The Cascade Methylation/Cyclization of ortho-Cyanoarylacrylamides with Dicumyl Peroxide

Article abstract of DOI:10.1002/ejoc.201900918

A radical cascade methylation/cyclization of ortho-cyanoarylacrylamides was developed by utilizing dicumyl peroxide as a methylation reagent. This transformation provides a simple and straightforward approach to methylated quinoline-2,4(1H,3H)-diones, and

Full text of DOI:10.1002/ejoc.201900918

A Journal of
Accepted Article
Title: The Cascade Methylation/Cyclization of ortho-
Cyanoarylacrylamides with Dicumyl Peroxide
Authors: Tao Yang, Wen-Jin Xia, Bin Zhou, Yangchun Xin, Yuehai
Shen, and Ya-Min Li
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201900918
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10.1002/ejoc.201900918
European Journal of Organic Chemistry
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The Cascade Methylation/Cyclization of ortho-
Cyanoarylacrylamides with Dicumyl Peroxide
Tao Yang,[a][‡] Wen-Jin Xia,[a][‡] Bin Zhou,[a] Yangchun Xin,[b] Yuehai Shen,[a] and Ya-Min Li*[a]
Abstract:
A
radical cascade methylation/cyclization of ortho-
multi-steps synthesis.[11] Recently, the cascade cyclization have
been developed for the construction of quinoline-2,4-diones by
our and other groups.[12] We disclosed a radical cascade
cyclization of ortho-cyanoarylacrylamides with CF3SO2Na to
form trifluoromethylated quinoline-2,4(1H,3H)-diones, in which
the cyclization was achieved through an intermolecular addition
of a trifluoromethyl radical to an activated alkene and an
intramolecular addition of alkyl radical to a cyano group.[12b] We
reasoned that the methyl substituted quinoline-2,4(1H,3H)-
diones might be also constructed if the trifluoromethyl radical
was replaced by a methyl radical. Herein, we report a radical
cascade methylation/cyclization of ortho-cyanoarylacrylamides
and dicumyl peroxide to give methylated quinoline-2,4(1H,3H)-
diones. (Scheme 1)
cyanoarylacrylamides was developed by utilizing dicumyl peroxide
as a methylation reagent. This transformation provides a simple and
straightforward approach to methylated quinoline-2,4(1H,3H)-diones,
and exhibits a wide substrate scope. Furthermore, this reaction
could be readily scaled up. A possible mechanism is also proposed.
Introduction
The methyl group is well known as one of the most important
functional groups in drugs and biologically active compounds
because such group could significantly impact the
pharmacological and biological properties of the molecule.[1]
Various reagents including methylborons, organometals, MeI,
MeOH, MeCO2H, DMF and DMSO, have been used as methyl
sources in the methylation.[2] Peroxides are commonly used as
radical initiators and oxidants because homolysis of its O-O
band could provide alkoxy or acyloxy radicals, which may
undergo further -cleavage to generate the alkyl radical.[3] Since
the pioneering studies by Kawazoe and co-workers,
demonstrated a methylation of the protonated nucleobases by
using tert-butyl hydroperoxide (TBHP) as the methylation
reagent,[4a]
a
series of peroxides such as tert-butyl
peroxybenzoate (TBPB), di-tert-butyl peroxide (DTBP), cumyl
hydroperoxide (CHP), and dicumyl peroxide (DCP), have been
successfully applied to the methylation of (hetero)arenes,[4]
alkenes,[5] carboxylic acids/amides,[6] sulfoximines,[7] and
isocyanides.[8] Although these advances have been made,
developing new methylation to construct valuable molecules is
still desirable.
In the past decades, the derivatives of quinoline-2,4-diones
have drawn much attention due to their varied biological
activities including antibacterial, antiplatelet, and herbicidal.[9]
Additionally, they are key precursors for the construction of
novel molecules and natural products.[10] Despite many methods
have been developed to synthesize such compounds, most of
them were limited in practical applications due to the
requirements of commercially unavailable starting materials and
Scheme 1. Radical cascade cyclization of ortho-cyanoarylacrylamides.
Results and Discussion
Our initial studies began with the reaction of N-(2-
cyanophenyl)-N-methylmethacrylamide 1a with DCP using Cu2O
as a catalyst in PhCl/H2O [2/1 (v/v)] at 110 °C for 24 h, and the
desired quinoline-2,4(1H,3H)-dione 2a was obtained in 52%
yield (Table 1, entry 1). A variety of copper salts including CuCl2,
CuCl, Cu(ClO4)2·6H2O, and CuF2, were subsequently tested,
and the results suggested that CuF2 was the best choice (entries
2-5). The effect of the amount of CuF2 was also examined, and 5
mol% of CuF2 proven to be more efficient than others (entries 5-
7). We also investigated other methyl sources including TBHP,
TBPB and DTBP, however, they proved to be less efficient than
DCP (entries 8-10). Especially, no product was observed when
TBHP was employed as the methyl source (entry 8). Solvent
screening revealed that DMSO/H2O [3/1 (v/v)] was the optimal
solvent for this cascade reaction (entries 11-17). Quinolinedione
2a was obtained in 89% yield when increasing the reaction
temperature from 110 to 130 °C (entry 18). Further elevating the
temperature negatively affected the cascade reaction (entry 19).
It should be noted that the reaction still worked well in the
[a]
T. Yang, W.-J. Xia, B. Zhou, Prof. Y. Shen and Prof. Y.-M. Li
Faculty of Life Science and Technology
Kunming University of Science and Technology
Kunming 650500, P. R. China
E-mail: liym@kmust.edu.cn
[b]
Dr. Y. Xin
Katzin Diagnostic & Research PET/MR Center
Nemours/Alfred I. DuPont Hospital for Children
Wilmington, DE 19803, United States
These authors contributed equally.
[‡]
Supporting information for this article is given via a link at the end of
the document.
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10.1002/ejoc.201900918
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absence of CuF2, giving 2a in a slightly lower yield (entry 20),
which suggested that the copper salt acts as a promoter rather
than a catalyst in this transformation.
transformation (2e-2g). Multi-substituted acrylamide was also
reacted well with DCP, giving the product 2s in 70% yield.
What’s more, the acrylamides bearing a variety of substituents
including phenyl, benzyl, phthalimide and ester at the  position
of carbon-carbon double bond also exhibited a high reactivity,
affording the products 2t-2w in moderate yields (61-71%).
However, the mono-substituted alkene (R3 = H) failed to form
the desired product 2x though the substrate was consumed in
the optimized conditions. Nonterminal alkene (R4 = Me) was
compatible with the system, providing 2y in 66% yield.
Additionally, heterocyclic substrate pyridineacrylamide also
exhibited good efficiency and the corresponding quinoline-2,4-
dione 2z was obtained in 71% yield.
Table 1. Reaction conditions screening.[a]
Entry
Metal salt (mol%)
Cu2O (5)
Solvent (v/v)
Yield (%)[b]
1
2
3
PhCl/H2O (2/1)
PhCl/H2O (2/1)
PhCl/H2O (2/1)
52
68
70
CuCl2 (5)
Table 2. Substrate scope [a,b]
CuCl (5)
4
Cu(ClO4)2·6H2O (5)
CuF2 (5)
CuF2 (3)
CuF2 (10)
CuF2 (5)
CuF2 (5)
CuF2 (5)
CuF2 (5)
CuF2 (5)
CuF2 (5)
CuF2 (5)
CuF2 (5)
CuF2 (5)
CuF2 (5)
CuF2 (5)
CuF2 (5)
-
PhCl/H2O (2/1)
PhCl/H2O (2/1)
PhCl/H2O (2/1)
PhCl/H2O (2/1)
PhCl/H2O (2/1)
PhCl/H2O (2/1)
PhCl/H2O (2/1)
Toluene/H2O (2/1)
DMF/H2O (2/1)
THF/H2O (2/1)
DCE/H2O (2/1)
DMSO/H2O (2/1)
DMSO/H2O (1/1)
DMSO/H2O (3/1)
DMSO/H2O (3/1)
DMSO/H2O (3/1)
DMSO/H2O (3/1)
71
74
63
69
0
5
6
7
8[c]
9[d]
10[e]
11
12
13
14
15
16
17
18[f]
19[g]
20[f]
62
59
61
73
Trace
41
79
71
83
89
76
72
[a] Reaction conditions: 1a (0.30 mmol), dicumyl peroxide (3.0 equiv), and
metal salt in 3.0 mL solvent at 110 °C for 24 h under air. [b] Isolated yield. [c]
TBHP (70% solution in water) instead of DCP. [d] TBPB instead of DCP. [e]
DTBP instead of DCP. [f] The reaction was carried out at 130 oC. [g] The
reaction was carried out at 140 oC.
With the optimal conditions in hand, we next investigated the
substrate scope (Table 2). Initially, the effect of substituted
groups on the nitrogen atom were examined. The N-methyl and
N-benzyl acrylamides reacted well with DCP providing the
products 2a and 2b, respectively, in good yields. However, N-H
and N-acetyl substrates were not compatible with the system.
No the desired products 2c and 2d could be detected though the
substrates were consumed. The acrylamides with electron-
donating or electron-withdrawing substituents, such as MeO, Me,
Cl, Br, F and CF3 on aromatic ring, were tolerated for this
cascade reaction, giving the quinoline-2,4-diones 2e-2r in good
[a] Reaction conditions: 1a (0.3 mmol), DCP (3.0 equiv), and CuF2 (5 mol%) in
3 mL DMSO/H2O [3/1 (v/v)] at 130 °C for 24 h. [b] Isolated yield.
This cascade methylation/cyclization could also occur under
metal-free conditions. As shown in Table 3, a variety of ortho-
cyanoarylacrylamides reacted well with DCP in the absence of
CuF2, provided the corresponding quinoline-2,4-diones in slightly
lower yields (2a, 2b, 2e, 2f, 2g, 2k, 2l, 2p, 2q and 2s).
yields. Ortho-substituted substrates also showed
a high
reactivity, which implied that steric effect was not obvious in this
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10.1002/ejoc.201900918
European Journal of Organic Chemistry
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Table 3. Metal-free cascade methylation/cyclization [a,b]
Scheme 3. Radical-trapping experiments.
Based on the experimental results and the literatures,4e,8a,12
a
plausible mechanism for the methylation/cyclization cascade is
proposed in Scheme 4. The thermal homolytic cleavage of DCP
generate the cumyloxyl radical, which underwent the -cleavage
to afford the methyl radical and acetophenone. Subsequently,
the methyl radical added to the carbon-carbon double bond of
acrylamide 1a, providing an alkyl radical A, which then attacked
to cyano group leading to an imine radical intermediate B.
Intermediate B furnished a H-abstraction to afford the imine C,
followed by hydrolysis with H2O giving the final product 2a.[13]
CuF2, as a Lewis acid, probably coordinated with O-atom of the
,-unsaturated alkene to increase the activity of carbon-carbon
double bond. It might also be used to stabilize the radical
intermediates generated in the reaction.[14] The pathway by
oxidizing intermediate B into an imine cation cannot be ruled out.
[a] Reaction conditions: 1a (0.3 mmol) and DCP (3.0 equiv) in
DMSO/H2O [3/1 (v/v)] at 130 °C for 24 h. [b] Isolated yield.
3 mL
A large-scale reaction was performed to demonstrate the
synthetic utility of this transformation (Scheme 2). When 9.0
mmol of N-(2-cyanophenyl)-N-methylmethacrylamide 1a was
treated with DCP, the product 2a was obtained in 80% yield,
which revealed that the cascade methylation/cyclization could be
readily scaled up without loss of efficiency.
Scheme 2. Gram-scale reaction.
Scheme 4. Proposed mechanism.
In order to investigate the mechanism for this reaction, several
radical-trapping experiments were conducted (Scheme 3). It was
found that the cascade process was almost completely
suppressed when 2,6-di-tert-butyl-4-methylphenol (BHT) or
2,2,6,6-tetramethyl-1-piperidinyloxy (TEMPO) was added, and
TEMPO−CH3 could be detected by HRMS (Scheme 3a). When
1,1-diphenylethylene was added to the standard reaction
conditions, inhibition of the reaction was also observed, and
alkene 3 was detected by HRMS (Scheme 3b). These results
illustrated that a radical pathway might be involved in the
reaction.
Conclusions
In conclusion, we have disclosed
a radical cascade
methylation/cyclization of ortho-cyanoarylacrylamides by utilizing
dicumyl peroxide as a methylation reagent. The present reaction
generates two carbon-carbon bonds in a single step, providing a
simple and straightforward way to construct a variety of methyl
substituted quinoline-2,4(1H,3H)-diones.
Experimental Section
General information
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10.1002/ejoc.201900918
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1H NMR, 13C NMR and spectra were recorded on Bruker AVANCE III HD
600 (600 MHz for 1H; 151 MHz for 13C) instruments internally referenced
to tetramethylsilane (TMS) signal. Chemical shifts (δ) and coupling
constants (J) were expressed in ppm and Hz, respectively. CDCl3 was
used as the NMR solvent in all cases. Mass spectra were mearsured
using Thermo LTQ Orbitrap XL spectrometer. IR spectra were recorded
on a Bruker Tensor 27 FT-IR spectrometer and only major peaks are
reported in cm-1. Unless otherwise noted, materials were obtained from
commercial suppliers and used without further purification. Column
chromatography was carried out on silica gel (particle size 200-300 mesh
ASTM).
9.2. IR (KBr, cm−1) υ 2981, 1659, 1631, 1339, 1297, 1181, 1123, 983,
874, 766, 685, 543. HRMS (ESI): calcd for C13H14ClNO2 [M+H]+,
252.0786; found, 252.0789.
5-Bromo-3-ethyl-1,3-dimethylquinoline-2,4(1H,3H)-dione (2g). The
product was isolated by column chromatography (petroleum ethyl/ethyl
acetate = 15/1, v/v). White solid (60 mg, 70% yield); mp: 80–82 oC. 1H
NMR (600 MHz, CDCl3) δ 7.42 (dd, J = 8.0, 0.9 Hz, 1H), 7.36 (t, J = 8.1
Hz, 1H), 7.13 (dd, J = 8.3, 0.7 Hz, 1H), 3.45 (d, J = 3.8 Hz, 3H), 1.87 (dt,
J = 10.3, 6.1 Hz, 2H), 1.44 (s, 3H), 0.86 (t, J = 7.5 Hz, 3H). 13C NMR (151
MHz, CDCl3) δ 196.3, 172.4, 144.3, 134.0, 129.7, 122.3, 120.6, 114.1,
58.7, 31.9, 30.6, 17.3, 9.2. IR (KBr, cm−1) υ 2972, 2937, 1695, 1603,
1473, 1371, 1252, 1102, 967, 756, 664, 456. HRMS (ESI): calcd for
C13H14BrNO2 [M+H]+, 296.0281; found, 296.0283.
General procedure for the methylation/cyclization of ortho-
cyanoarylacrylamides with dicumyl peroxide
3-Ethyl-1,3,6-trimethylquinoline-2,4(1H,3H)-dione (2h). The product
was isolated by column chromatography (petroleum ethyl/ethyl acetate =
15/1, v/v). White solid (57 mg, 82% yield); mp: 93–94 oC. 1H NMR (600
MHz, CDCl3) δ 7.81 (d, J = 1.4 Hz, 1H), 7.43 (dd, J = 8.4, 1.7 Hz, 1H),
7.06 (d, J = 8.4 Hz, 1H), 3.46 (s, 3H), 2.37 (s, 3H), 2.06–1.90 (m, 2H),
1.45 (s, 3H), 0.78 (t, J = 7.4 Hz, 3H). 13C NMR (151 MHz, CDCl3) δ 197.8,
173.6, 141.1, 136.7, 132.7, 127.9, 120.3, 114.7, 57.8, 32.7, 29.7, 22.0,
20.3, 9.5. IR (KBr, cm−1) υ 2984, 1664, 1611, 1474, 1352, 1295, 1184,
1069, 879, 610, 565, 475. HRMS (ESI): calcd for C14H17NO2 [M+H]+,
232.1332; found, 232.1331.
ortho-Cyanoarylacrylamide 1 (0.30 mmol), dicumyl peroxide (0.90
mmol), CuF2 (0.015 mmol) and DMSO/H2O [3.0 mL, 3/1 (v/v)] were
added in a sealed tube with a Teflon lined cap. The mixture was allowed
to stir at 130 oC for 24 hours. After cooling down to room temperature,
ethyl acetate was added, and the mixture was washed with H2O. The
organic phase was dried over anhydrous Na2SO4, and filtered. The
filtrate was concentrated by rotary evaporation and purified by flash
chromatography on silica gel with petroleum ether/ethyl acetate as the
eluent to afford the corresponding product 2.
3-Ethyl-1,3-dimethylquinoline-2,4(1H,3H)-dione (2a). The product was
isolated by column chromatography (petroleum ethyl/ethyl acetate = 15/1,
v/v). Colorless oil (58 mg, 89% yield). 1H NMR (600 MHz, CDCl3) δ 7.93
(d, J = 7.4 Hz, 1H), 7.55 (t, J = 7.5 Hz, 1H), 7.10 (t, J = 7.3 Hz, 2H), 3.40
3-Ethyl-6-fluoro-1,3-dimethylquinoline-2,4(1H,3H)-dione (2i). The
product was isolated by column chromatography (petroleum ethyl/ethyl
acetate = 15/1, v/v). White solid (52 mg, 74% yield); mp: 100–102 oC. 1H
NMR (600 MHz, CDCl3) δ 7.68 (dd, J = 8.0, 3.1 Hz, 1H), 7.34 (ddd, J =
9.1, 7.5, 3.1 Hz, 1H), 7.15 (dd, J = 9.1, 4.0 Hz, 1H), 3.48 (s, 3H), 2.08–
1.89 (m, 2H), 1.46 (s, 3H), 0.79 (t, J = 7.4 Hz, 3H). 13C NMR (151 MHz,
CDCl3) δ 196.8 (d, J = 1.7 Hz), 173.3, 158.4 (d, J = 245.1 Hz), 139.6 (d, J
= 2.3 Hz), 122.8 (d, J = 23.4 Hz), 121.6 (d, J = 6.1 Hz), 116.5 (d, J = 7.1
Hz), 113.7 (d, J = 23.2 Hz), 57.8, 32.7, 30.0, 21.8, 9.4. IR (KBr, cm−1) υ
2985, 1710, 1667, 1587, 1459, 1344, 1281, 1186, 961, 787, 528, 461.
HRMS (ESI): calcd for C13H14FNO2 [M+H]+, 236.1081; found, 236.1081.
(s, 3H), 1.98–1.82 (m, 2H), 1.38 (s, 3H), 0.71 (t, J = 7.3 Hz, 3H). 13
C
NMR (151 MHz, CDCl3) δ 197.6, 173.8, 143.2, 135.9, 128.0, 123.0,
120.4, 114.7, 57.9, 32.7, 29.7, 22.0, 9.5. IR (KBr, cm−1) υ 2963, 1701,
1663, 1600, 1468, 1334, 1179, 1002, 823, 770, 696, 492. HRMS (ESI):
calcd for C13H15NO2 [M+H]+, 218.1176; found, 218.1174.
1-Benzyl-3-ethyl-3-methylquinoline-2,4(1H,3H)-dione
(2b).
The
product was isolated by column chromatography (petroleum ethyl/ethyl
acetate = 9/1, v/v). White solid (57 mg, 65% yield); mp: 82–83 oC. 1H
NMR (600 MHz, CDCl3) δ 8.01 (dd, J = 7.7, 1.6 Hz, 1H), 7.51–7.43 (m,
1H), 7.33 (t, J = 7.5 Hz, 2H), 7.27–7.21 (m, 3H), 7.18–7.09 (m, 1H), 7.04
(d, J = 8.4 Hz, 1H), 5.41 (d, J = 15.6 Hz, 1H), 5.19 (d, J = 15.5 Hz, 1H),
2.21–1.92 (m, 2H), 1.54 (s, 3H), 0.87 (t, J = 7.4 Hz, 4H). 13C NMR (151
MHz, CDCl3) δ 197.4, 174.0, 142.5, 136.2, 135.8, 128.9, 128.0, 127.4,
126.3, 123.1, 120.6, 115.6, 58.0, 46.2, 32.4, 21.9, 9.5. IR (KBr, cm−1) υ
2985, 1709, 1668, 1589, 1459, 1346, 1189, 1052, 960, 790, 638, 547.
HRMS (ESI): calcd for C19H19NO2 [M+H]+, 294.1489; found, 294.1490.
6-Chloro-3-ethyl-1,3-dimethylquinoline-2,4(1H,3H)-dione (2j). The
product was isolated by column chromatography (petroleum ethyl/ethyl
acetate = 15/1, v/v). White solid (60 mg, 79% yield); mp: 80–81 oC. 1H
NMR (600 MHz, CDCl3) δ 7.96 (d, J = 2.6 Hz, 1H), 7.57 (dd, J = 8.8, 2.6
Hz, 1H), 7.12 (d, J = 8.8 Hz, 1H), 3.47 (s, 3H), 2.07–1.87 (m, 2H), 1.46 (s,
3H), 0.79 (t, J = 7.4 Hz, 3H). 13C NMR (151 MHz, CDCl3) δ 196.5, 173.4,
141.7, 135.5, 128.8, 127.4, 121.4, 116.3, 58.0, 32.7, 29.9, 21.7, 9.4. IR
(KBr, cm−1) υ 2978, 1682, 1590, 1475, 1374, 1254, 1174, 1074, 844, 796,
683, 478. HRMS (ESI): calcd for C13H14ClNO2 [M+H]+, 252.0786; found,
252.0787.
3-Ethyl-5-fluoro-1,3-dimethylquinoline-2,4(1H,3H)-dione (2e). The
product was isolated by column chromatography (petroleum ethyl/ethyl
acetate = 15/1, v/v). White solid (50 mg, 71% yield); mp: 77–79 oC. 1H
NMR (600 MHz, CDCl3) δ 7.54 (td, J = 8.4, 5.8 Hz, 1H), 6.96 (d, J = 8.4
Hz, 1H), 6.92–6.83 (m, 1H), 3.47 (s, 3H), 2.02–1.84 (m, 2H), 1.45 (s, 3H),
0.84 (t, J = 7.4 Hz, 3H). 13C NMR (151 MHz, CDCl3) δ 194.8, 173.0,
161.9 (d, J = 264.9 Hz), 144.2 (d, J = 3.5 Hz), 135.7 (d, J = 11.6 Hz),
111.2 (d, J = 21.6 Hz), 110.4 (d, J = 3.6 Hz), 110.3, 58.8, 32.1, 30.5, 19.8,
9.3. IR (KBr, cm−1) υ 2971 1699, 1597, 1463, 1338, 1097, 968, 848, 738,
654, 543, 473. HRMS (ESI): calcd for C13H14FNO2 [M+H]+, 236.1081;
found, 236.1082.
6-Bromo-3-ethyl-1,3-dimethylquinoline-2,4(1H,3H)-dione (2k). The
product was isolated by column chromatography (petroleum ethyl/ethyl
acetate = 15/1, v/v). White solid (65 mg, 73% yield); mp: 70–71 oC. 1H
NMR (600 MHz, CDCl3) δ 8.10 (d, J = 2.5 Hz, 1H), 7.70 (dd, J = 8.8, 2.5
Hz, 1H), 7.06 (d, J = 8.8 Hz, 1H), 3.46 (d, J = 4.5 Hz, 3H), 2.07–1.87 (m,
2H), 1.45 (s, 3H), 0.79 (t, J = 7.4 Hz, 3H). 13C NMR (151 MHz, CDCl3) δ
196.3, 173.4, 142.2, 138.3, 130.4, 121.7, 116.6, 116.0, 58.0, 32.7, 29.8,
21.6, 9.4. IR (KBr, cm−1) υ 2967, 1664, 1551, 1412, 1324, 1233, 1131,
966, 737, 696, 591, 438. HRMS (ESI): calcd for C13H14BrNO2 [M+H]+,
296.0281; found, 296.0283.
5-Chloro-3-ethyl-1,3-dimethylquinoline-2,4(1H,3H)-dione (2f). The
product was isolated by column chromatography (petroleum ethyl/ethyl
acetate = 15/1, v/v). White solid (48 mg, 64% yield); mp: 75–76 oC. 1H
NMR (600 MHz, CDCl3) δ 7.45 (t, J = 8.2 Hz, 1H), 7.20 (d, J = 8.0 Hz,
1H), 7.08 (d, J = 8.4 Hz, 1H), 3.45 (s, 3H), 1.88 (q, J = 7.5 Hz, 2H), 1.44
(s, 3H), 0.85 (t, J = 7.5 Hz, 3H). 13C NMR (151 MHz, CDCl3) δ 195.8,
172.5, 144.2, 134.6, 133.9, 126.1, 119.3, 113.4, 59.0, 31.8, 30.6, 17.5,
3-Ethyl-1,3,7-trimethylquinoline-2,4(1H,3H)-dione (2l). The product
was isolated by column chromatography (petroleum ethyl/ethyl acetate =
15/1, v/v). White solid (59 mg, 85% yield); mp: 62–64 oC. 1H NMR (600
MHz, CDCl3) δ 7.91 (d, J = 7.9 Hz, 1H), 6.99 (d, J = 7.9 Hz, 1H), 6.96 (s,
1H), 3.47 (s, 3H), 2.46 (s, 3H), 2.06–1.90 (m, 2H), 1.45 (s, 3H), 0.77 (t, J
= 7.4 Hz, 3H). 13C NMR (151 MHz, CDCl3) δ 197.2, 174.1, 147.3, 143.3,
128.0, 124.0, 118.2, 115.2, 57.6, 32.8, 29.6, 22.4, 22.3, 9.5. IR (KBr,
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10.1002/ejoc.201900918
European Journal of Organic Chemistry
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cm−1) υ 2972, 1683, 1655, 1609, 1510, 1455, 1299, 1114, 834, 773, 528,
446. HRMS (ESI): calcd for C14H17NO2 [M+H]+, 232.1332; found,
232.1331.
1708, 1674, 1589, 1455, 1345, 1177, 1077, 971, 804, 747, 470. HRMS
(ESI): calcd for C13H14ClNO2 [M+H]+, 252.0786; found, 252.0787.
3-Ethyl-6,7-dimethoxy-1,3-dimethylquinoline-2,4(1H,3H)-dione (2s).
The product was isolated by column chromatography (petroleum
ethyl/ethyl acetate = 4/1, v/v). White solid (58 mg, 70% yield); mp: 154–
155 oC. 1H NMR (600 MHz, CDCl3) δ 7.49 (s, 1H), 6.61 (s, 1H), 4.02 (s,
3H), 3.93 (s, 3H), 3.49 (s, 3H), 2.10–1.92 (m, 2H), 1.45 (s, 3H), 0.76 (t, J
= 7.4 Hz, 3H). 13C NMR (151 MHz, CDCl3) δ 196.2, 174.3, 155.5, 145.1,
139.5, 113.0, 108.7, 98.0, 57.1, 56.4, 56.2, 33.1, 29.7, 23.2, 9.6. IR (KBr,
cm−1) υ 2975, 2938, 1679, 1603, 1522, 1428, 1331, 1249, 1155, 825, 786,
534. HRMS (ESI): calcd for C15H19NO4 [M+H]+, 278.1387; found,
278.1385.
3-Ethyl-7-methoxy-1,3-dimethylquinoline-2,4(1H,3H)-dione (2m). The
product was isolated by column chromatography (petroleum ethyl/ethyl
acetate = 8/1, v/v). White solid (60 mg, 81% yield); mp: 53–54 oC. 1H
NMR (600 MHz, CDCl3) δ 8.00 (d, J = 8.7 Hz, 1H), 6.70 (dd, J = 8.7, 2.2
Hz, 1H), 6.61 (d, J = 2.2 Hz, 1H), 3.92 (s, 3H), 3.46 (d, J = 5.7 Hz, 3H),
2.09–1.88 (m, 2H), 1.45 (s, 3H), 0.76 (t, J = 7.4 Hz, 3H). 13C NMR (151
MHz, CDCl3) δ 196.0, 174.3, 165.8, 145.2, 130.4, 114.3, 108.1, 100.7,
57.2, 55.7, 33.0, 29.6, 22.7, 9.5. IR (KBr, cm−1) υ 2971, 1655, 1604, 1459,
1314, 1233, 1177, 1098, 976, 845, 767, 602. HRMS (ESI): calcd for
C14H17NO3 [M+H]+, 248.1281; found, 248.1281.
3-Benzyl-3-ethyl-1-methylquinoline-2,4(1H,3H)-dione
(2t).
The
3-Ethyl-7-fluoro-1,3-dimethylquinoline-2,4(1H,3H)-dione (2n). The
product was isolated by column chromatography (petroleum ethyl/ethyl
acetate = 15/1, v/v). White solid (57 mg, 81% yield); mp: 84–85 oC. 1H
NMR (600 MHz, CDCl3) δ 8.05 (dd, J = 8.5, 6.7 Hz, 1H), 6.92–6.79 (m,
2H), 3.45 (s, 3H), 2.08–1.88 (m, 2H), 1.46 (s, 3H), 0.78 (t, J = 7.4 Hz, 3H).
13C NMR (151 MHz, CDCl3) δ 196.0, 173.9, 167.4 (d, J = 255.7 Hz),
145.5 (d, J = 11.6 Hz), 130.9 (d, J = 11.1 Hz), 117.0 (d, J = 2.5 Hz),
110.3 (d, J = 22.2 Hz), 102.3 (d, J = 27.5 Hz), 57.8, 32.8, 29.8, 22.1, 9.4.
IR (KBr, cm−1) υ 2967, 1689, 1659, 1613, 1591, 1463, 1301, 1213, 1110,
862, 771, 466. HRMS (ESI): calcd for C13H14FNO2 [M+H]+, 236.1081;
found, 236.1082.
product was isolated by column chromatography (petroleum ethyl/ethyl
acetate = 10/1, v/v). White solid (62 mg, 71% yield); mp: 56–57 oC. 1H
NMR (600 MHz, CDCl3) δ 7.94 (dd, J = 7.8, 1.5 Hz, 1H), 7.49–7.42 (m,
1H), 7.05 (t, J = 7.5 Hz, 1H), 7.02–6.93 (m, 5H), 6.87 (d, J = 8.3 Hz, 1H),
3.32 (s, 3H), 3.26 (s, 2H), 2.29–2.15 (m, 2H), 0.76 (dd, J = 12.6, 5.2 Hz,
3H). 13C NMR (151 MHz, CDCl3) δ 197.5, 172.6, 143.0, 135.9, 135.7,
129.4, 127.7, 127.2, 126.6, 122.7, 121.3, 114.4, 63.9, 46.5, 32.6, 29.2,
9.7. IR (KBr, cm−1) υ 2935, 1690, 1655, 1601, 1473, 1364, 1301, 1246,
1101, 760, 702, 522. HRMS (ESI): calcd for C19H19NO2 [M+H]+,
294.1489; found, 294.1489.
3-Ethyl-1-methyl-3-phenylquinoline-2,4(1H,3H)-dione
(2u).
The
7-Chloro-3-ethyl-1,3-dimethylquinoline-2,4(1H,3H)-dione (2o). The
product was isolated by column chromatography (petroleum ethyl/ethyl
acetate = 15/1, v/v). White solid (61 mg, 81% yield); mp: 85–86 oC. 1H
NMR (600 MHz, CDCl3) δ 7.95 (d, J = 8.3 Hz, 1H), 7.19–7.12 (m, 2H),
product was isolated by column chromatography (petroleum ethyl/ethyl
acetate = 10/1, v/v). White solid (55 mg, 66% yield); mp: 95–96 oC. 1H
NMR (600 MHz, CDCl3) δ 7.99 (dd, J = 8.0, 1.5 Hz, 1H), 7.58 (td, J = 8.1,
1.6 Hz, 1H), 7.30–7.17 (m, 5H), 7.14 (t, J = 7.5 Hz, 2H), 3.56 (s, 3H),
2.55 (dq, J = 14.4, 7.2 Hz, 1H), 2.42 (dq, J = 14.5, 7.3 Hz, 1H), 0.93 (t, J
= 7.2 Hz, 3H). 13C NMR (151 MHz, CDCl3) δ 195.1, 171.4, 142.8, 138.8,
135.9, 128.9, 128.1, 127.7, 126.4, 123.1, 121.4, 114.8, 67.3, 30.2, 29.9,
10.6. IR (KBr, cm−1) υ 2968, 2222, 1720, 1593, 1471, 1345, 1263, 1144,
1057, 800, 698, 504. HRMS (ESI): calcd for C18H17NO2 [M+H]+,
280.1332; found, 280.1334.
3.47 (s, 3H), 2.06–1.88 (m, 2H), 1.46 (s, 3H), 0.78 (t, J = 7.4 Hz, 3H). 13
C
NMR (151 MHz, CDCl3) δ 196.4, 173.7, 144.2, 142.2, 129.4, 123.2,
118.7, 115.0, 58.0, 32.8, 29.8, 21.9, 9.5. IR (KBr, cm−1) υ 2981, 1699,
1663, 1599, 1545, 1432, 1337, 1289, 1101, 855, 770, 656. HRMS (ESI):
calcd for C13H14ClNO2 [M+H]+, 252.0786; found, 252.0787.
7-Bromo-3-ethyl-1,3-dimethylquinoline-2,4(1H,3H)-dione (2p). The
product was isolated by column chromatography (petroleum ethyl/ethyl
acetate = 15/1, v/v). White solid (70 mg, 79% yield); mp: 75–76 oC. 1H
NMR (600 MHz, CDCl3) δ 7.87 (d, J = 8.2 Hz, 1H), 7.37–7.28 (m, 2H),
3-((1,3-Dioxoisoindolin-2-yl)methyl)-3-ethyl-1-methylquinoline-
2,4(1H,3H)-dione (2v). The product was isolated by column
chromatography (petroleum ethyl/ethyl acetate = 3/1, v/v). White solid (66
mg, 61% yield); mp: 125–126 oC. 1H NMR (600 MHz, CDCl3) δ 8.02 (dd,
J = 8.0, 1.6 Hz, 1H), 7.79–7.72 (m, 2H), 7.70–7.63 (m, 2H), 7.63–7.57 (m,
1H), 7.16 (dd, J = 7.7, 6.5 Hz, 2H), 4.15 (q, J = 13.6 Hz, 2H), 3.49 (s, 3H),
2.24–2.02 (m, 2H), 0.81 (t, J = 7.4 Hz, 3H). 13C NMR (151 MHz, CDCl3) δ
194.3, 171.0, 168.2, 143.2, 136.0, 133.9, 131.7, 128.1, 123.3, 123.0,
120.7, 114.8, 60.7, 43.2, 30.3, 29.8, 9.2. IR (KBr, cm−1) υ 2919, 1724,
1659, 1599, 1473, 1395, 1060, 1008, 927, 839, 524, 471. HRMS (ESI):
calcd for C21H18N2O4 [M+Na]+, 385.1159; found, 385.1159.
3.46 (s, 3H), 2.06–1.87 (m, 2H), 1.45 (s, 3H), 0.78 (t, J = 7.4 Hz, 3H). 13
C
NMR (151 MHz, CDCl3) δ 196.6, 173.7, 144.1, 130.9, 129.3, 126.2,
119.1, 117.9, 58.0, 32.8, 29.8, 21.9, 9.4. IR (KBr, cm−1) υ 2968, 1699,
1666, 1591, 1427, 1337, 1102, 1084, 894, 764, 534, 469. HRMS (ESI):
calcd for C13H14BrNO2 [M+H]+, 296.0281; found, 296.0284.
3-Ethyl-1,3-dimethyl-7-(trifluoromethyl)quinoline-2,4(1H,3H)-dione
(2q). The product was isolated by column chromatography (petroleum
ethyl/ethyl acetate = 15/1, v/v). White solid (65 mg, 76% yield); mp: 78–
o
80 C. 1H NMR (600 MHz, CDCl3) δ 8.12 (d, J = 8.0 Hz, 1H), 7.43 (dd, J
(3-Ethyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinolin-3-yl)methyl
acetate (2w). The product was isolated by column chromatography
(petroleum ethyl/ethyl acetate = 7/1, v/v). White solid (52 mg, 63% yield);
mp: 91–92 oC. 1H NMR (600 MHz, CDCl3) δ 8.05 (dd, J = 7.9, 1.3 Hz,
1H), 7.71–7.65 (m, 1H), 7.25–7.19 (m, 2H), 4.60 (dd, J = 52.1, 10.0 Hz,
2H), 3.54 (s, 3H), 2.02–1.89 (m, 2H), 1.86 (s, 3H), 0.80 (t, J = 7.5 Hz, 3H).
13C NMR (151 MHz, CDCl3) δ 195.2, 171.4, 170.2, 143.3, 136.5, 127.8,
123.2, 120.9, 115.0, 67.8, 60.8, 30.5, 29.7, 20.6, 8.6. IR (KBr, cm−1) υ
2970, 1661, 1602, 1474, 1368, 1235, 1109, 1044, 868, 757, 664, 429.
HRMS (ESI): calcd for C15H17NO4 [M+Na]+, 298.1050; found, 298.1051.
= 8.0, 0.5 Hz, 1H), 7.39 (s, 1H), 3.53 (s, 3H), 2.07–1.90 (m, 2H), 1.48 (s,
3H), 0.80 (t, J = 7.4 Hz, 3H). 13C NMR (151 MHz, CDCl3) δ 196.7, 173.3,
143.5, 137.0 (q, J = 32.7 Hz), 128.8, 123.2 (q, J = 273.3 Hz), 122.5,
119.4 (q, J = 3.5 Hz), 111.8 (q, J = 3.9 Hz), 58.3, 32.6, 29.9, 21.4, 9.4. IR
(KBr, cm−1) υ 2998, 1705, 1672, 1621, 1509, 1443, 1339, 1287, 1134,
970, 871, 689. HRMS (ESI): calcd for C14H14F3NO2 [M+H]+, 286.1049;
found, 286.1047.
8-Chloro-3-ethyl-1,3-dimethylquinoline-2,4(1H,3H)-dione (2r). The
product was isolated by column chromatography (petroleum ethyl/ethyl
acetate = 20/1, v/v). White solid (60 mg, 79% yield); mp: 81–82 oC. 1H
NMR (600 MHz, CDCl3) δ 7.76 (dd, J = 7.6, 1.4 Hz, 1H), 7.61 (dd, J = 7.9,
1.4 Hz, 1H), 7.15 (t, J = 7.8 Hz, 1H), 3.57 (s, 3H), 1.87 (dq, J = 14.8, 7.4
Hz, 1H), 1.79 (dq, J = 14.7, 7.4 Hz, 1H), 1.42 (s, 3H), 0.80 (t, J = 7.4 Hz,
3H). 13C NMR (151 MHz, CDCl3) δ 197.5, 173.8, 141.9, 137.8, 125.9,
125.6, 125.0, 122.5, 58.4, 37.1, 32.1, 17.7, 9.1. IR (KBr, cm−1) υ 2974,
3-Isopropyl-1,3-dimethylquinoline-2,4(1H,3H)-dione (2y). The product
was isolated by column chromatography (petroleum ethyl/ethyl acetate =
15/1, v/v). White solid (46 mg, 66% yield); mp: 70–71 oC. 1H NMR (600
MHz, CDCl3) δ 7.94 (dd, J = 7.7, 1.6 Hz, 1H), 7.60 (ddd, J = 8.4, 7.4, 1.7
Hz, 1H), 7.19–7.10 (m, 2H), 3.46 (s, 3H), 2.19 (hept, J = 6.9 Hz, 1H),
1.41 (s, 3H), 0.93 (d, J = 6.9 Hz, 3H), 0.83 (d, J = 6.9 Hz, 3H). 13C NMR
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10.1002/ejoc.201900918
European Journal of Organic Chemistry
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(151 MHz, CDCl3) δ 197.8, 173.6, 143.1, 135.5, 127.6, 122.9, 121.4,
114.5, 61.1, 37.4, 29.7, 17.8, 17.7, 14.6. IR (KBr, cm−1) υ 2964, 1701,
1662, 1602, 1477, 1396, 1190, 1096, 971, 769, 754, 671. HRMS (ESI):
calcd for C14H17NO2 [M+H]+, 232.1332; found, 232.1332.
Li, L. Zhang, A. Shoberu, J.-P. Zou, W. Zhang, Green. Chem. 2017, 19,
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3-Ethyl-1,3-dimethyl-1,8-naphthyridine-2,4(1H,3H)-dione (2z). The
product was isolated by column chromatography (petroleum ethyl/ethyl
acetate = 15/1, v/v). White solid (46 mg, 71% yield); mp: 94–96 oC. 1H
NMR (600 MHz, CDCl3) δ 8.61 (dd, J = 4.8, 2.0 Hz, 1H), 8.26 (dd, J = 7.6,
2.0 Hz, 1H), 7.13 (dd, J = 7.6, 4.8 Hz, 1H), 3.60 (s, 3H), 2.08–1.92 (m,
2H), 1.48 (s, 3H), 0.80 (t, J = 7.4 Hz, 3H). 13C NMR (151 MHz, CDCl3) δ
197.1, 174.3, 154.4, 154.1, 136.4, 118.7, 115.5, 58.2, 32.8, 28.6, 22.1,
9.5. IR (KBr, cm−1) υ 2918, 1667, 1538, 1452, 1308, 1228, 1100, 858,
800, 763, 684, 532. HRMS (ESI): calcd for C12H14N2O2 [M+H]+,
219.1128; found, 219.1127.
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Acknowledgments
This research is supported by the National Natural Science
Foundation of China (Nos. 21662021 and 21871114) and the
Science and Technology Planning Project of Yunnan Province
(No. 2017FB016).
Keywords: Radical reaction • Cyclization • Methylation •
Quinoline-2,4-diones • Dicumyl peroxide
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The hydrogen atom donor might be acetophenone. The hydrogen atom
abstraction from acetophenone by imine radical intermediate
B
generates the imine C and the -carbonyl C-centered radical. The -
carbonyl C-centered radical could be captured by TEMPO, 1,1-
diphenylethylene or N,N-diallyl-4-methylbenzenesulfonamide in the
radical-trapping experiments, and the corresponding products could be
detected by HRMS (for details, see the Supporting Information).
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European Journal of Organic Chemistry
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FULL PAPER
Cascade Cyclization*
Tao Yang, Wen-Jin Xia, Bin Zhou,
Yangchun Xin, Yuehai Shen, Ya-Min Li*
Page No. – Page No.
The Cascade Methylation/Cyclization
of ortho-Cyanoarylacrylamides with
Dicumyl Peroxide
A radical cascade methylation/cyclization of ortho-cyanoarylacrylamides was
developed by utilizing dicumyl peroxide as
a methylation reagent. This
transformation provides a simple and straightforward approach to methylated
quinoline-2,4(1H,3H)-diones, and exhibits a wide substrate scope. Furthermore, this
reaction could be readily scaled up.
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