Fluorotetrahydroquinolines from diethyl 2-fluoromalonate ester

Article abstract of DOI:10.2533/chimia.2014.425

A short series of fluorotetrahydroquinolines was synthesised in two steps from diethyl fluoromalonate and appropriate ortho-nitrobenzyl bromide precursors. Schweizerische Chemische Gesellschaft.

Full text of DOI:10.2533/chimia.2014.425

Fluorine Chemistry
CHIMIA 2014, 68, Nr. 6 425
doi:10.2533/chimia.2014.425
Chimia 68 (2014) 425–429 © Schweizerische Chemische Gesellschaft
Fluorotetrahydroquinolines from Diethyl
2-Fluoromalonate Ester
Craig A. Fishera, Antal Harsanyia, Graham Sandford*a, Dmitri S. Yufitb, and Judith A. K. Howardb
Abstract: A short series of fluorotetrahydroquinolines was synthesised in two steps from diethyl fluoromalonate
and appropriate ortho-nitrobenzyl bromide precursors.
Keywords: Fluorinated heterocycle · Fluoromalonate · Fluorotetrahydroquinoline · Organofluorine chemistry ·
Selective fluorination
organic chemistry,[5] corresponding use of derivatives 2 with anions formed by depro-
2-fluoromalonate esters for the prepara- tonation of diethyl 2-fluoromalonate ester
1. Introduction
tion of multi-functional selectively fluor- 1 using sodium hydride in DMF gave good
The development of effective methods
inated products has not been developed yields (unoptimised) of diester derivatives
for the synthesis of selectively fluorinated
heterocyclic systems continues to grow in
importance due to the increasing number
of commercially significant fluorinated
heterocyclic structural units that are pres-
ent in valuable pharmaceuticals and agro-
chemicals.[1] While fluoroheteroaromatic
systems are sub-structures of many drugs,
there are comparatively very few instances
where saturated fluorinated heterocyclic
rings form part of an active pharmaceu-
tical ingredient (API) or marketed drug
structure.[1]
to any great extent.[5] A small number of 3 which were purified by column chro-
patents utilising 2-fluoromalonate esters matography on silica gel (Table 1). The
for the synthesis of a variety of biological- molecular structure of diester 3c was con-
ly active systems within pharmaceutical firmed by X-ray crystallography (Fig.1).
company pipelines have recently been dis-
By a similar process, reaction of the
closed[6] indicating the potential value of analogous mesylate system 4 with two
using 2-fluoromalonate esters as building equivalents of 1 gave the fluorinated di-
blocks in multi-stage API synthesis. It is, ester 3e and significant quantities of a
however, not necessarily the case that reac- tetraester derivative 5 by a mechanism
tions of fluoromalonate will mirror that of shown in Scheme 2. Dehydrofluorination
the corresponding hydrocarbon analogue of 3e to an intermediate alkene which then
and, indeed, reaction profiles of selective- reacts with a further equivalent of 1 by a
ly fluorinated systems can be very different Michael addition process gives 5 in good
As part of a long-term programme
exploring the synthesis of fluorinated or-
ganic systems using elemental fluorine[2]
for the crucial synthetic step of carbon–
fluorine bond formation, we have estab-
lished efficient methods for the large scale
preparation of fluorinated 1,3-dicarbonyl
derivatives including 1,3-ketoesters[3] and
malonate systems.[4] Whereas the appli-
cation of non-fluorinated malonate esters
to the synthesis of a wide range of struc-
turally sophisticated target molecules is,
of course, well documented in general
to analogous non-fluorinated substrates.[7] yield. The structure of 5 was confirmed by
In this paper, we describe the use of X-ray crystallography (Fig. 2) and con-
diethyl 2-fluoromalonate ester for the syn- tains two virtually identical independent
thesis of rare fluorotetrahydroquinoline molecules linked together by a number of
systems. Only very few related fluorodi- C–H…
hydroquinoline systems, prepared by elec- (2.934 Å) intermolecular F…Cl contacts
trophilic fluorination of the corresponding may be regarded as halogen bonds.[9]
dihydroquinoline, have been reported[8]
Reductions of the nitro groups in fluo-
and shown to act as potent nitric oxide rodiester substrates 3 and subsequent cy-
O interactions. The relatively short
synthase inhibitors.
clisation to fluorotetrahydroquinolines
6 were accomplished by using either so-
dium dithionite or hydrogenation over a
2. Results and Discussion
palladium on carbon catalyst (Table 2).
The molecular structure of fluorotetrahy-
Our strategy for the synthesis of droquinoline 6a was confirmed by X-ray
fluorotetrahydroquinolines from 2-diethyl crystallography (Fig. 3).
2-fluoromalonate ester 1 is outlined in
The conformation of the stereogenic
Scheme 1 in which, in principle, reaction centre in 6a is unusual in that the smaller
of fluoromalonate with ortho-nitrobenzyl fluorine atom occupies the equatorial posi-
bromide derivatives followed by reduc- tion while the larger ester functionality is
tion-cyclisation would lead to the fluoro- axial. α-Fluoroamides have a very strong
tetrahydroquinoline targets.
preference (syn-anti 7.5 kcal mol–1) for the
Reaction of ortho-nitrobenzyl bromide carbon–fluorine bond to adopt an anti-pla-
*Correspondence: Prof. G. Sandford
E-mail: Graham.Sandford@durham.ac.uk
aDepartment of Chemistry
Durham University, South Road
Durham, DH1 3LE, UK
bChemical Crystallography
Durham University
Scheme 1. Synthetic strategy for the preparation of fluorotetrahydroquinoline derivatives.

426 CHIMIA 2014, 68, Nr. 6
Fluorine Chemistry
Table 1. Synthesis of diesters 3.
4. Experimental
4.1 General
Proton, fluorine and carbon nuclear
magnetic resonance (NMR) spectra (1H,
19F and 13C NMR) were obtained from a
Bruker 400 Ultrashield spectrometer (1H
NMR at 400 MHz, 19F NMR at 376 MHz
and 13C NMR at 101 MHz) using residu-
Benzyl bromide 2
Diester 3
al solvent peaks as the internal standard
(1H NMR; CHCl3 at 7.26 ppm, 19F NMR;
CFCl at 0.00 ppm and 13C NMR; CDCl3 at
77.163 ppm). NMR spectroscopic data are
reported as follows: chemical shift (ppm),
integration, multiplicity (s = singlet, d =
doublet, t = triplet, q = quartet, m = mul-
tiplet), coupling constant (Hz) and assign-
ment.
GC-MS data were obtained from a
Trace GC-MS device (Thermo-Finnigan
Corporation) operating in electron impact
ionization (EI) mode. Accurate mass anal-
ysis was performed on a Xevo QtoF mass
spectrometer (Waters Ltd, UK) with an at-
mospheric solids analysis probe (ASAP).
Melting point data was obtained using
a Gallenkamp apparatus at atmospheric
pressure and are uncorrected. Infra-red
Fig. 1. Molecular structure of 3c.
Scheme 2. Reaction of mesylate derivative 4 with 1.
nar conformation relative to the amide
carbonyl group so that the C–F and amide
diploes maximally oppose one another.[10]
Consequently, we may expect the fluorine
atom to adopt an equatorial position in the
structure of 6a but, in the crystal analysed
at least, this is not the case.
(IR) spectroscopy was performed on a
Perkin Elmer 1600 Series FTIR with an
ATR probe.
Single crystal X-ray data were collect-
ed at 120.0 K on a Bruker SMART
CCD
1K (compounds 3c and 6a) and an Agilent
XCalibur (compound 5) diffractometers
(λ MoKα, graphite monochromators,
λ = 0.71073 Å, ω-scan) equipped with
Cryostream (Oxford Cryosystems) open-
flow nitrogen cryostats.All structures were
solved by direct methods and refined by
full-matrix least squares on F2 for all data
3. Conclusion
Inexpensive, readily available diethyl
2-fluoromalonate ester can be used to
synthesise a new class of fluorotetrahy-
droquinoline systems in two steps from
ortho-nitrobenzyl bromide precursors.
Fluorine occupies the equatorial position
in the solid-state structure of fluorotetrahy-
droquinoline 6a.
using SHELXTL software.[11]
All non-hy-
drogen atoms were refined with anisotrop-
ic displacement parameters, H-atoms in
the structures 3c and 6a were located on
the difference map and refined isotrop-
Fig. 2. Molecular structure of one of two inde-
pendent molecules of 5.
ically. The H atoms in twinned structure

Fluorine Chemistry
CHIMIA 2014, 68, Nr. 6 427
Table 2. Synthesis of fluorotetrahydroquinolines 6 by reduction-cyclisation processes.
4.2 Synthesis of Fluorodiesters 3
4.2.1 General Procedure
Sodium hydride (60% NaH in miner-
al oil) was washed with hexane (2 × 50
mL) and added to DMF (15 mL). Diethyl
2-fluoromalonate 1 in DMF (10 mL) and
the 2-nitrobenzyl bromide derivative 2 in
DMF (15 mL) were added dropwise to the
solution which was stirred at room temper-
Diester 3
Fluorotetrahydoquinoline 6
ature for 19 h. The reaction mixture was
added to ice/water (150 mL), extracted
with diethyl ether (3 × 50 mL), washed
sequentially with water (3 × 50 mL) and
brine (3 × 50 mL), dried (MgSO4), con-
centrated and purified by column chroma-
tography on silica gel or recrystallization
to give the pure fluorodiester 3.
4.2.2 Diethyl 2-fluoro-2-(2-nitro-
benzyl)malonate (3a)
Sodium hydride (0.31 g, 13.11 mmol),
1 (2.00 g, 11.24 mmol) and 2-nitroben-
zyl bromide 2a (2.11 g, 9.79 mmol), after
recrystallization, gave diethyl 2-fluoro-
2-(2-nitrobenzyl)malonate 3a (2.67 g, 87
o
%) as pale yellow crystals; mp 51–52 C;
([MH]+, 314.1053. C14H16NO6F requires
[MH]+, 314.1040); υmax (neat, cm–1) 2989,
1748, 1523, 1347, 1245, 1190, 1142, 1060;
1H NMR δ 7.88 (1H, dd, 3JHH 8.0, 4JHH 1.2,
Ar-H), 7.57–7.39 (3H, m,Ar-H), 4.37–4.14
(4H, m, OCH2), 3.95 (2H, d, 3JHF 23.5, CF-
CH2), 1.25 (6H, t, 3JHH 7.1, CH3); 19F NMR
δ –164.06 (t, 3JHF 23.5); 13C NMR δ 165.40
2
(d, JCF 25.5, C=O), 150.74 (s, C-NO2),
3
133.34 (d, J 2.4, C-1), 132.72 (s, Ar),
128.82 (s, ArC)F, 127.76 (s, Ar), 125.02 (s,
1
Ar), 93.90 (d, JCF 201.8, C-F), 63.10 (s,
OCH2), 35.36 (d, 2JCF 20.3, CF-CH2), 13.97
(s, CH3); m/z (ASAP) 314.1 ( [MH]+, 94%).
4.2.3 Diethyl 2-(4-cyano-2-nitro-
benzyl)-2-fluoromalonate (3b)
Sodium hydride (0.10 g, 4.32 mmol),
1 (0.62 g, 3.49 mmol) and 4-(bro-
momethyl)-3-nitrobenzonitrile 2b (0.80 g,
3.32 mmol), after column chromatography
and recrystallization, gave diethyl 2-(4-cy-
ano-2-nitrobenzyl)-2-fluoromalonate 3b
(0.61 g, 54%) as a yellow solid; mp 52–53
oC; ([MH]+, 339.1036. C15H15N2O6F re-
quires [MH]+, 339.0992); υmax (neat, cm–1)
Fig. 3. Molecule 6a (left) and the H-bonded dimer in the structure of 6a (right).
5 were placed in calculated positions and
refined in riding mode. Crystallographic
data for the structures have been deposit-
ed with the Chembridge Crystallographic
Data Centre as supplementary publications
CCDC 991436-991438.
c = 21.6317(11) Å, β = 114.838(6)°,
V = 4745.5(4) Å3, Z = 8, T = 120.0 K,
µ(MoKα)= 0.224 mm–1, Dcalc = 1.416 g/
mm3, 52581 reflections measured (5.14
≤ 2θ ≤ 56), 11455 unique (Rint = 0.1057)
2982, 2234, 1763, 1541, 1279, 1239, 1196,
1
were used in all calculations. The final R
1131, 1060; H NMR δ 8.19 (1H, s, H-3),
1
7.82 (1H, dd, 3J 8.1, 4J 1.5, H-5), 7.64
Crystal Data for 3c: C15H NO7F, M =
343.30, monoclinic, space gro1u8p P2 /c, a =
8.5269(7),b=11.8392(10),c=16.40198(14)
Å, β = 98.129(2)°, V = 1640.0(2) Å3, Z = 4,
T= 120.0 K, µ(MoKα) = 0.118 mm–1, Dcalc
= 1.390 g/mm3, 22040 reflections meas-
= 0.0633 (7562>2σ(I)) and wR2 = 0.1730
(1H, d, JHH 8.1H,HH-6), 4H.3H1–4.18 (4H, m,
3
(all data), GOOF = 1.033.
3
Crystal Data for 6a: C H NO3F
(M = 237.23): monoclinic, sp1a2ce12group
P21/c, a = 10.5275(12), b = 6.6687(8), c
= 15.6871(18) Å, β = 102.677(2)°, V =
1074.5(2)Å3, Z = 4, T = 120.0 K, µ(MoKα)
OCH2), 3.98 (2H, d, JHF 22.5, CF-CH2),
3
1.27 (6H, t, JHH 7.1, CH3); 19F NMR δ
3
–163.64 (t, J 22.5); 13C NMR δ 163.86
(d, JCF 25.3,HFC=O), 149.59 (s, C-NO2),
2
3
ured (4.26 ≤ 2θ ≤ 58), 4365 unique (Rint
=
134.36 (s, Ar), 133.62 (d, JCF 2.7, C-1),
–1
3
0.0427) were used in all calculations. The
= 0.117 mm , Dcalc = 1.466 g/mm , 9083
reflections measured (3.96 ≤ 2θ ≤ 58),
2841 unique (Rint = 0.0684) were used
132.02 (s, Ar), 127.46 (s, Ar), 115.25 (s,
C-4), 112.25 (s, CN), 92.22 (d, 1JCF 202.8,
final R1 = 0.0444 (3279 > 2σ(I)) and wR2 =
0.1133 (all data), GOOF = 1.010.
2
CF), 62.34 (OCH2), 34.28 (d, JCF 20.1,
Crystal Data for 5: C H ClFNO10,
M = 505.87, monoclinic, 21sp2a5ce group
P21/c, a = 25.4199(12), b = 9.5099(3),
in all calculations. The final R = 0.0643
(1827>2σ(I)) and wR2 = 0.1601 (all data),
GOOF = 1.020.
CF-CH2), 12.87 (s, CH3); m/z (ASAP)
1
339.1 ([MH]+, 100%), 311.1 (25), 265.1
(21), 173.0 (44).

428 CHIMIA 2014, 68, Nr. 6
Fluorine Chemistry
0.95 mmol) was added with NaH (0.09 g,
3.75 mmol), then after 20 h the solution
was added to ice/water (150 mL), extract-
ed with diethyl ether (3 × 50 mL), washed
with water and brine, dried (MgSO ), con-
centrated and purified by column c4hroma-
tography using hexane, ethyl acetate as
elutant to give diethyl 2-(5-chloro-2-ni-
trobenzyl)-2-fluoromalonate 3e (0.44 g,
4.2.4 Diethyl 2-fluoro-2-(4-methoxy-
2-nitrobenzyl)malonate (3c)
4.3.2 Method B: Sodium Dithionite
Sodium bicarbonate was added slow-
Sodium hydride (0.10 g, 4.23 mmol),
1 (0.61 g, 3.42 mmol) and 1-(bro-
momethyl)-4-methoxy-2-nitrobenzene 2b
(0.80 g, 3.25 mmol), after recrystalisa-
tion, gave diethyl 2-fluoro-2-(4-methoxy-
2-nitrobenzyl)malonate 3b (0.63 g, 56%)
ly to a solution of diester 3 in THF and
water. Sodium dithionite was added por-
tion wise over 10 minutes with vigorous
stirring. After 30 minutes, brine (8 mL)
and ethyl acetate (8 mL) were added, the
organic layer separated and washed with
sodium bicarbonate (3 × 50 mL) and brine
(3 × 50 mL), concentrated and the residue
purified by column chromatography using
hexane:ethyl acetate (9:1) as elutant to
give the desired fluorotetrahydroquinoline
product 6.
o
as white crystals; mp 66–67 C; ([MH]+,
o
322.1160. C15H18NO7F requires [MH]+,
344.1146); υmax (neat, cm–1) 2984, 1743,
1534, 1295.9, 1240, 1212, 1195, 1046; 1H
33%) as yellow crystals; mp 52–53 C;
([MH]+, 348.0648. C14H15NO6F35Cl re-
quires [MH]+, 348.0650); υmax (neat, cm–1)
2992, 1746, 1524, 1352, 1276, 1192, 1044;
1H NMR δ 7.87 (1H, d, 3JHH 8.6, H-3), 7.44
4
NMR δ 7.39 (1H, d, JHH 2.5, H-3), 7.34
3
3
(1H, d, JHH 8.6, H-6), 7.06 (1H, dd, JHH
3
4
4
(1H, s, H-6), 7.41 (dd, JHH 8.6, JHH 2.3,
H-4), 4.34–4.19 (4H, m, OCH2), 3.94 (2H,
d, 3JHF 22.8, CH2-CF), 1.27 (6H, t, 3JHH 7.1,
CH3); 19F NMR δ –164.12 (t, 3JHF 22.8); 13C
NMR δ 165.19 (d, 2JCF 25.4, C=O), 148.88
(s, C-NO2), 139.04 (s, C-Cl), 133.36 (s,
Ar), 129.84 (s, Ar), 128.99 (s, Ar), 126.54
(s, Ar), 93.55 (d, 1J 202.3, C-F), 63.27 (s,
OCH2), 35.29 (d, 2JCCFF 20.4, CF-CH2), 13.98
(s, CH ); m/z (ASAP) 348.1 ([MH]+),
100%),3274.0 (14), 228.0 (20); and, tetra-
ethyl 2-(5-chloro-2-nitrophenyl)-1-fluoro-
propane-1,1,3,3-tetracarboxylate 5 (0.73
g, 55%) as an orange oily solid; mp 40–41
oC; ([MH]+, 506.1210. C21H25NO10F35Cl re-
quires [MH]+, 506.1229); υmax (neat, cm–1)
2982, 1752, 1532, 1231, 1147, 1095, 1047:
1H NMR δ 7.83 (1H, d, 3JHH 8.7, H-3), 7.64–
7.58 (1H, m, H-8), 7.39 (1H, dd, 3JHH 8.7,
4J 2.2, H-4), 5.63 (1H, dd, 3JHF 27.4, 3JHH
9.H8H, CH-CF), 4.37–3.76 (9H, m, OCH ,
CH-C=O), 1.33 (3H, t, 3JHH 7.2, CH3), 1.227
(3H, t, 3JHH 7.1, CH3), 1.06 (3H, t, 3JHH 7.1,
CH3), 1.00 (3H, t, 3JHH 7.1, CH3); 19F NMR
δ –168.93 (d, 3JHF 27.4); 13C NMR δ 166.89
(s, C=O), 166.35 (s, C=O), 164.48 (d, 2JCF
8.6, JHH 2.6, H-5), 4.29–4.18 (4H, m,
OCH2), 3.87 (2H, d, JHF 22.9, CF-CH2),
3
4.3.3 Ethyl 3-fluoro-2-oxo-1,2,3,4-
tetrahydroquinoline-3-carboxylate
(6a)
3
3.85 (3H, s, OCH3), 1.26 (6H, t, JHH 7.1,
CH3); 19F NMR δ –164.25 (t, 3JHF 23.6); 13C
NMR δ 165.51 (d, 2JCF 25.6, C=O), 159.45
(s, C-OMe), 151.21 (s, C-NO ), 134.26 (d,
3JCF 2.3, C-1), 119.34 (s, Ar2), 119.12 (s,
Method A: Diethyl 2-fluoro-2-(2-ni-
trobenzyl)malonate3a(1.25g,4mmol)and
Pd/C (0.43 g, 5 mol% Pd) in acetic acid (40
mL) gave ethyl 3-fluoro-2-oxo-1,2,3,4-tet-
rahydroquinoline-3-carboxylate 6a (0.73
g, 78%) as a white powder; mp 84–85 oC;
([MH]+, 238.0862. C12H12FNO3 requires
[MH]+, 238.0879); υmax (neat, cm–1) 3215,
3096, 2992, 1752, 1688, 1493, 1200, 1131;
1H NMR δ 9.03 (1H, s, NH), 7.24 (1H, t,
3JHH 8, Ar-H), 7.18 (1H, d, 3J 7.4, Ar-H),
1
Ar), 110.01 (s, Ar), 94.00 (d, JCF 200.8 ,
C-F), 63.05 (s, OCH2), 55.94 (s, OCH3),
2
34.83 (d, JCF 20.3, CF-CH2), 14.00 (s,
CH3); m/z (ASAP) 344.1 ([MH]+, 100%),
270.1 (33), 224.0 (67), 178.0 (63).
4.2.5 Diethyl 2-fluoro-2-(2-fluoro-6-
nitrobenzyl)malonate (3d)
7.06 (1H, t, J 7.0, Ar-H),HH6.90 (1H, d,
3
Sodium hydride (0.13 g, 5.56 mmol),
1 (0.80 g, 4.49 mmol) and 2-fluoro-6-ni-
trobenzyl bromide 2d (1.00 g, 4.27
mmol), after recrystallization, gave di-
ethyl 2-fluoro-2-(2-fluoro-6-nitrobenzyl)
malonate 3d (1.25 g, 88%) as a yellow
3J 7.9, Ar-H)H, H4.35–4.21 (2H, m, OCH ),
3.H6H8–3.40 (2H, m, CF-CH2), 1.23 (3H,2t,
3JHH 7.1, CH3); 19F NMR δ –165.17 (dd,
3
3JHF 23.4, JHF 15.4); 13C NMR δ 166.57
2
2
(d, J 25.8, C=O), 164.05 (d, J 22.8,
solid; mp. 49–50 C; ([MH]+, 332.0953.
C=O)C,F135.52 (s, C-NH), 128.77 C(Fs, Ar),
o
C14H15NO6F2 requires [MH]+, 332.0946);
128.58 (s, Ar), 124.22 (s, Ar), 118.98 (d,
υmax (neat, cm–1) 2997, 1746, 1533, 1363,
3JCF 6.5, C-4a), 116.00 (s, Ar), 90.32 (d,
1
1252, 1173, 1075, 1055; H NMR δ 7.75
1JCF 195.1, C-F), 62.93 (s, OCH ) 35.65
(1H, m, JHH 8.2, H-3), 7.44 (1H, td, JHH
8.3,4JHF 5.5, H-4), 7.37–7.31 (1H, m, H-5),
4.34–4.22 (4H, m, OCH ), 4.06 (2H, dd,
(d, 2JCF 23.8, CF-CH2), 14.03 (s, C2H3); m/z
3
3
2
(ASAP) 238.1 ([MH]+, 23%), 210.1 (40),
24.5, FC-C=O), 164.22 (d, J 23.9, FC-
C=O), 148.96 (s, C-NO2), 139.C0F0 (s, C-Cl),
164.0 (100).
Method B: Sodium bicarbonate (1.51
g, 17.98 mmol), diethyl 2-fluoro-2-(2-ni-
trobenzyl)malonate 3a (1.00 g, 3.19 mmol)
in THF (8 mL) and water (8 mL) and so-
dium dithionite (2.85 g, 16.38 mmol) gave
ethyl 3-fluoro-2-oxo-1,2,3,4-tetrahydro-
quinoline-3-carboxylate 6a (0.43 g, 57%)
as a white powder; physical and spectral
data as above.
3JHF 20.6, JHF 1.8, CF-C2H2), 1.29 (6H, t,
4
3
4
132.56 (d, JCF 1.3, C-6), 130.95 (d, JCF
6.3, C-1), 129.19 (s, C-4), 126.37 (s, C-3),
94.91 (d,1JCF 207.2, C-F), 63.65 (s, OCH2),
63.23 (s, OCH2), 62.49 (s, OCH2), 62.12 (s,
OCH2), 52.85 (d, 3JCF 5.7, CH-C=O), 40.75
3JHH 7.1, CH3); 19F NMR δ –110.14 (1F, m,
Ar-F), –164.80 (1F, t, 3JHF 20.6, CH2-CF);
13C NMR δ 165.39 (d, JCF 25.6, C=O),
2
1
161.63 (d, JCF 250.9, Ar-F), 151.38 (d,
2
3JCF 3.9 Hz, C-NO2), 129.68 (d, JCF 9.5,
3
(d, J 18.6, CF-CH), 14.02 (s, CH3),
13.88C(Fs, CH3), 13.72 (s, CH3), 13.67 (s,
CH3); m/z (ASAP) 506.1 ([MH]+, 100%),
460.1 (85), 414.0 (72).
4
C-4), 121.02 (d, JCF 3.3, C-3), 120.20 (d,
2JCF 24.2, C-5), 116.37 (d, 2JCF 19.9, C-1),
92.69 (d, 1JCF 201.6, CF), 63.16 (s, OCH ),
28.25 (dd, JCF 21.4, JCF 3.1, CF-CH22),
13.95 (s, CH3); m/z (ESI) 332.1 ([MH]+,
100%).
2
3
4.3 Synthesis of Fluorotetra-
hydroquinolines 6 by Reduction-
Cyclisation
4.3.1 Method A: Hydrogenation over
Pd/C
Diester 3 and Pd/C in acetic acid were
placed in a Parr hydrogenator and pressur-
ised (40 psi) with hydrogen. After stirring
for 1 h the solution was filtered through
celite, concentrated, DCM (50 mL) added,
washed with sodium bicarbonate (3 × 50
mL), dried (MgSO4) and concentrated to
give the desired fluorotetrahydroquinoline
6 which was purified by recrystallization
if required.
4.3.4 Ethyl 7-cyano-3-fluoro-2-
oxo-1,2,3,4-tetrahydroquinoline-3-
carboxylate (6b)
4.2.6 Diethyl 2-(5-chloro-2-nitro-
benzyl)-2-fluoromalonate (3e) and
Tetraethyl 2-(5-chloro-2-nitro-
phenyl)-1-fluoropropane-1,1,3,3-
tetracarboxylate (5)
Sodium hydride (0.12 g, 4.91 mmol)
was washed with hexane (2 × 50 mL) and
added to dry DMF (15 mL). 1 (0.69 g, 3.89
mmol)indryDMF(10mL)wasaddeddrop
wise, followed by 5-chloro-2-nitrobenzyl
methanesulfonate 4 (1.00 g, 3.78 mmol) in
DMF (15 mL). After 5 h, more 1 (0.17 g,
Method B: Sodium bicarbonate
(1.51 g, 17.98 mmol), diethyl 2-(4-cy-
ano-2-nitrobenzyl)-2-fluoromalonate
3b (0.5 g, 1.48 mmol) in THF (8 mL)
and water (8 mL) and sodium dithionite
(2.85 g, 16.38 mmol), gave ethyl 7-cy-
ano-3-fluoro-2-oxo-1,2,3,4-tetrahydro-
quinoline-3-carboxylate 6b (0.30 g, 76%)
asanorangesolid;mp137–138oC;([MH]+,
263.0848. C13H11N2O3F requires [MH]+,
263.0832); υmax (neat, cm–1) 2981, 2922,
1
2226, 1758, 1695, 1257, 1205, 1103; H

Fluorine Chemistry
CHIMIA 2014, 68, Nr. 6 429
NMR δ 9.23 (1H, s, NH), 7.38 (1H, d, 3JHH
8.3, H-6), 7.32 (1H, d, 3J 7.8, H-5), 7.20
(1H, s, H-8), 4.38–4.28H(H2H, m, OCH ),
3.79–3.42 (2H, m, CF-CH2), 1.28 (3H,2t,
3JHH 7.1, CH3); 19F NMR δ –165.38 (dd,
[3] R. D. Chambers, J. Hutchinson, J. Thomson, J.
Fluorine Chem. 1996, 78, 165.
[4] a) R. D. Chambers, J. Hutchinson, J. Fluorine
4.3.6 Ethyl 3,5-difluoro-2-oxo-1,2,3,4-
tetrahydroquinoline-3-carboxylate
(6d)
Chem. 1998, 92, 45; b) R. D. Chambers, M.
Method A: Diethyl 2-fluoro-2-(2-
fluoro-6-nitrobenzyl)malonate 3d (1.00
g, 3.02 mmol) and Pd/C (0.32 g, 5 mol%
Pd) in acetic acid (30 mL) after 3.5 h gave
ethyl 3,5-difluoro-2-oxo-1,2,3,4-tetrahy-
droquinoline-3-carboxylate 6d (0.67 g,
87%) as a dark red viscous oil; ([MH]+,
256.0785. C12H11F2NO3 requires [MH]+,
256.0785); υmax (neat, cm–1) 3232, 2984,
A. Fox, D. Holling, T. Nakano, T. Okazoe, G.
Sandford, Chem. Eng. Tech. 2005, 28, 344.
3
3JHF 24.9, JHF 15.3); 13C NMR δ 165.94
[5] Use of dicarbonyl systems in organic synthesis:
a) S. Warren, ‘Designing Organic Syntheses:
The Synthon Approach’, John Wiley and Sons,
NewYork, 1978;b)S.Warren, P. Wyatt, ‘Organic
Synthesis: The Disconnection Approach’, 2nd
ed., John Wiley and Sons, Chichester, 2008;
c) S. Warren, P. Wyatt, ‘Organic Synthesis:
Strategy and Control’, 2nd ed., John Wiley
and Sons, Chichester, 2007; d) E. J. Corey, X.-
2
2
(d, J 25.4, C=O), 163.87 (d, J 22.3,
C=O)C,F136.47 (s, C-NHR), 129.70C(Fs, Ar),
127.86 (s, Ar), 124.48 (d, JCF 6.2, C-4a),
3
119.07 (s, Ar), 117.96 (s, C-7), 112.53
1
(s, CN), 89.51 (d, JCF 196.3, CF), 63.41
2
(OCH2), 35.68 (d, JCF 24.1, CF-CH2),
1
14.06 (s, CH3); m/z (ASAP) 263.1 ([MH]+,
1691, 1600, 1486, 1273, 1073; H NMR
M. Cheng, ‘The logic of chemical synthesis’,
Wiley-Interscience, New York, 1995.
(600 MHz, DMSO-d6) δ 11.18 (1H, s,
NH), 7.28 (1H, q, 3JHH 8.0, H-6), 6.91 (1H,
t, 3JHH 8.8, H-7), 6.81 (1H, d, 3J 8.0, H-8),
4.29–4.16 (2H, m, OCH2), 3.6H8H–3.46 (2H,
100%), 243.1 (43), 189.0 (27).
[6] Diethyl fluoromalonate in synthesis: a) T. A.
Miller, D. L. Sloman, M. G. Stanton, K. J.
Wilson, D. J. Witter, WO2007087129, 2007;
4.3.5 Ethyl 3-fluoro-7-methoxy
-2-oxo-1,2,3,4-tetrahydroquino-
b) J. Close, R. W. Heidebrecht, S. Kattar, T. A.
Miller, D. Sloman, M. G. Stanton, P. Tempest,
D. J. Witter, WO2007055941, 2007; c) J. L.
Hubbs, D. M. Mampreian, J. L. Methot, T.
A. Miller, K. M. Otte, P. Siliphaivanh, D.
L. Sloman, M. G. Stanton, K. J. Wilson, D.
J. Witter, WO2006115845, 2006; d) M. O.
Polla, L. Tottie, C. Nordén, M. Linchoten, D.
Müsil, S. Trumpp-Kallmeyer, I. R. Aukrust,
R. Ringom, K. H. Holm, S. M. Neset, M.
Sandberg, J. Thurmond, P. Yu, G. Hategan, H.
Anderson, Bioorg. Med. Chem. 2004, 12, 1151;
e) K. Kwon, S. M. Kim, D. Y. Kim, J. Fluorine
Chem. 2009, 130, 759; f) H. Li, L. Zu, H. Xie,
W. Wang, Synthesis 2009, 1525.
3
m, CF-CH2), 1.16 (3H, t, JHH 7.1, CH3);
line-3-carboxylate (6c)
19F NMR (564 MHz, DMSO-d6) δ –119.34
MethodA: Diethyl 2-fluoro-2-(4-meth-
oxy-2-nitrobenzyl)malonate 3c (0.50 g,
1.46 mmol) and Pd/C (0.16 g, 5 mol% Pd)
inaceticacid(20mL)aftercolumnchroma-
tography and recrystallization, gave ethyl
3-fluoro-7-methoxy-2-oxo-1,2,3,4-tet-
rahydroquinoline-3-carboxylate 6c (0.26
g, 67%) as white needles; mp 111–112 oC;
([MH]+, 268.0984. C13H15FNO4 requires
[MH]+, 268.0985); υmax (neat, cm–1) 2984,
– –119.44 (1F, m, Ar-F), –163.80 (1F, dd,
3
3JHF 24.4, JHF 20.6, C-F); 13C NMR (151
2
MHz, DMSO-d6) δ 166.05 (d, J 25.7,
C=O), 161.92 (d, JCF 22.7, C=O),C1F 59.73
2
1
3
(d, JCF 243.4, Ar-F), 138.08 (d, J 6.8,
C-8a), 129.35 (d, 3JCF 9.5, C-7), 111C.4F9 (d,
4JCF 2.8, C-8), 109.80 (d, J 21.3, C-6),
2
106.46 (dd, 2JCF 21.2, 3JCF 5.7C,FC-4a), 89.56
1
(d, JCF 192.0, CF-CH23), 62.27 (s, OCH ),
28.01 (dd, JCF 24.4, JCF 3.0, CF-CH22),
2
1
1761, 1693, 1288, 1255, 1068; H NMR
[7] D. Seebach, Angew. Chem. Intl. Ed. Engl. 1990,
13.73 (s, CH ); m/z (ASAP) 256.1 ([MH]+,
3
δ 7.84 (1H, s, NH), 7.08 (1H, d, JHH 8.4,
29, 1320.
34%), 236.13(100).
3
Ar-H), 6.59 (1H, d, JHH 8.4, Ar-H), 6.36
[8] a) S. Jaroch, H. Rehwinkel, P. Holscher,
D. Sulzle, G. Burton, M. Hillmann, F. M.
McDonald, H. Miklautz, Bioorg. Med. Chem.
Lett. 2004, 14, 743; b) S. Jaroch, H. Rehwinkel,
P. Holscher, D. Sulzle, M. Hillmann, G. Burton,
F. M. McDonald, PCT Intl. Pat. Appl., WO
00/29381, 2000.
(1H, s, Ar-H), 4.33–4.22 (2H, m, OCH2),
3.79 (3H, s, OCH3), 3.63–3.29 (2H, m,
Acknowledgements
We thank the Durham University M. Chem.
programme for funding.
3
CF-CH2), 1.24 (3H, t, JHH 7.1, CH3); 19F
NMR δ –165.75 (dd, 3JHF2 22.3, 3JHF 15.0);
13C NMR δ 166.59 (d, JCF 25.8, C=O),
Received: April 1, 2014
2
[9] A. C. Dikundwar, T. N. Guru Row, Cryst.
Growth Des. 2012, 12, 1713.
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163.95 (d, JCF 22.8, C=O), 159.97 (s,
C-OMe), 136.44 (s, C-NHR), 129.70 (s,
Ar), 110.92 (d, 3JCF 7.0, Ar), 109.41 (s, Ar),
Faeh, F. Diedrich, Science 2007, 317, 1881; b)
‘Fluorine in Medicinal Chemistry and Chemical
Biology’, Ed. I. Ojima, Wiley-Blackwell:
Oxford, 2009; c) S. Purser, P. R. Moore, S.
A. S. Batsanov, J. A. K. Howard, D. O’Hagan,
H. S. Rzepa, S. Martin-Santamaria, J. Chem.
Soc., Perkin Trans. 2 1999, 2409; D. O’Hagan,
Chem. Soc. Rev. 2008, 37, 308.
1
102.03 (s, Ar), 90.42 (d, J 195.5, C-F),
62.90 (s, OCH2), 55.63 (s,COF CH3), 34.97
(d, 2JCF 23.8, CF-CH2), 14.06 (s, CH3); m/z
(ASAP) 268.1 ([MH]+, 100%), 248.1 (28),
194.1 (39).
Swallow, V. Gouverneur, Chem. Soc. Rev. 2008, [11] a) G. M. Sheldrick, Acta Cryst., Sect. A 2008,
37, 320; d) C. Isanbor, D. O’Hagan, J. Fluorine
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Chem. 2006, 127, 1013.
64, 112; b) O. V. Dolomanov, L. J. Bourhis, R.
J. Gildea, J. A. K. Howard, H. Puschmann, J.
Appl. Cryst. 2009, 42, 339.
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