α-Lithiation and electrophilic substitution of 1,4,4-Trimethyl-3,4- dihydroquinolin-2-one

Article abstract of DOI:10.3390/molecules15117742

Treatment of 1,4,4-trimethyl-3,4-dihydroquinolin-2(1H)-one (2) with lithium diisopropylamide (LDA) followed by a wide range of electrophiles give the corresponding 4,4- dimethyl-3-substituted-3,4-dihydroquinolin-2-ones 3-13, providing a very mild electrop

Full text of DOI:10.3390/molecules15117742

Molecules 2010, 15, 7742-7749; doi:10.3390/molecules15117742
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molecules
ISSN 1420-3049
www.mdpi.com/journal/molecules
Communication
α-Lithiation and Electrophilic Substitution of 1,4,4-Trimethyl-
3,4-dihydroquinolin-2-one
Bouclé Sébastien, Guillard Jérôme * and Viaud-Massuard Marie-Claude
UMR CNRS 6239 GICC, Laboratoire de Chimie Organique & Thérapeutique, UFR des Sciences
Pharmaceutiques, Université François Rabelais de Tours, 31 avenue Monge, 37200 Tours, France
* Author to whom correspondence should be addressed; E-Mail: guillard@univ-tours.fr;
Tel.: +33-(0)2 47 36 72 28; Fax: +33-(0)2 47 36 72 29.
Received: 9 September 2010; in revised form: 27 October 2010 / Accepted: 28 October 2010 /
Published: 29 October 2010
Abstract: Treatment of 1,4,4-trimethyl-3,4-dihydroquinolin-2(1H)-one (2) with lithium
diisopropylamide (LDA) followed by a wide range of electrophiles give the corresponding 4,4-
dimethyl-3-substituted-3,4-dihydroquinolin-2-ones 3-13, providing a very mild electrophilic
substitution of the 4,4-dimethyl-1,2,3,4-tetrahydroquinoline core.
Keywords: tetrahydroquinoline; electrophilic substitution; anti-diabetic agents
1. Introduction
The chemistry of 4,4-dimethyl-3,4-dihydroquinolin-2-one has been the focus of interest of many
investigations during recent years. This growing interest can be explained because quinolinone
derivatives are an important class of natural product exhibiting a broad spectrum of biological
activities. Moreover, substituted or reduced 4,4-dimethyl-3,4-dihydroquinolin-2-ones are the core
structures of many pharmacological agents and drug molecules such as anti-cancer drugs [1,2], anti-
diabetic [3-5] or cardiovascular agents [6], pesticides [7,8] and active components of various dyes
[9-11]. Consequently, synthetic methodologies for preparing dihydroquinolin-2-one derivatives have
attracted considerable interest, and several methods offering good results have been reported [3-12].
The nature, number and relative location of the substituents are the key parameters to consider before
choosing a particular method, however, few methods have been investigated with the aim of obtaining
4,4-dimethyl-3-substituted-3,4-dihydroquinolin-2-ones. We have recently reported the design,
synthesis and biological data of a novel 4,4-dimethyl-1,2,3,4-tetrahydroquinoline-based series of

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PPARγ partial agonists and PPARα/γ dual agonists [3,4]. This study has led to the identification and
optimization of our lead compound 1 (Figure 1), which has noteworthy dual-activity on both subtypes.
Figure 1. Lead compound 1.
O
OH
O
structural variations studied
O
8
5
1
4
N
7
2
N
O
6
3
N
O
1
structural variations
under investigations
Our lead compound 1 possesses an acid head, α-ethoxy-β-phenylpropionic acid moiety, which is a
potent binding moiety for both PPARα and PPARγ, and a cyclic tail, consisting of the 4,4-dimethyl-
1,2,3,4-tetrahydroquinoline skeleton that tolerates more polar substituents. In order to investigate the
impact of changes on the transactivation activity, we decided to substitute position 3 of this cyclic tail.
2. Results and Discussion
Thus, our strategy was to carry out an α-lithiation and an electrophilic substitution on 1,4,4-
trimethyl-3,4-dihydroquinolin-2-one (2). This compound was prepared according to the synthetic
sequence outlined in Scheme 1 [6]. Aniline was treated with 3,3-dimethylacryloyl chloride to give the
corresponding amide, which was cyclized under Friedel-Crafts conditions and then methylated.
Scheme 1. Synthesis of 4,4-trimethyl-3,4-dihydroquinolin-2(1H)-one (2).
O
N
O
NH2
1)
Cl
2) AlCl3, DCM
3) MeI, NaH, DMF
2
86% within 3 steps
We then tried to lithiate 1,4,4-trimethyl-3,4-dihydroquinolin-2(1H)-one with 1 equiv of n-BuLi or
LDA in THF at −10 °C (Scheme 2). The α-anion thus obtained was condensed with methyl iodide,
providing the 3-methyl product in yields of 66% and 81%, respectively. When sodium hydride or
potassium tert-butoxide was used as the strong base, no reaction was observed.

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Scheme 2. Synthesis of compound 3.
N
O
N
O
1) Base, -10oC, THF
2) MeI
2
3
LDA = 81%; nBuLi = 66%,
NaH and t-BuOK= 0%
Consequently a wide range of electrophiles have been assayed in this reaction, and the resulting
products are summarized in Table 1. Most of these electrophilic substitutions gave good yields with no
detectable secondary substitution.
Table 1. Lithiation and Electrophilic Substitution of 2.
N
O
N
O
1) LDA, -10oC, THF
2) E+
E
2
4-13
Entry
E+
E
Producta
Yieldb (%)
1
2
EtI
Et
Bn
4
5
6
7
8
94
99
93
60
99
BnBr
3
Allyl-Br
Allyl
4
Br(CH2)5-Br
PhCHO
CH3-CO-Ph
I2
(CH2)5-Br
CH(OH)Ph
5
c
6
CH3-CH(OH)-Ph
-
7
I
9
88
68
90d
46
75
8
Ac2O
Ac
10
11
12
13
9
PhSO2Cl
PhSO2F
CO2
Cl
10
11
12
PhSO2
COOH
B(OH)2
c
-
B(O-iPr)3
b
c
a: all compounds were characterized by IR, NMR and GCMS. : Yield of isolated material. : no
reaction. d: only chlorinated product was isolated.
Reactions with halogenoalkanes (entries 1-4) provide an access to alkyl derivatives with excellent
yields. Alkylation using dibromoalkane provided a moderate yield of the target product and a cross-
coupling product. In the case of carbonyl derivatives (entries 5, 6, 8 and 11), only ketone did not react
with lithiated species. With sulfonyl compounds as the electrophile, we obtained two different
products, depending on the nature of the anion in the sulfonyl group. The target chlorinated product 11
(entry 9) was synthesized using benzenesulfonyl chloride [13-15]. However, using benzenesulfonyl

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fluoride provided the corresponding sulfonyl product 12 with moderate yield, and unreacted starting
compound 2.
3. Experimental
3.1. General
All reactions requiring anhydrous conditions were conducted in flame dried apparatus under an
atmosphere of argon. THF was freshly distilled from benzophenone-sodium. All reagents and starting
materials were purchased from commercial sources and used as received. All lithiations were carried
out using 2.0 M LDA in tetrahydrofuran/heptane/ethylbenzene (Sigma-Aldrich). Analytical TLC was
carried out on silica gel F254 plates. Visualization was achieved by UV light (254 nm). Flash column
chromatography was carried using Sigma-Aldrich Versaflash silica gel (particle size 20–45 µm).
Melting points (m.p.) were measured on a Büchi B-540 capillary melting point apparatus and are
uncorrected. 1H- and 13C-NMR spectra were recorded in CDCl3 using a Bruker Avance 300 (operating
frequencies: 1H, 300.13 MHz; 13C, 75.47 MHz) FT spectrometer at ambient temperature. The chemical
shifts (δ, ppm) for all compounds are listed in parts per million downfield from tetramethylsilane using
the NMR solvent as an internal reference. The reference values used for deuterated chloroform
(CDCl3) were 7.26 and 77.00 ppm for 1H- and 13C-NMR spectra, respectively. Multiplicities are given
as: s (singlet), brs (broad singlet), d (doublet), t (triplet), dd (doublet of doublets), td (triplet of
doublets) or m (multiplet). Low-resolution mass (MS) were recorded on a Shimadzu GCMS-QP 2010
Gas Chromatograph Mass Spectrometer and reported in units of mass to charge (m/z). The mode of
ionization used was electron-impact (EI).
3.2. General procedure
To a stirring solution of 2 (0.1 g, 0.53 mmol) in THF (5 mL) cooled at −10 °C under an argon
atmosphere was added 0.275 mL of LDA (1.3 equiv., 0.689 mmol, 2.0 M in tetrahydrofuran/heptane/
ethylbenzene). After completion of the addition, the mixture was stirred for 30 min at −10 °C, and then
the appropriate electrophile (1.2 equiv, 0.636 mmol) was added. The reaction mixture was stirred at
−10 °C for 2h and allowed to warm slowly to room temperature before being added dropwise to a
saturated aqueous solution of ammonium chloride (80 mL) and extracted with ethyl acetate (3 ×
40 mL), the combined organic layers were dried over anhydrous magnesium sulfate, and concentrated
in vacuo to afford the crude products, which were purified by column chromatography with
cyclohexane-ethyl acetate as the eluant.
1
1,3,4,4-Tetramethyl-3,4-dihydroquinolin-2(1H)-one (3): Yield 86%; white oil; H-NMR (CDCl3) δ:
1.04 (3H, d, J = 7.2 Hz, CH3), 1.22 (3H, s, CH3), 1.25 (3H, s, CH3), 2.44 (1H, q, J = 7.2 Hz, CH), 3.38
(3H, s, NCH3), 7.01 (1H, d, J = 8.1 Hz, Har), 7.07 (1H, td, J = 7.5, 1.2 Hz, Har), 7.26–7.30 (2H, m, 2 ×
Har); 13C-NMR (CDCl3) δ: 11.4 (CH3), 22.8 (CH3), 27.6 (CH3), 29.6 (CH3), 35.8 (C), 47.3 (CH), 114.8
(CH), 123.3 (CH), 124.8 (CH), 127.3 (CH), 133.9 (C), 138.8 (C), 173.1 (C); MS (EI) m/z 188, 100%
+
[M-CH3 ], 203, 55% [M+]; Calcd for C13H17NO: C, 76.81; H, 8.43; N, 6.89. Found: C, 76.26; H, 8.41;
N, 6.82.

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3-Ethyl-1,4,4-trimethyl-3,4-dihydroquinolin-2(1H)-one (4): Yield 94%; whitish solid; Mp 72–77 °C;
1H-NMR (CDCl3) δ: 0.92 (3H, t, J = 7.2 Hz, CH3), 1.07–1.18 (1H, m, CH), 1.21 (3H, s, CH3), 1.35
(3H, s, CH3), 1.49-1.63 (1H, m, CH), 2.24 (1H, dd, J = 10.8, 4.5 Hz, CH2), 3.40 (3H, s, NCH3), 7.00
(1H, d, J = 8.4 Hz, Har), 7.07 (1H, td, J = 7.5, 1.2 Hz, Har), 7.25 (2H, m, 2 × Har); 13C-NMR (CDCl3) δ:
12.5 (CH3), 19.7 (CH2), 23.4 (CH3), 28.9 (CH3), 29.4 (CH3), 36.1 (C), 55.3 (CH), 114.7 (CH), 123.2
(CH), 124.8 (CH), 127.2 (CH), 133.9 (C), 138.9 (C), 172.1 (C); MS (EI): m/z 174, 100% [M-CH3-
+
CH2CH3 ], 217, 62% [M+]; Calcd for C14H19NO: C, 77.38; H, 8.81; N, 6.45. Found: C, 77.90; H, 8.61;
N, 6.52.
3-Benzyl-1,4,4-trimethyl-3,4-dihydroquinolin-2(1H)-one (5): Yield 99%; yellowish solid; Mp
1
46–51 °C; H-NMR (CDCl3) δ: 1.32 (3H, s, CH3), 1.42 (3H, s, CH3), 2.64 (1H, dd, J = 12.8, 8.9 Hz,
CH), 2.73 (1H, dd, J = 8.9, 4.5 Hz, CHaHbPh), 2.86 (1H, dd, J = 12.9, 4.5 Hz, CHaHbPh), 3.37 (3H, s,
NCH3), 7.03 (1H, d, J = 8.1 Hz, Har), 7.1–7.35 (8H, m, 8 × Har); 13C-NMR (CDCl3) δ: 23.6 (CH3), 28.4
(CH3), 29.6 (CH3), 33.1 (CH2), 36.6 (C), 55.2 (CH), 114.9 (CH), 123.3 (CH), 124.9 (CH), 126.2 (CH),
127.5 (CH), 128.2 (2xCH), 128.9 (2xCH), 133.8 (C), 139.0 (C), 139.8 (C), 171.2 (C); MS (EI): m/z 91,
+
100% [C6H5CH2 ], 279, 21% [M+]; Calcd for C19H21NO: C, 81.68; H, 7.58; N, 5.01. Found: C, 81.90;
H, 7.61; N, 5.10.
3-Allyl-1,4,4-trimethyl-3,4-dihydroquinolin-2(1H)-one (6): Yield 93%; yellowish solid; Mp 55–58 °C;
1H-NMR (CDCl3) δ: 1.24 (3H, s, CH3), 1.35 (3H, s, CH3), 1.96–2.01 (1H, m, CH), 2.27–2.32 (1H, m,
CH), 2.44 (1H, dd, J = 10.2, 4.8 Hz, CH), 3.39 (3H, s, NCH3), 4.90–4.96 (2H, m, CH=CH2), 5.76–5.84
(1H, m, CH=CH2), 7.01 (1H, d, J = 7.2 Hz, Har), 7.08 (1H, t, J = 7.5 Hz, Har), 7.26–7.30 (2H, m, 2 ×
Har); 13C-NMR (CDCl3) δ: 23.4 (CH3), 28.6 (CH3), 29.4 (CH2), 31.4 (CH2), 36.1 (C), 53.7 (CH), 114.8
(CH), 116.1 (CH2), 123.3 (CH), 124.8 (CH), 127.3 (CH), 133.6 (C), 136.2 (CH), 138.8 (C), 171.4 (C);
MS (EI): m/z 214, 100% [M-CH3 ], 229, 73% [M+]; Calcd for C15H19NO: C, 78.56; H, 8.35; N, 6.11.
+
Found: C, 78.66; H, 8.41; N, 6.02.
1
3-(5-Bromopentyl)-1,4,4-trimethyl-3,4-dihydroquinolin-2(1H)-one (7): Yield 60%; yellowish oil; H-
NMR (CDCl3) δ: 1.21 (3H, s, CH3), 1.34 (3H, s, CH3), 1.30–1.50 (6H, m, 3 × CH2), 1.80 (2H, m,
CH2), 2.30 (1H, dd, J = 7.8, 3.9 Hz, CH), 3.37 (2H, t, J = 6.8 Hz, CH2), 3.40 (3H, s, NCH3), 7.00 (1H,
d, J = 8.1 Hz, Har), 7.08 (1H, td, J = 7.5, 1.2 Hz, Har), 7.24-7.30 (2H, m, 2 × Har); 13C-NMR (CDCl3) δ:
23.4 (CH3), 26.4 (CH2), 27.2 (CH2), 28.3 (CH2), 28.7 (CH3), 29.5 (CH3), 32.6 (CH2), 33.9 (CH2), 36.1
(C), 53.5 (CH), 114.8 (CH), 123.3 (CH), 124.8 (CH), 127.2 (CH), 133.8 (C), 138.9 (C), 172.1 (C); MS
+
+
+
(EI): m/z 174, 100% [M-(CH2)5Br-CH3 ], 337, 4% [M(Br79) ], 339, 4% [M(Br81) ]; Calcd for
C17H25BrNO: C, 60.36; H, 7.15; N, 4.14. Found: C, 59.98; H, 7.21; N, 4.32.
3-(Hydroxy(phenyl)methyl)-1,4,4-trimethyl-3,4-dihydroquinolin2(1H)-one (8): Yield 99%; white solid;
1
Mp 143–146 °C; H-NMR (CDCl3) δ: 1.11 (3H, s, CH3), 1.54 (3H, s, CH3), 2.80 (1H, d,
J = 4.5 Hz, CH), 2.90 (3H, s, NCH3), 3.26 (1H, brs, OH), 4.75 (1H, d, J = 4.5 Hz, CH), 6.42 (1H, dd,
J = 8.1, 1.5 Hz, Har), 6.77–6.80 (2H, m, 2 × Har), 6.87–6.98 (5H, m, 5 × Har), 7.09 (1H, dd, J = 7.2,
1.8 Hz, Har); 13C-NMR (CDCl3) δ: 24.1 (CH3), 29.1 (CH3), 30.5 (CH3), 35.5 (C), 61.2 (CH), 72.3
(CH), 114.4 (CH), 123.4 (CH), 124.3 (CH), 126.0 (2xCH), 127.1 (CH), 127.2 (2 × CH), 127.6 (CH),

Molecules 2010, 15
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132.9 (C), 138.2 (C), 140.9 (C), 171.1 (C); MS (EI, DI): m/z = 174, 100% [M-CH3-C6H5CHOH+], 295,
13% [M+] ; Calcd for C19H21NO2: C, 77.26; H, 7.17; N, 4.74. Found: C, 78.02; H, 7.23; N, 4.75.
3-Iodo-1,4,4-trimethyl-3,4-dihydroquinolin-2(1H)-one (9): Yield 88%; beige solid; Mp 128–136 °C;
1H-NMR (CDCl3) δ: 1.27 (3H, s, CH3), 1.47 (3H, s, CH3), 3.30 (3H, s, NCH3), 4.50 (1H, s, CH), 7.00
(1H, dd, J = 8.1, 0.9 Hz, Har), 7.07 (1H, td, J = 7.2, 0.9 Hz, Har), 7.18 (1H, dd, J = 7.8,
13
1.5 Hz, Har), 7.25 (1H, td, J = 7.5, 1.8 Hz, Har); C-NMR (CDCl3) δ: 23.2 (CH3), 28.3 (CH3), 30.1
(CH3), 37.4 (CH), 37.8 (C), 115.1 (CH), 123.9 (CH), 124.6 (CH), 127.9 (CH), 132.1 (C), 138.7 (C),
+
167.3 (C); MS (EI): m/z 144, 100% [M-I-CH3-NCH3 ], 315, 74% [M+]; Calcd for C12H14INO: C,
45.73; H, 4.48; N, 4.44. Found: C, 46.03; H, 4.51; N, 4.47.
3-Acetyl-1,4,4-trimethyl-3,4-dihydroquinolin-2(1H)-one (10): Yield 68%; white solid; Mp 97–99 °C;
1H-NMR (CDCl3) δ: 1.29 (3H, s, CH3), 1.43 (3H, s, CH3), 2.17 (3H, s, COCH3), 3.43 (3H, s, NCH3),
3.59 (1H, s, CH), 7.03 (1H, dd, J = 8.4, 1.2 Hz, Har), 7.11 (1H, td, J = 7.8, 1.2 Hz, Har), 7.29 (2H, m, 2
× Har). 13C-NMR (CDCl3) δ: 23.6 (CH3), 28.6 (CH3), 29.9 (CH3), 31.9 (CH3), 36.1 (C), 66.2 (CH),
115.0 (CH), 123.9 (CH), 124.0 (CH), 127.5 (CH), 133.4 (C), 138.5 (C), 166.2 (C), 203.0 (C); MS (EI):
+
m/z 174, 100% [M-COCH3-CH3 ], 231, 32% [M+]; Calcd for C14H17NO2: C, 72.70; H, 7.41; N, 6.06.
Found: C, 72.43; H, 7.39; N, 6.11.
3-Chloro-1,4,4-trimethyl-3,4-dihydroquinolin-2(1H)-one (11): Yield 90%; yellowish solid; Mp
90–93 °C; 1H-NMR (CDCl3) δ: 1.20 (3H, s, CH3), 1.39 (3H, s, CH3), 3.35 (3H, s, NCH3), 4.17 (1H, s,
CH), 6.98 (1H, dd, J = 8.1, 1.5 Hz, Har), 7.06 (1H, td, J = 7.8, 1.2 Hz, Har), 7.21–7.27 (2H, m, 2 × Har);
13C-NMR (CDCl3) δ: 23.1 (CH3), 26.2 (CH3), 30.1 (CH3), 38.5 (C), 64.7 (CH), 115.2 (CH), 124.0
+
(CH), 125.3 (CH), 127.9 (CH), 131.2 (CH), 138.0 (C), 165.3 (C); MS (EI): m/z 208, 100%[M-CH3 ],
223, 92% [M(Cl35) +], 225, 31% [M(Cl37) +]; Calcd for C12H14ClNO: C, 64.43; H, 6.31; N, 6.26. Found:
C, 64.72; H, 6.49; N, 6.30.
1,4,4-Trimethyl-3-(phenylsulfonyl)-3,4-dihydroquinolin-2(1H)-one (12): Yield 46%; yellowish solid;
1
Mp 110–114 °C; H-NMR (CDCl3) δ: 1.26 (3H, s, CH3), 1.90 (3H, s, CH3), 3.22 (3H, s, NCH3), 4.04
(1H, s, CH), 6.80 (1H, dd, J = 7.8, 0.9 Hz, Har), 7.12 (1H, td, J = 7.5, 1.2 Hz, Har), 7.21 (1H, td,
J = 7.8, 1.5 Hz, Har), 7.32 (1H, dd, J = 7.5, 1.5 Hz, Har), 7.40 (2H, t, J = 7.8 Hz, 2 × Har), 7.55 (1H, t,
J = 7.5 Hz, Har), 7.60–7.63 (2H, m, 2 × Har); 13C-NMR (CDCl3) δ: 23.9 (CH3), 30.1 (CH3), 31.1 (CH3),
37.0 (C), 77.6 (CH), 115.1 (CH), 124.3 (CH), 124.4 (CH), 127.9 (CH), 128.6 (2 × CH), 128.7 (2 ×
CH), 131.3 (C), 133.9 (CH), 138.1 (C), 138.6 (C), 161.8 (C); MS (EI): m/z 250, 100%, 329, 57% [M+];
Calcd for C18H19NO3S: C, 65.63; H, 5.81; N, 4.25. Found: C, 64.84; H, 5.89; N, 4.20.
1,4,4-Trimethyl-2-oxo-1,2,3,4-tetrahydroquinoline-3-carboxylic acid (13): Yield 75%; Brown solid;
1
Mp 138–140 °C; H-NMR (CDCl3) δ: 1.31 (3H, s, CH3), 1.35 (3H, s, CH3), 3.35 (3H, s, NCH3), 3.36
(1H, s, CH), 6.95 (1H, d, J = 8.1 Hz, Har), 7.03 (1H, t, J = 7.2 Hz, Har), 7.19–7.27 (2H, m, 2 × Har),
10.25 (1H, brs, COOH); 13C-NMR (CDCl3) δ: 23.7 (CH3), 27.5 (CH3), 30.1 (CH3), 36.3 (C), 58.8
(CH), 115.3 (CH), 124.0 (CH), 124.1 (CH), 127.7 (CH), 133.3 (C), 138.4 (C), 166.2 (C), 172.7 (C);
MS (EI, DI): m/z 174, 100% [M-CH3-COOH+], 233, 19% [M+]; Calcd for C13H15NO3: C, 66.94; H,
6.48; N, 6.00. Found: C, 66.87; H, 6.41; N, 6.13.

Molecules 2010, 15
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4. Conclusions
In summary, we have described in this paper the lithiation and electrophilic substitution of
1,4,4-trimethyl-3,4-dihydroquinolin-2(1H)-one in position 3 and the unexpected reaction with
different sulfonyl derivatives under the same conditions, providing either a chlorinated or sulfonyl
compound. The enantioselective substitution of this position is currently under investigation in our
laboratory. The biological evaluation of these new compounds is also now under investigation.
Acknowledgements
We thank the Comité du Cher de la Ligue National Contre le Cancer for financial support and
the Department of Analytical Chemistry of University of Tours François Rabelais for technical
support. We thank also Monika Ghosh for her translation assistance.
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