112.6,
51.5, 45.7, 42.4, 38.7.
4.3.2. 1,6-dimethyl-3-phenyl-2,3-dihydroquinoline-4,4(1H)-dicarbonitrile (3ba)16
White solid, m.p. 192-194 oC, 1H NMR (600 MHz, CDCl3) δ 7.43-7.46 (m, 5H), 7.30-7.35 (m,
1H), 7.13-7.15 (m, 1H), 6.65-6.68 (m, 1H), 3.89 (t, J = 11.8 Hz, 1H), 3.60 (dd, J = 11.3, 3.6 Hz, 1H),
3.48 (dd, J = 11.3, 3.6 Hz, 1H), 2.99 (s, 3H), 2.29 (s, 3H). 13C NMR (151 MHz, CDCl3) δ 140.8,
134.5, 129.5, 129.2, 128.4, 118.9, 118.8, 115.4, 114.7, 113.8, 113.6, 51.6, 45.8, 42.3, 39.1, 20.3.
4.3.3. 6-fluoro-1-methyl-3-phenyl-2,3-dihydroquinoline-4,4(1H)-dicarbonitrile (3ca)
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White solid, m.p. 207-209 oC, 1H NMR (600 MHz, CDCl3) δ 7.48-7.52 (m, 1H), 7.43-7.46 (m,
2H), 7.36-7.39 (m, 1H), 7.27-7.30 (m, 1H), 7.22-7.25 (m, 1H), 6.66-6.69 (m, 2H), 3.95 (t, J = 11.8
Hz, 1H), 3.57 (dd, J = 11.3, 3.5 Hz, 1H), 3.52(dd, J = 11.3, 3.5 Hz, 1H), 3.02 (s, 3H). 13C NMR (151
MHz, CDCl3) δ 142.6, 134.3, 131.8, 129.6, 129.3, 128.4, 122.3, 115.0, 114.6, 113.7, 113.6, 51.4,
45.5, 42.1, 38.8. HRMS(ESI) m/z: calcd for C18H14FN3 [M+Na]+ 314.1064, found 314.1068.
4.3.4. 6-chloro-1-methyl-3-phenyl-2,3-dihydroquinoline-4,4(1H)-dicarbonitrile (3da)
White solid, m.p. 165-167 oC, 1H NMR (600 MHz, CDCl3) δ 7.49-7.51 (m, 2H), 7.44-7.45(m,
2H), 7.29-7.30 (m, 1H), 7.27-7.29 (m, 1H), 6.67-6.68 (m, 1H), 6.60-6.66 (m, 1H), 3.95 (t, J = 11.8
Hz, 1H), 3.57 (dd, J = 12.3, 4.0 Hz, 2H), 3.53 (dd, J = 12.4, 4.0 Hz, 2H), 3.02 (s, 3H). 13C NMR (151
MHz, CDCl3) δ 142.6, 134.3, 131.8, 129.6, 129.3, 128.4, 122.3, 114.6, 114.0, 113.7, 113.6, 51.4,
45.5, 42.1, 38.8. HRMS(ESI) m/z: calcd for C18H14ClN3 [M+Na]+ 330.0768, found 330.0772.
4.3.5. 3-(4-methoxyphenyl)-1-methyl-2,3-dihydroquinoline-4,4(1H)-dicarbonitrile (3ab)
o
1
Pale yellow solid, m.p. 158-160 C, H NMR (600 MHz, CDCl3) δ 7.50-7.52 (m, 1H),
7.36-7.39 (m, 2H), 7.30-7.34 (m, 1H), 6.95-6.97 (m, 2H), 6.79-6.81 (m, 1H), 6.72-6.74 (m, 1H),
3.91 (t, J = 11.9 Hz, 1H), 3.83 (s, 3H), 3.56 (d, J = 11.3 Hz, 1H), 3.48 (d, J = 11.3 Hz, 1H), 3.02 (s,
3H). 13C NMR (151 MHz, CDCl3) δ 160.4, 144.1, 131.7, 129.6, 128.8, 126.8, 117.6, 115.3, 114.6,
114.2, 112.9, 112.5, 55.3, 51.6, 45.0, 42.8, 38.7. HRMS(ESI) m/z: calcd for C19H17N3O [M+H]+
304.1444, found 304.1442.
4.3.6. 3-(4-ethoxyphenyl)-1-methyl-2,3-dihydroquinoline-4,4(1H)-dicarbonitrile (3ac)
o
1
Pale yellow solid, m.p. 138-140 C, H NMR (600 MHz, CDCl3) δ 7.50-7.52s (m, 1H),
7.36-7.38 (m, 2H), 7.30-7.34 (m, 1H), 6.94-6.96 (m, 2H), 6.79-6.82 (m, 1H), 6.72-6.74 (m, 1H),
4.06 (q, J = 6.8 Hz, 2H), 3.91 (t, J = 11.9 Hz, 1H), 3.56 (dd, J = 11.4, 3.5 Hz, 1H), 3.48 (dd, J = 11.4,
3.5 Hz, 1H), 3.02 (s, 3H), 1.43 (s, 3H). 13C NMR (151 MHz, CDCl3) δ 159.8, 144.0, 133.5, 131.7,
129.6, 128.8, 126.6, 117.6, 115.6, 115.1, 114.2, 112.5, 63.6, 51.6, 45.0, 42.8, 38.7, 14.7. HRMS(ESI)
m/z: calcd for C20H19N3O [M+Na]+ 340.1420, found 340.1420.
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4.3.7. 3-(3-methoxyphenyl)-1-methyl-2,3-dihydroquinoline-4,4(1H)-dicarbonitrile (3ad)
White solid, m.p. 160-163 oC, 1H NMR (600 MHz, CDCl3) δ 7.52-7.54(m, 1H), 7.33-7.38 (m,
2H), 7.04-7.06 (m, 1H), 7.00-7.02(m, 1H), 6.96-6.99 (m, 1H), 6.80-6.84 (m, 1H), 6.73-6.75 (m, 1H),
3.93 (t, J = 11.9 Hz, 1H), 3.83 (s, 3H), 3.57 (dd, J = 11.2, 3.9 Hz, 1H), 3.52 (dd, J = 11.2, 3.9 Hz, 1H),
3.03 (s, 3H). 13C NMR (151 MHz, CDCl3) δ 159.1, 143.0, 135.3, 130.7, 129.2, 128.6, 127.8, 119.7,
116.6, 113.9, 113.2, 111.5, 54.3, 50.5, 44.7, 41.3, 37.7. HRMS(ESI) m/z: calcd for C19H17N3O
[M+Na]+ 326.1264, found 326.1268.
4.3.8. 1-methyl-3-(m-tolyl)-2,3-dihydroquinoline-4,4(1H)-dicarbonitrile (3ae)
White solid, m.p. 102-104 oC, 1H NMR (600 MHz, CDCl3) δ 7.51-7.53 (m, 1H), 7.42-7.43 (m,
3H), 7.32-7.34 (m, 2H), 6.79-6.82 (m, 1H), 6.73-6.74 (m, 1H), 3.95 (t, J = 11.9 Hz, 1H), 3.55 (dd, J
= 11.5, 3.8 Hz, 1H), 3.49 (dd, J = 11.5, 3.8 Hz, 1H), 3.02 (s, 3H), 2.40 (s, 3H). 13C NMR (151 MHz,
CDCl3) δ 160.0, 144.0, 131.2, 129.5, 129.1, 127.9, 125.4, 117.6, 115.2, 114.1, 113.8, 112.5, 51.5,
45.6, 42.4, 38.7, 21.2. HRMS(ESI) m/z: calcd for C19H17N3 [M+Na]+ 310.1315, found 310.1312.
4.3.9. 3-([1,1'-biphenyl]-4-yl)-1-methyl-2,3-dihydroquinoline-4,4(1H)-dicarbonitrile (3af)
White solid, m.p. 147-149 oC, 1H NMR (600 MHz, CDCl3) δ 7.65-7.67 (m, 2H), 7.60-7.61 (m,
2H), 7.52-7.54 (m, 3H), 7.44-7.46 (m, 2H), 7.32–7.38 (m, 2H), 6.81-6.83 (m, 1H), 6.74-6.76 (m,
1H), 3.99 (t, J = 11.9 Hz, 1H), 3.65 (dd, J = 11.4, 3.7 Hz, 1H), 3.55 (dd, J = 11.4, 3.7 Hz, 1H), 3.04 (s,
3H). 13C NMR (151 MHz, CDCl3) δ 144.0, 142.3, 140.2, 133.7, 131.8, 128.8, 127.8, 127.1, 117.7,
115.2, 114.1, 112.9, 112.6, 51.5, 45.4, 42.4, 38.8. HRMS(ESI) m/z: calcd for C24H19N3 [M+Na]+
372.1471, found 372.1470.
4.3.10. 1-methyl-3-(4-(trifluoromethyl)phenyl)-2,3-dihydroquinoline-4,4(1H)-dicarbonitrile (3ag)
White solid, m.p. 138-140 oC, 1H NMR (600 MHz, CDCl3) δ 7.71-7.73 (m, 2H), 7.59-7.60 (m,
2H), 7.52-7.53 (m, 1H), 7.34-7.37 (m, 1H), 6.83-6.86 (m, 1H), 6.76-6.77 (m, 1H), 3.95 (t, J = 11.8
Hz, 1H), 3.69 (d, J = 11.0 Hz, 1H), 3.54 (d, J = 11.0 Hz, 1H), 3.04 (s, 3H). 13C NMR (151 MHz,
CDCl3) δ 143.9, 131.9, 129.0, 128.8, 126.2, 118.0, 114.9, 113.8, 112.7, 112.4, 51.2, 45.4, 41.9, 38.8.
HRMS(ESI) m/z: calcd for C19H14F3N3 [M+Na]+ 364.1032, found 364.1035.
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4.3.11. 3-(4-fluorophenyl)-1-methyl-2,3-dihydroquinoline-4,4(1H)-dicarbonitrile (3ah)
o
1
Pale yellow solid, m.p. 141-143 C, H NMR (600 MHz, CDCl3) δ 7.51-7.52 (m, 1H),
7.44-7.46 (m, 2H), 7.33-7.35 (m, 1H), 7.13-7.16(m, 2H), 6.81-6.83 (m, 1H), 6.74-6.75 (m, 1H), 3.91
(t, J = 11.8 Hz, 1H), 3.61 (dd, J = 12.3, 3.8 Hz, 1H), 3.50 (dd, J = 12.4, 3.8 Hz, 1H), 3.03 (s, 3H). 13C
NMR (151 MHz, CDCl3) δ 163.3, 144.0, 131.8, 130.7, 130.2, 128.8, 117.8, 116.2, 115.1, 114.0,
112.6, 51.5, 45.0, 42.5, 38.7. HRMS(ESI) m/z: calcd for C18H14FN3 [M+H]+ 292.1245, found
292.1242.
4.3.12. 3-(4-chlorophenyl)-1-methyl-2,3-dihydroquinoline-4,4(1H)-dicarbonitrile (3ai)
White solid, m.p. 208-210 oC, 1H NMR (600 MHz, CDCl3) δ 7.50-7.52 (m, 1H), 7.39-7.44 (m,
4H), 7.33 -7.36 (m, 1H), 6.81-6.84 (m, 1H), 6.74-6.75 (m, 1H), 3.90 (t, J = 11.8 Hz, 1H), 3.60 (dd, J
= 11.2, 3.8 Hz, 1H), 3.51 (dd, J = 11.2, 3.8 Hz, 1H), 3.02 (s, 3H). 13C NMR (151 MHz, CDCl3) δ
143.9, 135.6, 133.3, 131.8, 129.8, 129.5, 128.8, 117.9, 115.0, 113.9, 112.6, 51.3, 45.1, 42.2, 38.8.
HRMS(ESI) m/z: calcd for C18H15ClN3 [M+H]+ 308.0949, found 308.0947.
4.3.13. 3-(4-bromophenyl)-1-methyl-2,3-dihydroquinoline-4,4(1H)-dicarbonitrile (3aj)
White solid, m.p. 218-220 oC, 1H NMR (600 MHz, CDCl3) δ 7.58-7.59 (m, 2H), 7.50-7.52 (m,
1H), 7.33-7.36 (m, 3H), 6.81-6.84 (m, 1H), 6.74-6.75 (m, 1H), 3.90 (t, J = 11.8 Hz, 1H), 3.58 (dd, J
= 12.4, 3.7 Hz, 1H), 3.50 (dd, J = 12.4, 3.7 Hz, 1H), 3.03 (s, 3H). 13C NMR (151 MHz, CDCl3) δ
143.9, 133.8, 132.4, 131.9, 130.1, 128.8, 123.8, 117.9, 115.0, 113.9, 112.6, 51.3, 45.2, 42.1, 38.8.
HRMS(ESI) m/z: calcd for C18H14BrN3 [M+H]+ 352.0444, found 352.0441.
4.3.14. 3-(3-chlorophenyl)-1-methyl-2,3-dihydroquinoline-4,4(1H)-dicarbonitrile (3ak)
White solid, m.p. 170-172 oC, 1H NMR (600 MHz, CDCl3) δ 7.51-7.52 (m, 1H), 7.32–7.45(m,
5H), 6.81-6.84 (m, 1H), 6.74-6.75 (m, 1H), 3.90 (t, J = 11.8 Hz, 1H), 3.58 (d, J = 11.2 Hz, 1H), 3.51
(d, J = 11.2 Hz, 1H), 3.03 (s, 3H). 13C NMR (151 MHz, CDCl3) δ 143.9, 136.8, 131.9, 130.4, 129.7,
128.8, 128.6, 126.7, 117.9, 114.9, 113.8, 112.7, 51.3, 45.3, 42.1, 38.8. HRMS(ESI) m/z: calcd for
C18H14ClN3 [M+Na]+ 330.0768, found 330.0766.
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4.3.15. 3-(2-chlorophenyl)-1-methyl-2,3-dihydroquinoline-4,4(1H)-dicarbonitrile (3al)
White solid, m.p. 128-130 oC, 1H NMR (600 MHz, CDCl3) δ 7.52–7.54 (m, 1H), 7.44–7.48 (m,
3H), 7.28-7.30 (m, 3H), 6.74-6.78 (m, 1H), 6.67-6.68 (m, 1H), 4.34 (dd, J = 10.7, 4.1 Hz, 1H), 3.76
(dd, J = 12.4, 4.1 Hz, 1H), 3.43 (dd, J = 12.5, 4.1 Hz, 1H), 2.95 (s, 3H). 13C NMR (151 MHz, CDCl3)
δ 142.9, 131.8, 130.8, 129.4, 129.2, 127.3, 127.2, 126.7, 116.7, 113.4, 113.2, 111.9, 111.5, 50.5, 39.8,
39.6, 37.6. HRMS(ESI) m/z: calcd for C18H14ClN3 [M+Na]+ 330.0768, found 330.0772.
4.3.16. 3-(4-methoxyphenyl)-1,6-dimethyl-2,3-dihydroquinoline-4,4(1H)-dicarbonitrile (3bb)
White solid, m.p. 192-194 oC, 1H NMR (600 MHz, CDCl3) δ 7.37-7.39 (m, 2H), 7.30-7.32 (m,
1H), 7.12-7.14 (m, 1H), 6.95-6.97 (m, 2H), 6.64-6.67 (d, J = 8.5 Hz, 1H), 3.83 (s, 3H), 3.56 (dd, J =
12.3, 3.6 Hz, 1H), 3.45 (dd, J = 12.3, 3.6 Hz, 1H), 2.97 (s, 3H), 2.28 (s, 3H). 13C NMR (151 MHz,
CDCl3) δ 160.3, 142.1, 132.4, 129.6, 129.1, 127.3, 127.0, 115.5, 114.6, 114.4, 112.8, 55.3, 51.8,
45.2, 42.76, 38.9, 20.1. HRMS(ESI) m/z: calcd for C20H19N3O [M+Na]+ 340.1420, found 340.1423.
4.3.17. 3-(4-ethoxyphenyl)-1,6-dimethyl-2,3-dihydroquinoline-4,4(1H)-dicarbonitrile (3bc)
White solid, m.p. 170-172 oC, 1H NMR (600 MHz, CDCl3) δ 7.35-7.37 (m, 2H), 7.30-7.31 (m,
1H), 7.12-7.14 (m, 1H), 6.93-6.96 (m, 2H), 6.64-6.66 (m, 1H), 4.05 (q, J = 6.9 Hz, 2H), 3.84 (t, J =
11.8 Hz, 1H), 3.55 (dd, J = 11.3, 3.4 Hz, 1H), 3.44 (dd, J = 11.3, 3.4 Hz, 1H), 2.98 (s, 3H), 2.28 (s,
3H), 1.43 (t, J = 6.9 Hz, 3H). 13C NMR (151 MHz, CDCl3) δ 159.7, 142.1, 132.4, 129.6, 129.1,
127.2, 126.8, 115.5, 115.1, 114.4, 112.9, 112.8, 63.6, 51.8, 45.3, 42.8, 38.9, 20.1, 14.8. HRMS(ESI)
m/z: calcd for C21H21N3O [M+Na]+ 354.1577, found 354.1579.
4.3.18. 1-ethyl-3-phenyl-2,3-dihydroquinoline-4,4(1H)-dicarbonitrile (3ea)
Pale yellow solid, m.p. 109-112 oC, 1H NMR (600 MHz, CDCl3) δ 7.54-7.41 (m, 6H), 7.33-7.29
(m, 1H), 6.75-6.78 (m, 2H), 3.96 (t, J = 12.0 Hz, 1H), 3.59-3.49 (m, 3H), 3.37 (dd, J = 15.0, 7.2 Hz, 1H),
1.21 (t, J = 7.1 Hz, 3H). 13C NMR (151 MHz, CDCl3) δ 142.7, 134.9, 131.7, 129.4, 129.2, 129.1, 128.5,
117.15, 115.2, 114.1, 112.4, 48.9, 45.5, 45.4, 42.51, 11.09. HRMS(ESI) m/z: calcd for C19H17N3
[M+Na]+ 310.1315, found 310.1316.
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4.3.19. 1,3-diphenyl-2,3-dihydroquinoline-4,4(1H)-dicarbonitrile (3fa)
Pale yellow solid, m.p. 125-127 oC, 1H NMR (600 MHz, CDCl3) δ 7.58-7.60 (m, 1H), 7.47-7.50
(m, 2H), 7.47-7.39 (m, 5H), 7.15-7.18 (m, 1H), 6.91-6.85 (m, 1H), 6.69-6.72S (m, 1H), 4.24 (t, J = 11.5
Hz, 1H), 3.94 (dd, J = 11.4, 3.7 Hz, 1H), 3.75 (dd, J = 11.4, 3.7 Hz, 1H). 13C NMR (151 MHz, CDCl3) δ
145.7, 143.1, 134.6, 131.1, 130.2, 129.5, 129.2, 129.0, 128.5, 126.4, 126.2, 119.4, 116.4, 115.2, 114.1,
114.0, 51.6, 46.0, 42.5. HRMS(ESI) m/z: calcd for C23H13N3 [M+Na]+ 358.1315, found 358.1318.
4.3.20. 5-phenyl-1,2,4a,5-tetrahydro-[1,4]oxazino[4,3-a]quinoline-6,6(4H)-dicarbonitrile (3ga)
White solid, m.p. 172-174 oC, 1H NMR (600 MHz, CDCl3) δ 7.58-7.40 (m, 6H), 7.40-7.34 (m,
1H), 6.97-6.84 (m, 2H), 4.03 (dd, J = 11.4, 3.4 Hz, 1H), 3.87 (m, 1H), 3.78 (d, J = 12.8 Hz, 1H),
3.74-3.62 (m, 2H), 3.28 (d, J = 10.7 Hz, 1H), 3.17 (m, 2H). 13C NMR (151 MHz, CDCl3) δ 143.5, 133.2,
131.8, 129.7, 129.4, 129.1, 128.9, 119.5 , 114.6, 114.2, 113.6, 69.9, 66.5, 55.3, 49.4, 45.9. HRMS(ESI)
m/z: calcd for C20H17N3 [M+Na]+ 338.1264, found 338.1265.
Acknowledgements
This work was financially supported by the Basic and Frontier Research Project of Chongqing
(cstc2015jcyjBX0106), and the National Natural Science Foundation of China (No. 21672174 and
No. 21472152).
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