The synthesis of 7,8,9,10-Tetrafluoroellipticine

Article abstract of DOI:10.24820/ark.5550190.p010.414

We have synthesized a novel ellipticine analogue, 7,8,9,10-Tetrafluoroellipticine, in nine steps from hexafluorobenzene and ethyl cyanoacetate, via 1-(phenysulfonyl)-4,5,6,7-Tetrafluoroindole. The key step is lithiation of the indole and subsequent coupling with 3,4-pyridinedicarboxylic acid anhydride to afford a ketolactam. Reaction of the lactam with methyllithium followed by reduction with sodium borohydride yields 7,8,9,10-Tetrafluoroellipticine. formula presented.

Full text of DOI:10.24820/ark.5550190.p010.414

The Free Internet Journal
for Organic Chemistry
Paper
Archive for
Arkivoc 2018, part iii, 144-152
Organic Chemistry
The synthesis of 7,8,9,10-tetrafluoroellipticine
E. James Gruver , Evans O. Onyango, and Gordon W. Gribble*
Department of Chemistry, Dartmouth College, Hanover, NH 03755, USA
ggribble@dartmouth.edu
Received 11-29-2017
Abstract
Accepted 01-21-2018
Published on line mm-02-05-2018
We have synthesized a novel ellipticine analogue, 7,8,9,10-tetrafluoroellipticine, in nine steps from hexa-
fluorobenzene and ethyl cyanoacetate, via 1-(phenysulfonyl)-4,5,6,7-tetrafluoroindole. The key step is
lithiation of the indole and subsequent coupling with 3,4-pyridinedicarboxylic acid anhydride to afford a keto-
lactam. Reaction of the lactam with methyllithium followed by reduction with sodium borohydride yields
7,8,9,10-tetrafluoroellipticine.
F
F
Me
O
F
F
F
F
F
F
CO2Et
CN
N
N
O
N
H
O
F
F
Me
Keywords: Ellipticine, 7,8,9,10-tetrafluoroellipticine, 4,5,6,7-tetrafluoroindole, lithiation
DOI: https://doi.org/10.24820/ark.5550190.p010.414
Page 144
©ARKAT USA, Inc

Arkivoc 2018, iii, 144-152
Gruver, E. J. et al.
Introduction
The synthesis and biological evaluation of substituted ellipticine (5,11-dimethyl-6H-pyrido[4,3-b]carbazole)
derivatives has been of intense interest for several decades.1-3 Notably, ring-A substitution can have a major
impact on the biological activity of ellipticine (1a).4-11 The prototypical example is 9-hydroxyellipticine (1b),
which has a high affinity for DNA, high activity against L1210 mice leukemia, and low toxicity at a therapeutic
dose.12 Of special interest is 9-fluoroellipticine (1c), which inhibits aryl hydrocarbon hydroxylase without
inducing mutagenicity.13,14
In continuation of our synthetic efforts in this area, we now report the synthesis of the novel 7,8,9,10-
tetrafluoroellipticine (2); the method is illustrative of its versatility in the construction of pyridocarbazoles.15-17
This ellipticine analogue seemed to be an attractive target given the profound biological effect that fluorine
has both on ellipticine (i.e, 1c) and in other biological molecules.18-24 Thus, tetrafluorination should both
increase the acidity of the NH and mitigate against metabolism of this ring. Moreover, the basicity of the
pyridine nitrogen should be decreased by the strongly electron-withdrawing ability of multiple fluorines.
Me
F
Me
R
F
F
N
N
N
H
N
H
Me
F
Me
2
1a, R = H
1b, R = OH
1c, R = F
Results and Discussion
Our synthesis of 2 is summarized in Schemes 1 and 2. Our first goal became the synthesis of 4,5,6,7-
tetrafluoroindole (8), which was first synthesized by Brooke in 1967.25 The low yield from this procedure
precluded its use here, so we adopted a method described by Petrov26 and later by Filler.27 Cyano-ester 3 was
prepared by condensation of hexafluorobenzene with the anion of ethyl cyanoacetate to give ethyl α-cyano-
(pentafluorophenyl)acetate (3) in 52% yield (Scheme 1). Hydrolysis and decarboxylation was achieved in
refluxing acid to afford 2,3,4,5,6-pentafluorophenylacetonitrile (4) in 82% yield. Whereas Filler reduced the
nitrile 4 to amine 5 using catalytic hydrogenation,27 we employed sodium trifluoroacetoxyborohydride as
reported by Umino,28 which led to 2-(pentafluorophenyl)ethanamine (5) in 67% yield. Subjecting amine 5 to KF
in hot DMF gave 4,5,6,7-tetrafluoroindoline (6) in 65% yield. Oxidation of indoline 6 to 4,5,6,7-
tetrafluoroindole (7) using manganese dioxide as described by Filler proceeded only in 47% yield despite
several attempts. Therefore, we protected the indole NH using lithium diisopropylamide followed by
benzenesulfonyl chloride to give the desired 1-(phenylsulfonyl)-4,5,6,7-tetrafluoroindole (8) in 37% yield. The
disappointing two-step yield of only 17% urged us to seek an alternative route to 8 (Scheme 2).
Page 145
©ARKAT USA, Inc

Arkivoc 2018, iii, 144-152
Gruver, E. J. et al.
F
CO2Et
CN
F
F
F
F
F
F
F
F
F
F
F
F
CO2Et
CN
K2CO3
DMF
AcOH
CN
H2SO4
reflux
F
F
52%
F
82%
F
3
4
F
F
F
NH2
F
F
NaBH4
KF
DMF
reflux
CF3CO2H
THF, rt
67%
F
N
H
F
F
65%
5
6
F
F
F
F
F
F
F
MnO2
benzene, rt
47%
1. LDA
2. PhSO2Cl
37%
N
N
H
F
SO2Ph
7
8
Scheme 1
In the event, we treated indoline 6 with benzenesulfonyl chloride to give 1-(phenylsulfonyl)-4,5,6,7-
tetrafluoroindoline (9) in 82% yield. Whereas oxidation to indole 8 failed using chloranil, N-bromosuccinimide
worked beautifully to give 1-(phenylsulfonyl)-4,5,6,7-tetrafluoroindole (8) in 93% yield (Scheme 2).
F
F
F
F
F
F
F
F
F
PhSO2Cl
NBS
NaOH
Bz2O2
CCl4
N
N
N
H
H2O, rt
F
SO2Ph
F
SO2Ph
F
reflux
93%
6
8
9
82%
F
F
F
F
F
F
F
F
K2CO3
1. LDA
O
N
N
aq MeOH
reflux
N
N
H
N
O
SO2Ph
CO2H
O
CO2H
2.
O
90%
11
12
O
10
74%
F
F
Me
F
F
F
1. MeLi (2 equiv.)
Ac2O
N
O
80–90 °C
53%
2. NaBH4
70%
F
N
N
H
F
F
Me
O
2
N
13
Scheme 2
Page 146
©ARKAT USA, Inc

Arkivoc 2018, iii, 144-152
Gruver, E. J. et al.
The key step in the final synthesis of 2 is the regioselective acylation of 2-lithio-1-(phenylsulfonyl)-4,5,6,7-
tetrafluoroindole with 3,4-pyridinedicarboxylic acid (cinchomeronic acid) anhydride (10).29,30 This sequence
proceeded to give the keto acid 11 in 74% yield, after recrystallization to remove traces of the regioisomer.
This material was directly hydrolyzed to keto acid 12 (90% yield) and, without purification, was cyclized to keto
lactam 13 in hot acetic anhydride in 53% yield after recrystallization. Finally, treatment of 13 with
methyllithium (2 equivalents) followed by work-up and treatment of the crude mixture of diols with NaBH4
gave the desired 7,8,9,10-tetrafluoroellipticine (2) in 70% yield after flash chromatography. The overall yield of
2 from 1-(phenylsulfonyl)-4,5,6,7-tetrafluoroindole (8) is 25%. By comparison, our related synthesis of
ellipticine from indole gave a yield of 54%.15 Not unexpectedly, the proton NMR spectrum of 2 shows long-
range, through-space coupling (3.7 Hz) between the C-11 methyl group and the C-10 fluorine.31
Experimental Section
General. Melting points were determined in open capillaries with a Büchi 510 melting point apparatus and are
1
uncorrected. Infrared spectra were recorded on a Perkin-Elmer 599 instrument. H NMR spectra were
routinely obtained at 70 MHz with a Varian EM360A spectrometer, while 13C NMR spectra were obtained with
a Varian XL-300 spectrometer. Chemical shifts are reported in parts per million downfield from
tetramethylsilane as an internal reference. Low-resolution mass spectra were determined on a Finnegan EI-CI
gas chromatograph-mass spectrometer. Flash chromatography employed 230-400 mesh silica gel. Thin layer
chromatography was performed on precoated (0.2 mm) silica gel 60 F254 plastic sheets (E. Merck). Spots were
visualized under 254 nm ultraviolet light. The alkyllithium reagents were purchased from Aldrich and were
standardized by titration against diphenylacetic acid. Tetrahydrofuran was distilled from sodium
metal/benzophenone, and diisopropylamine was distilled over sodium hydride. All reactions were performed
in oven-dried (130 oC) or flame dried glassware under prepurified nitrogen or argon.
Ethyl α-cyanopentafluorophenylacetate (3). A mixture of spectral grade dimethylformamide (350 mL) and
anhydrous K2CO3 (77 g, 0.55 mol) was heated to reflux in a 1 L, three-neck flask equipped with a mechanical
stirrer, thermometer, an addition funnel, and a condenser. When the temperature of the mixture reached 150
oC, H2O was allowed to flow through the condenser and ethyl cyanoacetate (62.0 g, 0.55 mol) was added
dropwise rapidly without further heating. The temperature of the bright orange mixture was allowed to drop
o
to 110–120 C and maintained within this range while hexafluorobenzene (102.0 g, 0.55 mol) was added
dropwise. The deep brown mixture was stirred, at the above temperature, for 3 h after the addition, then
poured into 1 L of ice-cold H2O and acidified with H2SO4 solution (20%) until all K2CO3 dissolved. A dark brown
layer settled to the bottom, and after cooling for 2 h, the top layer was decanted and exhaustively extracted
with Et2O. The organic layer was dissolved in Et2O, washed with H2O, saturated NaHCO3 solution, and dried
(MgSO4). The combined ethereal layers were then concentrated in vacuo to yield 107.9 g (52%) of 3 as a
brown oil which formed yellow crystals when cooled to 0 oC. The solid was filtered off and recrystallized from
o
o
1
95% EtOH to yield white crystals: mp 34–35 C (lit.27 mp 32 C); H NMR (CDCl3) δ 5.10 (s, 1H), 4.33 (q, 2H),
1.33 (t, 3H).
2,3,4,5,6-Pentafluorophenylacetonitrile (4). Ethyl α-cyanopentafluorophenylacetate (105.3 g, 397 mmol) was
refluxed for 12 h in 50% AcOH (300 mL) containing H2SO4 (conc., 10 mL). The mixture was then cooled to rt,
diluted with an equal volume of H2O, stirred, and a viscous, dark layer settled to the bottom of the flask. The
mixture was chilled in an ice bath, the top layer was decanted until the remaining mixture consisted mostly of
Page 147
©ARKAT USA, Inc

Arkivoc 2018, iii, 144-152
Gruver, E. J. et al.
the dark layer, which was then transferred to a separatory funnel, where the remaining water layer was
removed. The dark layer was then extracted with Et2O, and the ethereal layers were combined, washed with
H2O, saturated NaHCO3 solution, and dried (MgSO4) to yield 79.74 g of crude pentafluorophenylacetonitrile.
Distillation gave 67.1 g (324 mmol, 82%) of 4: bp 65 oC (0.20 Torr) (lit.27 bp 105–107 oC (8 Torr)). IR (neat) 2975,
2260, 1660, 1540, 1140 cm-1; mass spectrum, m/e 207 (M+, 100%), 188, 181, 161, 157, 117, 93, 69.
2-(Pentafluorophenyl)ethanamine (5). To a stirred suspension of NaBH4 (12.4 g, 324 mmol) in dry THF (200
mL) under predried argon was added CF3CO2H (36.9 g, 324 mmol) in dry THF (30 mL) over a period of 10 min
at 20 oC. 2,3,4,5,6-Pentafluorophenylacetonitrile (4) (67.07 g, 324 mmol) was then added dropwise in dry THF
(30 mL), and the mixture was stirred at rt for 4 h after this addition. The excess reagent was then cautiously
o
decomposed with H2O below 10 C in an ice bath, and the resulting mixture was concentrated to dryness in
vacuo, and extracted with CH2Cl2. The extract was washed with saturated NaHCO3 solution, H2O, and dried
over anhydrous Na2SO4. Concentration in vacuo yielded of 5 as a residual green oily layer (45.74 g, 67%), which
was used without further purification for the preparation of 4,5,6,7-tetrafluoroindole. In order to characterize
the amine, a small amount was distilled to give a colorless liquid; bp 96–102 oC (33 Torr) (lit.27 bp 80–90 oC (20
1
Torr)); IR (neat) 3350, 2940, 2860, 1660, 1525, 1510 cm-1; H NMR (CDCl3) δ 1.25 (m, 2H), 3.25 (m, 2H); UV
(95% EtOH) λmax 225, 247 nm.
4,5,6,7-Tetrafluoroindoline (6). Pentafluorophenylethylamine (6.5 g, 32 mmol) as the residual dark olive oil
was taken up in spectroscopic grade DMF (300 mL). Anhydrous KF (3.0 g) was then added and the mixture was
refluxed for 3 h with mechanical stirring under an atmosphere of dry N2. The mixture was allowed to cool to rt
and DMF ( 250 mL) was removed by vacuum distillation. The reaction flask was transferred to a steam
~
distillation apparatus and its contents were exhaustively steam distilled ( 1 L condensed water collected). The
~
cloudy effluent was filtered, then extracted with Et2O (3
×
50 mL) to yield a combined proiduct (3.82 g. 65%)
as odiferous white crystals. Further purification by sublimation in vacuo yielded 6 as white crystals (3.52 g): mp
o
o
o
61–62 C (lit.26 mp 60-61 C; lit.27 mp 60 C), IR (CCl4) 3410, 2870, 1655, 1520, 1510 cm-1; UV (95% EtOH) λmax
223, 282 nm; 1H NMR (CDCl3) δ 3.70 (m, 3H), 3.13 (t, 2H).
4,5,6,7-Tetrafluoroindole (7). A magnetically stirred mixture of indoline 6 (4.50 g, 23.5 mmol), activated MnO2
(22.0 g), type 4A molecular sieves, and 190 ml of dry benzene was stirred for 60 h during which time the
o
o
temperature was maintained at 20 C, occasionally reaching 30 C. After the mixture was filtered using
Filtercell, the solid residue was placed in a Soxhlet apparatus and extracted with 300 mL of dry benzene for 7
h. The filtrate and the extraction liquid were then combined and concentrated in vacuo to yield a brown oil.
The oil was then purified by chromatography over neutral alumina (25 g) in hexanes (3 cm column), eluting
first with hexanes (250 mL), then 50:50 hexane-Et2O (250 mL), and finally, with Et2O (250 mL). The hexane and
hexane-ether fractions were concentrated in vacuo to yield 2.1 g (47%) of 7: mp 92–94 oC (lit.26 mp 93–93.5 oC;
lit.27 mp 91–92.5 oC). IR (KBr) 3470, 1540, 1480, 1420, 1390, 1350, 980, 880 cm-1; UV (95% EtOH) λmax 227, 250
nm; 1H NMR (CDCl3) δ 8.36 (s, broad, 1H), 7.20 (m, 1H), 6.62 (m, 1H).
1-(Phenylsulfonyl)-4,5,6,7-tetrafluoroindoline (9). A magnetically stirred solution of tetrafluoroindoline (6)
(8.40 mg, 44.0 mmol) in aq NaOH solution (10%, 600 mL) was treated dropwise with benzenesulfonyl chloride
(44.6 g, 0.264 mol, 33.7 mL) over 2 h at rt maintaining the temperature at 20 oC with a cold water bath. Two
~
more equivalents of benzenesulfonyl chloride (2 x 33.7 mL, 0.528 mol) were added over 8 h to drive the
reaction to completion. NaOH (pellets, 20 g) were also added to maintain a strongly alkaline solution, and the
~
reaction mixture was stirred overnight to complete the hydrolysis of excess benzenesulfonyl chloride. The
solution was then slowly acidified with 20% aq HCl (20%, 500 mL) with adequate stirring and cooling, and the
~
resulting aqueous mixture was exhaustively extracted with CH2Cl2 (6
washed with 10% HCl (3 x 200 mL), 5% NaHCO3 (1 x 200 mL), H2O (1
×
200 mL). The combined extracts were
×
200 mL), brine (2
×
300 mL), and dried
Page 148
©ARKAT USA, Inc

Arkivoc 2018, iii, 144-152
Gruver, E. J. et al.
(Na2SO4). Concentration in vacuo yielded 9 (11.98 g, 82%) as a bright orange product. Recrystallization from
o
Et2O yielded 9 (9.60 g, 66%) as light orange fluffy crystals: mp 127 C; UV (95% EtOH) λmax 240, 271 (sh), 273
(sh) nm; 1H NMR (CDCl3) δ 7.66 (m, 5H), 4.22 (t, 2H), 2.75 (t, 2H); 13C NMR (CDCl3) δ 139.2, 138.7, 137.0, 135.6,
135.5, 131.0, 130.8, 130.6, 130.5, 128.8, 128.5, 128.4, 126.6, 118.0, 117.6; mass spectrum, m/e 331 (M+), 190,
189, 170, 163, 141, 77 (100%), 51; HRMS (ES+) m/z calcd for C14H9F4NO2S (M+1) 332.0368, found 332.0371.
1-(Phenylsulfonyl)-4,5,6,7-tetrafluoroindole (8)
(a) from the indoline 9. A mixture of the protected tetrafluoroindoline 9 (7.95 g, 24.0 mmol), N-bromo-
succinimide (4.28 g, 24.0 mmol), and benzoyl peroxide (0.60 g) in reagent grade CCl4 (500 mL) was heated to
reflux. After 12 h of refluxing, the reaction mixture was allowed to cool to rt, and then evaporated to dryness
in vacuo. The residue was dissolved in Et2O (500 mL), washed with H2O (3
×
100 mL), aq NaHCO3 (10%, 2
×
100
mL), and dried (Na2SO4). The combined ethereal layers were then concentrated in vacuo to yield 9.24 g of a
crude brown solid. Flash chromatography over silica gel with hexane:Et2O (20:1) yielded 7.35 g (93%) of 8 as
o
off-white crystals. Recrystallization from diethyl ether gave 8 as white crystals in three crops: mp 124–125 C;
1H NMR (CDCl3) δ 7.66 (m, 6H), 6.83 (q, 1H); UV (95% EtOH) λmax 213, 245 (sh), 276, 286 nm; mass spectrum,
m/e 329 (M+), 188, 161, 141, 78, 77 (100%), 69, 51, 50; HRMS (ES+) m/z calcd for C14H8F4NO2S (M+1) 330.0212,
found 330.0228.
(b) from the indole 7. To a magnetically stirred solution of lithium diisopropylamide (LDA) (11.8 mmol, 1.1
equiv) prepared from diisopropylamine (1.31 g, 12.9 mmol, 1.81 mL), and n-butyllithium (2.22 M in hexane,
o
5.32 mL, 11.8 mmol) in dry THF (50 mL) at -78 C was added via syringe over 40 min a solution of 7 (2.03 g,
o
10.7 mmol) in dry THF (35 mL). The temperature of the solution was not allowed to rise above -70 C during
the addition, and then the red mixture was allowed to warm to rt over 8 h. The solution was then recooled to -
o
78 C and treated via syringe with neat benzenesulfonyl chloride (1.89 g, 10.7 mmol, 1.36 mL) over 15 min
o
while keeping the internal temperature below -70 C. The reaction mixture was then allowed to warm slowly
to rt overnight, and then poured into aq NaHCO3 (2%, 100 mL) and extracted with Et2O (2
×
100 mL). The
75
combined ethereal layers were washed with 10% NaHCO3 solution (2 100 mL), H2O (2 50 mL), brine (2
×
×
×
mL), dried (Na2SO4), and concentrated in vacuo to yield 4.07 g of a crude brown oil that solidified.
o
Recrystallization from Et2O gave 8 (1.02 g, 37%) as a tan powder in three crops, mp 126 C. This material was
identical to the sample prepared above by mp, 1H NMR, UV and IR spectra.
3,4-Pyridinedicarboxylic acid anhydride (10). A magnetically stirred mixture of 3,4-pyridinedicarboxylic acid
(25.0 g, 0.15 mol) and Ac2O (100 mL) was refluxed for 45 min. All of the solid material dissolved to form a black
o
colored solution. The Ac2O was removed by distillation at 40 C (15 Torr) and the product was distilled to
afford 10 (19.6 g (88%) as a white solid: mp 77–78 oC (lit.30 mp 76–77 oC).
4-{[1-(Phenylsulfonyl)-4,5,6,7-tetrafluoroindol-2-yl]carbonyl}pyridine-3-carboxylic acid
(11). To
a
magnetically stirred solution of lithium diisopropylamide (LDA) (18.8 mmol, 1.1 equiv) prepared from
diisopropylamine (2.08 g, 20.5 mmol, 288 mL), and n-butyllithium (2.22 M in hexane, 8.49 mL, 18.8 mmol) in
o
dry THF (50 mL) at -50 C was added via syringe over 5 min a solution of 8 (5.64 g, 17.1 mmol) in dry THF (45
mL). The orange-red mixture was then allowed to warm to rt over 4 h. The solution was then cooled to -100 oC
(dry ice/pentane/liquid nitrogen bath) and treated as rapidly as possible with a solution of 3,4-
pyridinedicarboxylic acid anhydride (10) (2.81 g, 18.8 mol) in dry THF (40 mL) while maintaining efficient
o
stirring at -100 C for 1 h, and then allowed to warm slowly to rt overnight. Removal of the solvent in vacuo
left a dark solid, which was dissolved in H2O (300 mL), and slowly acidified to pH 2–3 with 20% HCl. The
o
resulting white precipitate was filtered, and dried in vacuo at 80 C/0.5 Torr to yield a tan solid (7.84, 96%).
o
Recrystallization in Me2CO gave 6.02 g (74%) of 11 as an off-white powder in three crops: mp 181–182 C; UV
Page 149
©ARKAT USA, Inc

Arkivoc 2018, iii, 144-152
Gruver, E. J. et al.
(95% EtOH) λmax 220, 269 (sh), 276 (sh), 292 nm; IR (KBr) 3400, 3100, 1690, 1555, 1505, 1490, 1450, 1340,
1225, 1045, 1015, 750, 720 cm-1; mass spectrum, m/e (M+ 478) 320, 264, 187, 161, 78, 77 (100%), 51. This
crude material was used directly in the next step.
4-[(4,5,6,7-Tetrafluoroindol-2-yl)carbonyl]pyridine-3-carboxylic acid (12). A magnetically stirred mixture of
the protected keto acid 11 (3.00 g, 6.26 mmol), K2CO3 (3.45 g, 25.0 mmol), H2O (80 mL), and MeOH (240 mL)
was refluxed under N2 for 4.5 h. After cooling, the solvents were removed to give a dark brown oil, which was
dissolved in distilled H2O (250 mL), and acidified to pH 2–4 with 20% HCl while maintaining efficient cooling
~
and stirring. The aqueous portion was then saturated with NaCl, and extracted with EtOAc (4
×
200 mL). The
combined extracts were washed with H2O (2 150 mL), brine (2 150 mL), and dried (Na2SO4). Rotary
×
×
evaporation of the solution afforded 1.90 g (90%) of 12 as a yellow solid. This product was difficult to purify,
o
and was used crude in the next step: mp 178–182 C; UV (95% EtOH) λmax 223, 301 nm; IR (KBr) 3100, 1715,
1550, 1495, 1380, 1340, 1230, 750 cm-1; mass spectrum, m/e 320 (M+, 100%) 264, 187, 161, 105, 78, 77, 50.
7,8,9,10-Tetrafluoroindolo[2,1-g]isoquinoline-5,12-dione (13). A mixture of the crude keto acid 12 (1.80 g,
o
5.31 mmol) was heated under N2 with magnetic stirring in neat Ac2O (300 mL) at 80–90 C for 24 h. The Ac2O
o
was almost completely removed by distillation at 40 C ( 15 Torr). The cooled residue was treated with H2O
~
(250 mL), stirred, and filtered to afford a crude yellow-brown product. Recrystallization from Me2CO gave 0.91
o
g (53%) of keto lactam (13) as dark yellow prisms: mp 240 C. UV (95% EtOH) λmax 215 (sh), 232, 307, 370 nm,
addition of 3 drops 10% NaOH gave UV λmax 219, 240 (sh), 270, 332 nm; IR (KBr) 3100, 1715, 1670, 1560, 1520,
1
1365, 1340, 1140, 1045, 1020, 995, 870, 800, 720; H NMR (d6-DMSO) δ 9.52 (s, 1H), 9.19 (d, 1H), 8.06 (d, 2H)
13
cm-1; C NMR (d6-DMSO) δ 110.7, 118.2, 136.2, 138.2, 150.4, 155.6, 155.7, 156.5, 174.5; mass spectrum, m/e
321, 320 (M+, 100%), 292, 264, 237, 187, 77, 50. Anal. Calcd for C15H4F4N2O2: C, 56.27; H, 1.26; N, 8.75. Found:
C, 56.00; H, 1.21; N, 8.68.
7,8,9,10-Tetrafluoroellipticine (2). A magnetically stirred solution of the fluoro keto lactam 13 (0.50 g, 1.55
o
mmol) in dry THF (60 mL) was cooled to -100 C and treated over 10 sec with methyllithium (0.176 M CH3Li in
Et2O, 17.6 mL, 3.10 mmol). The resulting tan mixture was stirred at -100 oC for 1 h, and was allowed to warm rt
over 5 h. Distilled H2O (5 mL) was added the mixture was stirred for 15 min, and the THF was removed in
vacuo to give a brown yellow residue. This material was immediately treated with absolute EtOH (100 mL),
and excess NaBH4 (5 pellets, ca. 1.25 g), and then refluxed with magnetic stirring for 18 h. The NaBH4 was
added in four portions during the 18 h reaction time. After 1 h, the reaction mixture became yellow, and was
brightly fluorescent. The reaction mixture was then cooled, and the solvents were removed in vacuo. The
resulting tan solid was dissolved in CHCl3 (200 mL), stirred for 15 min, and then treated with distilled H2O (200
mL). The phases were separated and the aqueous portion was extracted with additional CHCl3 (3 x 50 mL). The
aqueous layer was then partitioned over fresh CHCl3 (75 mL), and slowly acidified to pH 2–4 with 20% HCl, and
then basified with aqueous 2 M NaOH to pH 10. The aqueous layer was further extracted with CHCl3 (1 x 100
~
mL), and the organic layers were combined, washed with H2O (1 x 150 mL), and dried (Na2SO4). The compound
was then absorbed onto silica gel in vacuo, and flash chromatography over silica gel (25 cm column) with
EtOAc gave 0.34 g (70%) of 7,8,9,10-tetrafluoroellipticine 2 as a bright yellow solid which fluorescences light
o
blue under UV (254 nm) light: mp 281–282 C; UV (95% EtOH) λmax 212, 232 (sh), 274, 312 (sh), 325 (sh), 395
nm, addition of 2 drops 20% HCl to the cuvette gave UVmax 212, 240, 290, 343 (sh), 425 nm; IR (KBr) 3450,
3000, 1665, 1600, 1530, 1315, 1005, 860, 800 cm-1; 1H NMR (d4-MeOH) δ 9.58 (s, 1H), 8.41 (d, 1H, J = 6.2 Hz),
8.22 (d, 1H, J = 6.2 Hz), 3.21 (d, 3H, J = 3.7 Hz, through-space coupling to fluorine at C-10), 3.01 (s, 3H); mass
spectrum, m/e 318 (M+, 100%) 317, 303, 81, 73, 69, 60, 55; HRMS (ES+) m/z calcd for C17H11F4N2 (M+1)
319.0858, found 319.0867.
Page 150
©ARKAT USA, Inc

Arkivoc 2018, iii, 144-152
Gruver, E. J. et al.
Acknowledgements
We thank Dartmouth College for support, and Drs. Milind Rajopadhye for technical assistance.
References
1. Garbett, N. C.; Graves, D. E. Curr. Med. Chem. – Anti-Cancer Agents 2004, 4, 149.
https://doi.org/10.2174/1568011043482070
2. Miller, C. M.; McCarthy F. O. RSC Adv. 2012, 2, 8883.
https://doi.org/10.1039/c2ra20584j
3. Stiborova, M.; Frei, E. Curr. Med. Chem. 2014, 21, 575.
https://doi.org/10.2174/09298673113206660272
4. Ferlin, M. G.; Marzano, C.; Gandin, V.; Dall’Acqua, S.; Via, L. D. ChemMedChem 2009, 4, 363.
https://doi.org/10.1002/cmdc.200800368
5. Vehar, B.; Hrast, M.; Kovač, A.; Konc, J.; Mariner, K.; Chopra, I.; O’Neill, A.; Janežič, D.; Gobec, S. Bioorg.
Med. Chem. 2011, 19, 5137.
https://doi.org/10.1016/j.bmc.2011.07.020
6. Miller, C. M.; O’Sullivan, E. C.; Devine, K. J.; McCarthy, F. O. Org. Biomol. Chem. 2012, 10, 7912.
https://doi.org/10.1039/c2ob26181b
7. Mori, R.; Kato, A.; Komenoi, K.; Kurasaki, H.; Iijima, T.; Kawagoshi, M.; Kiran, Y. B.; Takeda, S.; Sakai, N.;
Konakahara, T. Eur. J. Med. Chem. 2014, 82, 16.
https://doi.org/10.1016/j.ejmech.2014.05.032
8. Montoia, A.; Rocha e Silva, L. F.; Torres, Z. E.; Costa, D. S.; Henrique, M. C.; Lima, E. S.; Vasconcellos, M.
C.; Souza, R. C. Z.; Costa, M. R. F.; Grafov, A.; Grafova, I.; Eberlin, M. N.; Tadei, W. P.; Amorim, R. C. N.;
Pohlit, A. M. Bioorg. Med. Chem. Lett. 2014, 24, 2631.
https://doi.org/10.1016/j.bmcl.2014.04.070
9. Shimazu, A.; Kawagoshi, M.; Takeda, S.; Kurasaki, H.; Kato, A.; Morii, N.; Sakai, N.; Konakahara, T. Bioorg.
Med. Chem. 2017, 25, 1024.
https://doi.org/10.1016/j.bmc.2016.12.031
10. Russell, E. G.; Guo, J.; O’Sullivan, E. C.; O’Driscoll, C. M.; McCarthy, F. O.; Cotter, T. G. Invest. New Drugs
2016, 34, 15.
https://doi.org/10.1007/s10637-015-0302-y
11. Sato, N.; Kawai, Y.; Akaba, Y.; Honma, S.; Sakai, N.; Konakahara, T. Heterocycles 2016, 92, 664.
https://doi.org/10.3987/COM-16-13404
12. Le Pecq, J.-B.; Nguyen-Dat-Xuong; Gosse, C.; PaoLetti, C. Proc. Nat. Acad. Sci. USA 1974, 71, 5078.
https://doi.org/10.1073/pnas.71.12.5078
13. Lesca, P.; Lecointe, P.; Pelaprat, D.; PaoLetti, C.; Mansuy, D. Biochem. Pharmacol. 1980, 29, 3231.
https://doi.org/10.1016/0006-2952(80)90296-8
14. Lesca, P.; Lecointe, P.; PaoLetti, C.; Mansuy, D. Chem-Biol. Interactions 1979, 25, 279.
https://doi.org/10.1016/0009-2797(79)90052-8
15. Saulnier, M. G.; Gribble, G. W. J. Org. Chem. 1982, 47, 2810.
https://doi.org/10.1021/jo00135a034
16. Gribble, G. W.; Fletcher, G. L.; Ketcha, D. M.; Rajopadhye, M. J. Org. Chem. 1989, 54, 3264.
https://doi.org/10.1021/jo00275a008
Page 151
©ARKAT USA, Inc

Arkivoc 2018, iii, 144-152
Gruver, E. J. et al.
17. Gribble, G. W.; Saulnier, M. G.; Obaza-Nutaitis, J. A.; Ketcha, D. M. J. Org. Chem. 1992, 57, 5891.
https://doi.org/10.1021/jo00048a022
18. Isanbor, C.; O’Hagan, D. J. Fluorine Chem. 2006, 127, 303.
https://doi.org/10.1016/j.jfluchem.2006.01.011
19. Bégué, J.-P.; Bonnet-Delpon, D. J. Fluorine Chem. 2006, 127, 992.
https://doi.org/10.1016/j.jfluchem.2006.05.006
20. Kirk, K. L. J. Fluorine Chem. 2006, 127, 1013.
https://doi.org/10.1016/j.jfluchem.2006.06.007
21. Müller, K.; Faeh, C.; Diederich, F. Science 2007, 317, 1881.
https://doi.org/10.1126/science.1131943
22. Purser, S.; Moore, P. R.; Swallow, S.; Gouverneur, V. Chem. Soc. Rev. 2008, 37, 320.
https://doi.org/10.1039/B610213C
23. Kirk, K. L. Org. Proc. Res. Dev. 2008, 12, 305.
https://doi.org/10.1021/op700134j
24. Gillis, E. P.; Eastman, K. J.; Hill, M. D.; Donnelly, D. J.; Meanwell, N. A. J. Med. Chem. 2015, 58, 8315.
https://doi.org/10.1021/acs.jmedchem.5b00258
25. Brooke, G. M.; Rutherford, R. J. D. J. Chem. Soc. (C) 1967, 1189.
https://doi.org/10.1039/j39670001189
26. Petrov, V. P.; Barkhash, V. A.; Schegoleva, G. S.; Petrova, T. D.; Savchenko, T. I.; Yakobson, G. G. Doklady
Akad. Nauk 1968, 178, 864.
27. Filler, R.; Woods, S. M.; Freudenthal, A. F. J. Org. Chem. 1973, 38, 811.
https://doi.org/10.1021/jo00944a043
28. Umino N.; Iwakuma, T.; Itoh, N. Tetrahedron Lett. 1976, 2875.
https://doi.org/10.1016/S0040-4039(01)85525-8
29. Bachman, G. B.; Barker, R. S. J. Org. Chem. 1949, 14, 97.
https://doi.org/10.1021/jo01153a015
30. Goldschmiedt. G.; Strache, H. Monatsh. Chem. 1890, 10, 156.
https://doi.org/10.1007/BF01516426
31. Gribble, G. W.; Douglas Jr., J. R. J. Am. Chem. Soc. 1970, 92, 5764.
https://doi.org/10.1021/ja00722a053
Page 152
©ARKAT USA, Inc