4-Fluoro-5-methylacridine: In Search of Long-Range “Lone-Pair Mediated” H-F and C-F Spin-Spin Coupling

Full text of DOI:10.1080/00304948.2020.1851123

Organic Preparations and Procedures International
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4-Fluoro-5-methylacridine: In Search of Long-
Range “Lone-Pair Mediated” H-F and C-F Spin-Spin
Coupling
Erik R. Olson & Gordon W. Gribble
To cite this article: Erik R. Olson & Gordon W. Gribble (2021) 4-Fluoro-5-methylacridine:
In Search of Long-Range “Lone-Pair Mediated” H-F and C-F Spin-Spin Coupling, Organic
Preparations and Procedures International, 53:1, 100-104, DOI: 10.1080/00304948.2020.1851123
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ORGANIC PREPARATIONS AND PROCEDURES INTERNATIONAL
2021, VOL. 53, NO. 1, 100–104
https://doi.org/10.1080/00304948.2020.1851123
OPPI BRIEF
4-Fluoro-5-methylacridine: In Search of Long-Range
“Lone-Pair Mediated” H-F and C-F Spin-Spin Coupling
Erik R. Olson and Gordon W. Gribble
Department of Chemistry, Dartmouth College, Hanover, New Hampshire
ARTICLE HISTORY Received 14 April 2020; Accepted 17 June 2020
In continuation of our interest in long-range “through-space” H-F and C-F spin-
spin coupling in planar aromatic molecules,1–5 we desired to explore the presence
(or absence) of such coupling between the fluorine and the methyl group as pos-
sibly mediated via the nitrogen lone pair in 4-fluoro-5-methylacridine (1). Some
examples of through-space H-F and C-F coupling from our laboratory are shown
in Figure 1.
The subject of “through-space” H-F and C-F spin-spin coupling has been reviewed6–8
and several recent examples have been described.9–14 However, to our knowledge, no
H-F or C-F spin-spin coupling via a nitrogen lone pair of electrons has been reported.
Our synthesis of this new compound 1 is shown in Scheme 1 and extends from a
modification of a reported preparation of 4-methyl-5-aminoacridine (7).15 The commer-
cially available 3-methyl-2-nitrobenzoic acid (2) was hydrogenated to afford 2-amino-3-
methylbenzoic acid (3) (93%), which was coupled with 2-bromonitrobenzene under
Ullmann copper coupling conditions to give 2-methyl-2’-nitrophenylamine-6-carboxylic
acid (4) (78%). Ring closure of 4 to 4-methyl-5-nitroacridin-9-one (5) was accomplished
with hot conc. sulfuric acid (quant.). Reduction of the nitro group in acridinone 5 with
SnCl2, HCl gave 4-amino-5-methylacridin-9-one (6) in low yield after recrystallization
from EtOH (18%). However, reduction of the carbonyl group in 7 with sodium/mercury
amalgam gave 4-amino-5-methylacridine (7) in 50% yield. Diazotization was carried out
using nitrosylsulfuric acid, followed by fluoboric acid to afford 4-(5-methylacridino)dia-
zonium tetrafluoroborate (8) in 88% yield. Heating salt 8 at 180 ꢀC afforded the desired
4-fluoro-5-methylacridine (1) in low yield (21%).
An examination of the proton and carbon NMR spectra of 1 revealed no spin-spin
coupling (>0.5 Hz) between the fluorine and the methyl group hydrogens and carbon,
respectively. Although this result is disappointing, based on theory7 such long-range
spin-spin coupling between fluorine and either hydrogen and/or carbon as mediated by
a lone pair of electrons remains an intriguing possibility and should be pursued in other
systems. It might be noted that 4-(5-methylacridino)diazonium tetrafluoroborate (8)
could serve as a useful entry to the synthesis of other 4,5-disubstituted acridines.
CONTACT Gordon W. Gribble
ggribble@dartmouth.edu
Department of Chemistry, Dartmouth College, Hanover,
NH 03755
ß 2020 Taylor & Francis Group, LLC

ORGANIC PREPARATIONS AND PROCEDURES INTERNATIONAL
101
Figure 1. Examples of through-space H-F and C-F coupling.
Scheme 1. Synthesis of 4-fluoro-5-methylacridine.
Experimental section
Melting points were determined on a Buchi 510 apparatus and are uncorrected. Infrared
(IR) spectra were recorded on a Perkin-Elmer 599 spectrometer and are referenced to the
1
1601cmꢁ1 band of polystyrene. H NMR spectra were acquired either at 60MHz on a
Varian EM-360A spectrometer or at 300 MHz on a Varian XL-300 multinuclear Fourier
transform spectrometer. 13C NMR spectra were recorded at 75MHz on a Varian XL-300
multinuclear Fourier transform spectrometer. Chemical shifts are reported in parts per
million (d) downfield from tetramethylsilane (TMS) using either TMS (dH 0.00, dC 77.0;

102
E. R. OLSON AND G. W. GRIBBLE
DMSO-d6: dH 2.49, dC 39.5) as an internal reference. The apparent multiplicity
(s ¼ singlet, d ¼ doublet, t ¼ triplet, q ¼ quartet, m ¼ multiplet, br ¼ broad), number of
protons, and coupling constants (Hz) are also reported. Elemental analysis was performed
by Atlantic Microlab Inc., Norcross, GA. Analytical thin-layer chromatography (TLC) was
performed on pre-coated Silica Gel 60 F254 plates from EM Reagents. Visualization was
accomplished with 254 nm UV light, iodine vapor, ceric ammonium sulfate spray (3% in
10% sulfuric acid), “Van Urk’s reagent” spray (p-dimethylaminobenzaldehyde in ethanolic
sulfuric acid), or anisaldehyde spray (p-anisaldehyde in sulfuric acid). It is noted that mul-
tiple batches were used for some of the reactions.
2-Amino-3-methylbenzoic acid (3)
Commercially available 3-methyl-2-nitrobenzoic acid (2) (10.45g, 58mmol) was dissolved
in MeOH (140 mL), to which was added activated Pd/C (550mg, 10%). The mixture was
shaken under 3 atm of H2 on a Parr hydrogenator at room temperature for 21h.
Filtration through Filter-Cel and evaporation of the filtrate in vacuo gave an off-white
solid. Recrystallization from absolute EtOH afforded 3 as white needles (8.13g, 93%), mp
1
174–176 ꢀC (lit.16 mp 172 ꢀC); H NMR (CDCl3) d 11.96 (s, 1 H), 7.76 (dd, J ¼ 8.2,
1.1 Hz, 1 H), 7.19 (dd, J ¼ 7.1, 0.8 Hz, 1 H), 6.53 (t, J ¼ 7.6 Hz, 1 H), 4.5 (br s), 2.17
(s, 3 H).
2-Methyl-2’-nitrodiphenylamine-6-carboxylic acid (4)
o-Bromonitrobenzene (3.08 g, 15.2 mmol), amino acid 3 (3.05 g, 20.2 mmol), K2CO3
(3.11 g, 22.5 mmol), activated Cu powder (210 mg, 3.3 mmol), and cyclohexanol (11 mL)
were added sequentially to a round bottom flask (100 mL) equipped with a reflux con-
denser and drying tube. The mixture was heated to 175 ꢀC over 1.5 h and maintained at
that temperature for an additional 2 h with stirring. After the mixture had cooled to
below 100 ꢀC, H2O (100 mL) was added and the solution was steam distilled for 5 h; the
heat source was removed and the pot residue was filtered. The filtrate was acidified
with 2 N HCl and a yellow precipitate formed. The solution was heated to boiling and
filtered while hot to give 4 as a gold-brown powder, which was recrystallized from 60%
EtOH. The yield of 4 as brown needles was 3.22 g (78%), mp 188-189.5 ꢀC (lit.17 mp
1
188–189 ꢀC); H NMR (DMSO) d 9.95 (s, 1 H), 8.14 (d, J ¼ 8.7 Hz, 1 H), 7.81 (d, J ¼
8.7 Hz, 1 H), 7.56 (d, J ¼ 8.0 Hz, 1 H), 7.46 (t, J ¼ 7.7 Hz, 1 H), 7.33 (t, J ¼ 7.7 Hz, 1 H),
6.87 (t, J ¼ 8.0 Hz, 1 H), 6.39 (d, J ¼ 8.7 Hz, 1 H), 2.21 (s, 3 H).
4-Methyl-5-nitroacridin-9-one (5)
A solution of 4 (5.84g, 21.5 mmol) in conc H2SO4 (47mL) was heated on the steam bath
for 15min, then poured cautiously (safety shield) into hot H2O (250 mL) in a beaker over
20min, to give 5 as a bright orange precipitate amid much spattering. The mixture was
heated on a steam bath for 40min and then filtered to give additional product. Washing
5 successively with H2O, hot (70ꢀC) 1 M NH4OH (150mL), and hot (70 ꢀC) H2O
(200 mL), and drying in vacuo (20ꢀC/ꢂ1 Torr) for 16h afforded 5.47g (ꢂquant) of 5,

ORGANIC PREPARATIONS AND PROCEDURES INTERNATIONAL
103
1
mp 231.5–232.5 ꢀC (lit.17 mp 228 ꢀC); H NMR (DMSO) d 11.16 (s, 1 H), 8.75 (d, J ¼
8.6 Hz, 1 H), 8.69 (dd, J ¼ 8.6, 1.7 Hz, 1 H), 8.13 (dd, J ¼ 8.4, 1.5 Hz, 1 H), 7.75 (d, J ¼
8.6 Hz, 1 H), 7.45 (t, J ¼ 8.6 Hz, 1 H), 7.33 (t, J ¼ 8.4 Hz, 1 H), 2.63 (s, 3 H).
4-Amino-5-methylacridin-9-one (6)
A mixture of acridinone 5 (2.13g, 8.4 mmol), concentrated HCl (15 mL), and SnCl2ꢃ2H2O
(9.03g, 40mmol) was heated on the steam bath for 3.5 h, during which time the yellow-
green solution turned red. The mixture was allowed to cool and made strongly alkaline
with 6 N NaOH to afford an army-green precipitate. The solid was collected by filtration,
washed with H2O, and recrystallized from EtOH to yield 0.33g (18%) of 6 as a red-
orange solid, mp 270 ꢀC (dec) (lit.17 mp 111 ꢀC); IR (KBr) 3180, 1654, 1604, 1558, 1525,
1
1459, 1224; H NMR (DMSO) d 8.71 (br s, 1 H), 8.10 (d, J ¼ 8.4 Hz, 1 H), 7.56 (m, 2 H),
7.15 (t, J ¼ 7.2 Hz, 1 H), 7.10–7.00 (m, 2 H), 5.77 (s, 2 H), 2.65 (s, 3 H).
4-Amino-5-methylacridine (7)
Compound 6 (0.45 g, 2.0 mmol), 95% EtOH (6 mL), and NaHCO3 (0.48 g, 5.7 mmol)
were added sequentially to a 25-mL round bottom flask. The mixture was heated to
70 ꢀC with stirring and H2O (0.4 mL) was added. Sodium/mercury amalgam (6%, 2.04 g)
was introduced in portions over 45 min, and the mixture became brown. The solution
was heated at reflux for 1.5 h and then was poured into ice-H2O (100 mL). A yellow
solid (0.13 g) was isolated upon filtration, which was determined to be starting material
1
by H NMR. The filtrate was extracted with hexane, dried (K2CO3), and concentrated
in vacuo to give 7 as an orange-yellow solid. The solid was chromatographed over silica
gel (Et2O) to afford 0.15 g (50% based on recovered starting material) of 7, mp
1
96–98 ꢀC (lit.15 mp 110-111 ꢀC); H NMR (DMSO) d 8.84 (s, 1 H), 7.92 (d, J ¼ 8.1 Hz,
1 H), 7.62 (m, 1 H), 7.44 (m, 1 H), 7.33 (t, J ¼ 7.8 Hz, 1 H), 7.25 (dd, J ¼ 8.1, 1.6 Hz,
1 H), 6.88 (dd, J ¼ 7.6, 1.6 Hz, 1 H), 6.17 (s, 2 H), 2.83 (s, 3 H); 13C NMR (DMSO) d
145.3, 144.8, 138.8, 136.2, 135.4, 128.9, 127.2, 126.6, 126.4, 126.2, 125.5, 113.7,
106.5, 17.9.
4-(5-Methylacridino)diazonium tetrafluoroborate (8)
Nitrosylsulfuric acid (255 mg, 2 mmol) was dissolved in 78% H2SO4 (3 mL), to which
was added 4-amino-5-methylacridine (7) (207 mg, 1 mmol), and the mixture was stirred
at room temperature for 3.25 h. Fluoboric acid (6 mL, 48%) was added to the red solu-
tion and the mixture was stirred in an ice-bath to induce precipitation. The resulting
orange solid was filtered and was dried overnight in vacuo (20 ꢀC/ꢂ1 Torr) to afford
1
269 mg (88%) of 8, mp 165 ꢀC (dec); H NMR (DMSO) d 8.07 (d, J ¼ 7.9 Hz, 1 H), 7.72
(m, 2 H), 7.59 (m, 1 H), 7.43 (d, 1 H), 7.36 (t, J ¼ 7.4 Hz, 1 H), 6.12 (s, 1 H), 2.91 (s,
3 H); 13C NMR (DMSO) d 142.5, 132.3, 130.9, 130.7, 129.4, 129.2, 126.7, 126.6, 126.1,
124.1, 117.7, 64.2, 22.7 (missing one signal, likely due to signal overlap).

104
E. R. OLSON AND G. W. GRIBBLE
4-Fluoro-5-methylacridine (1)
The diazonium salt 8 (155 mg, 0.5 mmol) was added in portions to a flask preheated to
180 ꢀC via an oil bath. The salt decomposed rapidly as a yellow gas evolved. The residue
was extracted by stirring with 3 N HCl overnight. Gravity filtration of the mixture
removed some solid residue and left a red-brown filtrate, which was made slightly basic
with aqueous Na2CO3. As the pH increased, the solution turned orange and a solid pre-
cipitated. Suction filtration gave an ochre solid, which was washed with H2O and dried
under vacuum (20 ꢀC/1 Torr) to yield 22.4 mg (21%), mp 70 ꢀC (dec); IR (CHCl3) 3030,
1
1532, 1433, 1211, 935 cmꢁ1; H NMR (CDCl3) d 8.75 (d, J ¼ 1.5 Hz, 1 H), 7.85 (dt, J ¼
8.1, 0.6 Hz, 1 H), 7.78 (m, 1 H), 7.66 (dt, J ¼ 6.6, 1.2 Hz, 1 H), 7.49–7.42 (m, 3 H), 2.97
(s, 3 H); 13C NMR (DMSO) d 157.1 (d, J ¼ 255.7 Hz), 147.5, 138.5, 136.55, 136.50,
130.4, 127.41, 127.38, 126.54, 126.46 (d, J ¼ 9.3 Hz), 125.2 (d, J ¼ 7.7 Hz), 124.4 (d, J ¼
4.9 Hz), 113.1 (d, J ¼ 18.5 Hz), 18.0; 19F NMR (DMSO) d –123.52.
Anal. Calcd for C14H10HF: C, 79.60; H, 4.77; N, 6.63. Found: C, 79.69; H, 4.72; N, 6.65.
Acknowledgment
We gratefully acknowledge support from Dartmouth College.
ORCID
Gordon W. Gribble
http://orcid.org/0000-0002-7573-0927
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