A facile procedure for synthesis of 3-[2-(N,N-dialkylamino)ethyl]-3- fluorooxindoles by direct fluorination of N,N-dialkyltryptamines

Article abstract of DOI:10.1016/j.jfluchem.2010.12.014

A practical procedure for the synthesis of 3-fluorooxindole derivatives having basic amine moieties was developed, which involves Selectfluor- mediated oxidative fluorination of N,N-dialkyltryptamines in the presence of Lewis acid. This procedure was appl

Full text of DOI:10.1016/j.jfluchem.2010.12.014

Journal of Fluorine Chemistry 132 (2011) 181–185
Contents lists available at ScienceDirect
Journal of Fluorine Chemistry
journal homepage: www.elsevier.com/locate/fluor
A facile procedure for synthesis of 3-[2-(N,N-dialkylamino)ethyl]-3-
fluorooxindoles by direct fluorination of N,N-dialkyltryptamines
*
Takayuki Seki, Tomoya Fujiwara , Yoshio Takeuchi
Graduate School of Medicine and Pharmaceutical Sciences for Research, University of Toyama, Sugitani 2630, Toyama 930-0194, Japan
A R T I C L E I N F O
A B S T R A C T
Article history:
A practical procedure for the synthesis of 3-fluorooxindole derivatives having basic amine moieties was
developed, which involves SelectfluorTM-mediated oxidative fluorination of N,N-dialkyltryptamines in
the presence of Lewis acid. This procedure was applied to an antimigraine drug, rizatriptan, to afford the
corresponding 3-fluorooxindole, which is a potential fluorine-containing drug candidate.
ß 2011 Elsevier B.V. All rights reserved.
Received 13 December 2010
Accepted 25 December 2010
Available online 7 January 2011
Keywords:
Fluorination
Oxindole
N,N-Dialkyltryptamine
SelectfluorTM
Lewis acid
1. Introduction
dialkyltryptamines 6 having the rather basic amino group.
Compounds 6 are known to be effective ligands for serotonin
receptors [11] and the corresponding 3-fluorooxindoles 7 are
expected to be potential analogs for the putative oxindole-type
Fluorine-containing drugs and drug candidates have been
synthesized in pharmaceutical research over the last 20 years [1]
because introduction of fluorine atoms into bioactive compounds
often induces dramatic changes in their chemical, physical, and
pharmacological properties [2]. The 3-fluorooxindole compounds
1 have received much attention as synthetic targets for develop-
ment of novel medicinal agents (Fig. 1). Owing to the steric and
electronic similarities of a fluorine to a hydrogen and a hydroxyl
group [2], 3-fluorooxindoles are potential mimics of the corre-
sponding oxindoles 2 and 3-hydroxyoxindoles 3 that are often
found in natural products [3], biologically active compounds [4],
and metabolites of indoles [5]. For example, BMS-204352
(MaxiPostTM, 4) was reported to be effective for the treatment
of stroke [6]. As a part of our studies on the design, synthesis, and
biological evaluation of fluorine-containing bioactive compounds
[7], we have been developing the oxidative fluorination of indoles
with SelectfluorTM [1-chloromethyl-4-fluoro-1,4-diazoniabicy-
clo[2.2.2]octane bis(tetrafluoroborate)] (5) [8] to obtain the
corresponding 3-fluorooxindoles [9].
metabolites of
6 and as drug candidates having enhanced,
additional and/or altered biological activities. Herein, we report
an efficient procedure for the synthesis of 3-fluorooxindoles 7 by
direct, oxidative fluorination of 6 with 5 in the presence of Lewis
acid.
2. Results and discussion
We first attempted fluorination of N,N-dimethyltryptamine
(6a) as a model compound according to our procedure [9,10] which
employs 3 equiv of 5 in MeCN/H2O (1/1). However, unlike the
fluorination of Nb-acyl or -acyloxycarbonyl protected tryptamines
8a–c (Table 1, entries 1–3), only a trace amount of 3-fluorooxindole
7a was obtained (Table 1, entry 4) together with a substantial
amount of unidentified products. We then examined fluorination
of 6a in other solvents. Using MeOH/H2O in place of MeCN/H2O
increased the yield to 13% (entry 5). Further improvement of the
yield (24%) was observed when the reaction was performed in a 1/1
mixture of MeCN/MeOH (entry 6). Use of MeOH alone again
produced 7a, in low yield (7%) (entry 7). Interestingly, a trace
amount of N-methyltryptamine 10 could be isolated under the
conditions in entry 7.
In our recent studies on the application of the above
fluorination to Nb-acyl or -acyloxycarbonyl protected tryptamines
[10], we noticed that this fluorination is drastically affected by the
character of the Nb-amino group of tryptamines. In order to make
this fluorination versatile, we focused on
a class of N,N-
Formation of the N-demethylated product 10 suggested that
the dimethylamino group of 6a can be oxidized by 5. The
mechanism of this oxidation would involve formation of the
iminium ion 12 and carbinolamine 13 (Scheme 1, path A). Path B
* Corresponding author. Fax: +81 76 434 5053.
E-mail address: tfuji@pha.u-toyama.ac.jp (T. Fujiwara).
0022-1139/$ – see front matter ß 2011 Elsevier B.V. All rights reserved.
doi:10.1016/j.jfluchem.2010.12.014

182
T. Seki et al. / Journal of Fluorine Chemistry 132 (2011) 181–185
aminonitriles 17 and 18 in 58% and 8% yields, respectively (Scheme
2), which strongly supports the oxidative pathways shown in
Scheme 1. It should be noted that oxidation of tertiary amines is
known to trigger various transformations including N-dealkyla-
tion, dimerization, deamination, etc. [14]. Thus, formation of the
complex mixture in the reaction of 6a with 5 is probably due to the
high nucleophilicity of the dimethylamino group of 6a.
With these results in mind, we attempted the fluorination of 6a
in the presence of acid so as to decrease the nucleophilicity of the
dimethylamino group. Results are shown in Table 2. Fluorination of
6a in the presence of 1.1 equiv of BF3ÁMeOH in MeCN/MeOH (1/1)
produced 7a in 73% yield (entry 1). Use of a larger or smaller
amount of BF3ÁMeOH did not improve the results (entries 2 and 3).
After screening several Lewis acids for further optimization
(entries 4–7), the best result (96% yield) was obtained when the
fluorination was carried out using 1.1 equiv of AlCl3 (entry 4). Next,
we examined the reaction in the presence of some Brønsted acids.
Treatment of 6a with 1.1 equiv of acetic acid or trifluoroacetic acid
furnished 3-fluorooxindole 7a in moderate yields (entries 8 and 9).
We also attempted the fluorination using N,N-dimethyltryptamine
hydrochloride salt (6a Á HCl) as a substrate. However, the yields of
7a did not meet our expectation (entries 10–12).
Fig. 1. Structures of compounds 1–7.
would be an alternative possibility although we could not isolate
aldehyde 16. Actually, similar mechanisms have been proposed for
the demethylation of tertiary methylamines using halogenating
reagents [12] and heme enzymes [13].
To confirm these reaction pathways, we attempted to trap the
intermediates 12 and 14 with a cyanide anion. Reaction of 6a with
For scope and limitations we applied the newly developed
procedure for other N,N-dialkyltryptamines 6b–h having various
acyclic and cyclic amino groups (Table 3). Fluorination of 6b–h
5 and sodium cyanide in MeOH at 0 8C for 30 min produced
a-
Table 1
Fluorination of tryptamines 6a and 8a–c with SelectfluorTM (5).
.
Entry
Substrate
R1
R2
R3
Solvent (ratio)
Product
Yield (%)
1
2
3
4
5
6
7
8aa
8bb
8cc
6a
Ac
H
CO2Me
MeCN/H2O (1/1)
MeCN/H2O (1/1)
MeCN/H2O (1/1)
MeCN/H2O (1/1)
MeOH/H2O (1/1)
MeCN/MeOH (1/1)
MeOH
9a
9b
9c
7a
7a
7a
7a
70
Boc
Boc
Me
Me
Me
Me
Boc
Boc
Me
Me
Me
Me
CO2Me
71
H
H
H
H
H
71d
Trace
13
6a
6a
24
7 (13)e
6a
a
Ref. [9].
b
c
Ref. [10a].
Ref. [10b].
d
e
Yields of the Nb-Boc diprotected fluorooxindole and the Nb-Boc monoprotected fluorooxindole are 20% and 51%, respectively.
Yield of the recovered starting material in parenthesis.
Scheme 1. Possible mechanism for oxidation of tertiary amine 6a mediated by 5.

T. Seki et al. / Journal of Fluorine Chemistry 132 (2011) 181–185
183
Scheme 2. Trapping of the iminium ion intermediates using sodium cyanide.
Table 2
Fluorination of 6a and its hydrochloride 6a Á HCl in the presence of various acids.
Fig. 2. 1H NMR spectra of 6a before and after addition of AlCl3.
.
Entry
Substrate
Additive (equiv)
Solvent (ratio)
Yield (%)
1
2
6a
BF3ÁMeOH (1.1)
BF3ÁMeOH (0.1)
BF3ÁMeOH (10)
AlCl3 (1.1)
SnCl4 (1.1)
ZnCl2 (1.1)
TiCl4 (1.1)
AcOH (1.1)
TFA (1.1)
MeCN/MeOH (1/1)
MeCN/MeOH (1/1)
MeCN/MeOH (1/1)
MeCN/MeOH (1/1)
MeCN/MeOH (1/1)
MeCN/MeOH (1/1)
MeCN/MeOH (1/1)
MeCN/MeOH (1/1)
MeCN/MeOH (1/1)
MeCN/H2O (1/1)
73
54
33
96
76
13
75
27
64
35
27
55
6a
3
6a
4
6a
5
6a
6
6a
Scheme 3. Synthesis of 3-fluorooxindole 20 from rizatriptan (19).
7
6a
8
6a
CD3OD (1/1) at room temperature. The original N-Me signal of 6a
observed at 2.32 ppm shifted to lower field, appearing at 2.88,
upon addition of 1 equiv of AlCl3 (Fig. 2). This result suggested that
the nucleophilicity of the dialkylamino group would be decreased
by the coordination to AlCl3 in the course of fluorination of 6a.
However, considering that similar low-field shift was observed by
addition of 1 equiv of H2SO4, the nucleophilicity would be also
decreased by protonation with the Lewis-acid-assisted Brønsted
acid derived from MeOH and AlCl3 [15].
Finally, we applied this new protocol to a tryptamine-based
medicinal, rizatriptan (19), which is a potent agonist toward both
serotonin 5-HT1B and 5-HT1D receptors, and is currently used for
treatment for migraine headache [16]. Reaction of 19 with 3 equiv
of 5 in the presence of 1.1 equiv of AlCl3 in MeCN/MeOH (1/1)
produced 20 in 75% yield (Scheme 3).
9
6a
10
11
12
6aÁHCl
6aÁHCl
6aÁHCl
None
None
MeOH/H2O (1/1)
MeCN/MeOH (1/1)
None
with 5, in the presence of 1.1 equiv of AlCl3, successfully produced
the corresponding 3-fluorooxindoles 7b–h in excellent yields
(entries 1–7). Fluorination of 6i–k having electron-donating and -
withdrawing groups at the 5-position of indole ring also gave
satisfactory results (entries 8–10). Thus, we have developed a
practical oxidative fluorination of N,N-dialkyltryptamines 6 with
broad applicability.
In order to investigate the effect of AlCl3 on the fluorination, we
performed a 1H NMR spectroscopic investigation of 6a in CD3CN/
3. Conclusion
Table 3
We have developed a facile procedure for the synthesis of 3-[2-
(N,N-dialkylamino)ethyl]-3-fluorooxindoles 7 by direct oxidative
fluorination of N,N-dialkyltryptamines 6 with SelectfluorTM (5) in
the presence of Lewis acid. The new procedure will enable the
synthesis of 3-fluorooxindole derivatives having basic amine
moieties in only one step from the corresponding tryptamines.
Enantiomer separation and biological evaluation of the obtained 3-
fluorooxindoles are currently underway.
Oxidative fluorination of various N,N-dialkyltryptamines 6b–k with
5 in the
presence of AlCl3.
.
4. Experimental
Entry
Substrate
R1
R2
R3
Product
Yield (%)
4.1. General
1
2
6b
6c
6d
6e
6f
Et
Et
H
7b
7c
7d
7e
7f
90
98
98
99
92
93
90
88
95
96
i-Pr
i-Pr
H
3
–(CH2)4–
–(CH2)5–
H
Melting points were measured with a Yanaco micro melting
point apparatus and are uncorrected. Spectroscopic measurements
were carried out with the following instruments: IR spectra, JASCO
FT/IR-460Plus; mass spectra (MS), JEOL JMS-GCmate II; high
resolution mass spectra (HRMS), JEOL JMS-GCmate II; 1H NMR
spectra, JEOL ECX-400P (400 MHz) in CDCl3 with TMS (=0.00 ppm)
as an internal standard; 13C NMR spectra, JEOL ECX-400P
4
H
5
Me
Et
H
6
6g
6h
6i
Me
Me
Me
Me
Me
n-Pr
Bn
H
7g
7h
7i
7
H
8
Me
Me
Me
Me
Br
Cl
9
6j
7j
10
6k
7k

184
T. Seki et al. / Journal of Fluorine Chemistry 132 (2011) 181–185
(100 MHz) in CDCl3 with CDCl3 (=77.0 ppm) as an internal
standard; 19F NMR spectra, JEOL ECX-400P (376 MHz) in CDCl3
with CFCl3 (=0.00 ppm) as an internal standard. Column chroma-
tography and thin layer chromatography were performed on
Merck 9385 silica gel 60 (0.040–0.063 mm) and on Merck 5715,
respectively.
4.2.4. 3-(2-Piperidinoethyl)-3-fluorooxindole (7e)
Yield: 99%; pale yellow oil; IR (neat) 3063 (NH), 1733 (C55O)
cmÀ1 1H NMR
1.28–1.34 (2H, m), 1.40–1.46 (4H, m), 2.04–2.09
(2H, m), 2.21–2.35 (5H, m), 2.59 (1H, ddt, J = 20.8, 13.0, 4.7 Hz),
6.92 (1H, d, J = 7.8 Hz), 7.07 (1H, t, J = 7.8 Hz), 7.31 (1H, tt, J = 7.8,
1.4 Hz), 7.36 (1H, dd, J = 7.8, 1.4 Hz), 9.05 (1H, brs); 13C NMR
d 24.1,
n
;
d
25.5, 31.9 (d, J = 26.8 Hz), 52.8 (d, J = 9.6 Hz), 54.3, 93.6 (d,
J = 183.1 Hz), 110.5 (d, J = 1.9 Hz), 122.8 (d, J = 2.9 Hz), 124.9,
125.9 (d, J = 18.2 Hz), 131.1 (d, J = 2.9 Hz), 142.0 (d, J = 4.8 Hz),
4.2. General procedure for the synthesis of 3-fluorooxindole
derivatives 7 and 20 by the fluorination of tryptamines 6 and 19 with
SelectfluorTM (5) in the presence of AlCl3: 3-[2-(N,N-
dimethylamino)ethyl]-3-fluorooxindole (7a)
175.1 (d, J = 21.1 Hz); 19F NMR
d –154.37 (1F, brs); MS (EI) m/z: 262
(M+), 242 (M+–HF); HRMS (EI) calcd for C15H19FN2O (M+):
262.1481; found 262.1466.
To a stirred MeCN/MeOH (1/1, 5 ml) solution of 6a (50 mg,
0.27 mmol) were added AlCl3 (39 mg, 0.29 mmol) and Select-
fluorTM (5) (282 mg, 0.80 mmol) at 0 8C. The mixture was stirred for
30 min at room temperature. Concentration of the mixture gave a
residue, which was purified by silica gel column chromatography
(eluent: CHCl3/MeOH/NH4OH = 93/7/0.5) to give 3-fluorooxindole
4.2.5. 3-[2-(N-Ethyl-N-methylamino)ethyl]-3-fluorooxindole (7f)
Yield: 92%; pale yellow oil; IR (neat)
n 3207 (NH), 1739 (C55O)
cmÀ1 1H NMR
;
d
0.87 (3H, t, J = 7.3 Hz), 2.11 (3H, s), 2.18–2.42
(5H, m), 2.53 (1H, m), 6.91 (1H, d, J = 7.8 Hz), 7.08 (1H, t,
J = 7.8 Hz), 7.32 (1H, tt, J = 7.8, 1.4 Hz), 7.38 (1H, dd, J = 7.8,
1.4 Hz), 9.06 (1H, brs); 13C NMR
d 11.7, 32.1 (d, J = 26.8 Hz), 41.1,
7a (57 mg, 96%) as a pale yellow oil: IR (neat)
n 2952 (NH), 1735
(C55O) cmÀ1 1H NMR
;
d
2.14 (6H, s), 2.25–2.36 (3H, m), 2.48 (1H,
50.8 (d, J = 8.6 Hz), 51.2, 93.4 (d, J = 184.0 Hz), 110.7, 122.9 (d,
J = 2.9 Hz), 125.0, 125.9 (d, J = 18.2 Hz), 131.2 (d, J = 2.9 Hz),
m), 6.91 (1H, d, J = 7.8 Hz), 7.08 (1H, t, J = 7.8 Hz), 7.32 (1H, tt,
J = 7.8, 1.8 Hz), 7.38 (1H, dd, J = 7.8, 1.8 Hz), 9.18 (1H, brs); 13C NMR
142.0 (d, J = 5.8 Hz), 175.1 (d, J = 21.1 Hz); 19F NMR
d –154.82
(1F, t, J = 12.4 Hz); MS (EI) m/z: 236 (M+), 221 (M+–CH3), 216
(M+–HF), 187 (M+–HF–C2H5); HRMS (EI) calcd for C13H17FN2O
(M+): 236.1325; found 236.1323.
d
32.7 (d, J = 27.8 Hz), 45.1, 53.0 (d, J = 7.7 Hz), 93.1 (d,
J = 185.0 Hz), 110.6 (d, J = 1.9 Hz), 123.0 (d, J = 2.9 Hz), 124.9 (d,
J = 1.9 Hz), 125.9 (d, J = 18.2 Hz), 131.2 (d, J = 3.8 Hz), 141.8 (d,
J = 5.8 Hz), 174.9 (d, J = 21.1 Hz); 19F NMR
d –155.74 (1F, dd,
J = 13.0, 10.8 Hz); MS (EI) m/z: 222 (M+), 202 (M+–HF), 187 (M+–
HF–CH3); HRMS (EI) calcd for C12H15FN2O (M+): 222.1168; found
222.1147.
4.2.6. 3-[2-(N-Methyl-N-propylamino)ethyl]-3-fluorooxindole (7g)
Yield: 93%; pale brown oil; IR (neat)
n 3208 (NH), 1739 (C55O)
cmÀ1 1H NMR
;
d
0.79 (3H, t, J = 7.3 Hz), 1.31 (2H, sex, J = 7.3 Hz),
2.10–2.57 (6H, m), 2.13 (3H, s), 6.91 (1H, d, J = 7.8 Hz), 7.07 (1H, t,
J = 7.8 Hz), 7.31 (1H, tt, J = 7.8, 1.4 Hz), 7.37 (1H, dd, J = 7.8, 1.4 Hz),
4.2.1. 3-[2-(N,N-Diethylamino)ethyl]-3-fluorooxindole (7b)
Yield: 90%; colorless oil; IR (neat)
n 3208 (NH), 1737 (C55O)
9.25 (1H, brs); 13C NMR
d 11.7, 19.9, 32.0 (d, J = 26.8 Hz), 41.5, 51.3
cmÀ1 1H NMR
;
d
0.84 (6H, t, J = 7.3 Hz), 2.22–2.37 (3H, m), 2.41–
(d, J = 8.6 Hz), 59.6, 93.2 (d, J = 184.0 Hz), 110.6, 123.0 (d,
J = 2.9 Hz), 124.9, 125.9 (d, J = 18.2 Hz), 131.2 (d, J = 3.8 Hz),
2.58 (5H, m), 6.89 (1H, d, J = 7.8 Hz), 7.08 (1H, t, J = 7.8 Hz), 7.32
(1H, tt, J = 7.8, 1.8 Hz), 7.38 (1H, dd, J = 7.8, 1.8 Hz), 8.30 (1H, brs);
141.8 (d, J = 5.8 Hz), 174.8 (d, J = 21.1 Hz); 19F NMR
d –155.05
13C NMR
d 11.1, 31.5 (d, J = 26.8 Hz), 46.4, 46.6 (d, J = 8.6 Hz), 93.3
(1F, brs); MS (EI) m/z: 250 (M+), 230 (M+–HF), 221 (M+–C2H5), 201
(d, J = 183.1 Hz), 110.5, 123.0 (d, J = 2.9 Hz), 125.0 (d, J = 1.9 Hz),
125.9 (d, J = 18.2 Hz), 131.2 (d, J = 2.9 Hz), 141.8 (d, J = 5.8 Hz),
(M+–HF–C2H5), 187 (M+–HF–C3H7); HRMS (EI) calcd for
C
14H19FN2O (M+): 250.1481; found 250.1475.
174.5 (d, J = 21.1 Hz); 19F NMR
d –153.70 (1F, brs); MS (EI) m/z: 250
(M+), 235 (M+–CH3), 230 (M+–HF), 201 (M+–HF–C2H5); HRMS (EI)
calcd for C14H19FN2O (M+): 250.1481; found 250.1471.
4.2.7. 3-[2-(N-Benzyl-N-methylamino)ethyl]-3-fluorooxindole (7h)
Yield: 90%; colorless oil; IR (neat) 3418 (NH), 1733 (C55O)
cmÀ1 1H NMR
2.08 (3H, s), 2.32–2.63 (4H, m), 3.34 (1H, d,
n
;
d
4.2.2. 3-[2-(N,N-Diisopropylamino)ethyl]-3-fluorooxindole (7c)
J = 13.3 Hz), 3.40 (1H, d, J = 13.3 Hz), 6.88 (1H, d, J = 7.8 Hz), 7.05
(1H, t, J = 7.8 Hz), 7.15–7.25 (5H, m), 7.29 (1H, tt, J = 7.8, 1.4 Hz),
Yield: 98%; pale yellow solid; mp 119–122 8C; IR (KBr)
n 3170
(NH), 1730 (C55O) cmÀ1; 1H NMR
d
0.84 (6H, d, J = 6.4 Hz), 0.89 (6H,
7.34 (1H, dd, J = 7.8, 1.8 Hz), 8.83 (1H, brs); 13C NMR
d 32.2 (d,
d, J = 6.9 Hz), 2.26 (1H, m), 2.41–2.52 (3H, m), 2.96 (2H, sept,
J = 6.4 Hz), 6.93 (1H, d, J = 7.8 Hz), 7.10 (1H, t, J = 7.8 Hz), 7.32 (1H,
tt, J = 7.8, 1.8 Hz), 7.39 (1H, dd, J = 7.8, 1.8 Hz), 8.91 (1H, brs); 13C
J = 27.8 Hz), 41.5, 51.4 (d, J = 8.6 Hz), 62.3, 93.2 (d, J = 185.0 Hz),
110.6 (d, J = 1.9 Hz), 123.0 (d, J = 2.9 Hz), 125.0, 125.9 (d,
J = 18.2 Hz), 126.9, 128.1, 128.9, 131.1 (d, J = 2.9 Hz), 138.3,
NMR d 19.8, 20.7, 35.6 (d, J = 25.9 Hz), 38.9 (d, J = 9.6 Hz), 48.1, 93.3
141.5 (d, J = 5.8 Hz), 174.7 (d, J = 21.1 Hz); 19F NMR
d –154.37
(d, J = 184.0 Hz), 110.8 (d, J = 1.9 Hz), 123.0 (d, J = 2.9 Hz), 124.9,
126.1 (d, J = 18.2 Hz), 131.1 (d, J = 3.8 Hz), 141.7 (d, J = 5.8 Hz),
(1F, brs); MS (EI) m/z: 298 (M+), 283 (M+–CH3), 278 (M+–HF), 207
(M+–C7H7), 187 (M+–HF–C7H7); HRMS (EI) calcd for C18H19FN2O
(M+): 298.1481; found 298.1481.
175.2 (d, J = 21.1 Hz); 19F NMR
d –153.65 (1F, brs); MS (EI) m/z: 278
(M+), 263 (M+–CH3), 258 (M+–HF), 215 (M+–HF–C3H7); HRMS (EI)
calcd for C16H23FN2O (M+): 278.1794; found 278.1788.
4.2.8. 3-[2-(N,N-Dimethylamino)ethyl]-3-fluoro-5-methyloxindole
(7i)
4.2.3. 3-(2-Pyrrolidinoethyl)-3-fluorooxindole (7d)
Yield: 88%; pale brown oil; IR (neat)
cmÀ1; 1H NMR
2.15 (6H, s), 2.22–2.33 (3H, m), 2.33 (3H, s), 2.47
(1H, tt, J = 13.3, 5.1 Hz), 6.80 (1H, d, J = 7.8 Hz), 7.11 (1H, d,
J = 7.8 Hz), 7.19 (1H, s), 9.05 (1H, brs); 13C NMR
21.0, 32.8 (d,
n 2951 (NH), 1737 (C55O)
Yield: 98%; pale yellow oil; IR (neat)
n 3210 (NH), 1738 (C55O)
cmÀ1 1H NMR
;
d
1.65–1.73 (4H, m), 2.31–2.42 (3H, m), 2.44–2.58
d
(5H, m), 6.91 (1H, d, J = 7.8 Hz), 7.07 (1H, t, J = 7.8 Hz), 7.31 (1H, tt,
J = 7.8, 1.4 Hz), 7.38 (1H, dd, J = 7.8, 1.4 Hz), 9.21 (1H, brs); 13C NMR
d
J = 27.8 Hz), 45.1, 52.9 (d, J = 8.6 Hz), 93.3 (d, J = 185.0 Hz), 110.4,
125.5, 125.9 (d, J = 18.2 Hz), 131.5 (d, J = 2.9 Hz), 132.6 (d,
d
23.4, 34.0 (d, J = 27.8 Hz), 49.5 (d, J = 8.6 Hz), 53.8, 93.2 (d,
J = 185.0 Hz), 110.6 (d, J = 1.9 Hz), 122.9 (d, J = 1.9 Hz), 124.9, 126.0
(d, J = 18.2 Hz), 131.1 (d, J = 2.9 Hz), 141.8 (d, J = 5.8 Hz), 175.1 (d,
J = 2.9 Hz), 139.2 (d, J = 5.8 Hz), 175.0 (d, J = 21.1 Hz); 19F NMR
d
–155.45 (1F, dd, J = 13.3, 12.6 Hz); MS (EI) m/z: 236 (M+), 216 (M+–
HF), 201 (M+–HF–CH3); HRMS (EI) calcd for C13H17FN2O (M+):
236.1325; found 236.1318.
J = 21.1 Hz); 19F NMR
d –155.65 (1F, dd, J = 11.7, 10.3 Hz); MS (EI)
m/z: 248 (M+), 228 (M+–HF); HRMS (EI) calcd for C14H17FN2O (M+):
248.1325; found 248.1316.

T. Seki et al. / Journal of Fluorine Chemistry 132 (2011) 181–185
185
(b) G.D. Zhu, V.B. Gandhi, J. Gong, Y. Luo, X. Liu, Y. Shi, R. Guan, S.R. Magnone, V.
Klinghofer, E.F. Johnson, J. Bouska, A. Shoemaker, A. Oleksijew, K. Jarvis, C. Park,
R.D. Jong, T. Oltersdorf, Q. Li, S.H. Rosenberg, V.L. Giranda, Bioorg. Med. Chem. Lett.
16 (2006) 3424–3429;
(c) L. Buckbinder, D.T. Crawford, H. Qi, H.Z. Ke, L.M. Olson, K.R. Long, P.C. Bonnette,
A.P. Baumann, J.E. Hambor, W.A. Grasser III, L.C. Pan, T.A. Owen, M.J. Luzzio, C.A.
Hulford, D.F. Gebhard, V.M. Paralkar, H.A. Simmons, J.C. Kath, W.G. Roberts, S.L.
Smock, A. Guzman-Perez, T.A. Brown, M. Li, Proc. Natl. Acad. Sci. U.S.A. 104 (2007)
10619–10624.
4.2.9. 5-Bromo-3-[2-(N,N-dimethylamino)ethyl]-3-fluorooxindole
(7j)
Yield: 95%; pale yellow oil; IR (neat)
cmÀ1; 1H NMR
2.13 (6H, s), 2.21–2.36 (3H, m), 2.48 (1H, m), 6.81
(1H, dd, J = 8.2, 1.8 Hz), 7.45 (1H, dt, J = 8.2, 1.8 Hz), 7.50 (1H, t,
J = 1.8 Hz); 13C NMR
32.6 (d, J = 26.8 Hz), 45.0, 52.9 (d, J = 7.7 Hz),
n 2953 (NH), 1742 (C55O)
d
d
92.9 (d, J = 185.9 Hz), 112.2, 115.4 (d, J = 2.9 Hz), 127.8 (d,
J = 18.2 Hz), 128.2, 134.0 (d, J = 2.9 Hz), 140.9 (d, J = 5.8 Hz),
[5] For selected examples: (a) Z. Yang, M.Z. Wrona, G. Dryhurst, J. Neurochem. 68
(1997) 1929–1941.
174.4 (d, J = 21.1 Hz); 19F NMR
d –155.81 (1F, dd, J = 13.5,
(b) K.W. Skordos, G.L. Skiles, J.D. Laycock, D.L. Lanza, G.S. Yost, Chem. Res. Toxicol.
11 (1998) 741–749;
(c) E.M.J. Gillam, L.M. Notley, H. Cai, J.J. De Voss, F.P. Guengerich, Biochemistry 39
(2000) 13817–13824;
11.7 Hz); MS (EI) m/z: 302 (M++2), 300 (M+), 282 [(M++2)–HF],
280 (M+–HF), 267 [(M++2)–HF–CH3], 265 (M+–HF–CH3); HRMS (EI)
calcd for C12H14BrFN2O (M+): 300.0274; found 300.0273.
(d) R.E. Staub, B. Onisko, L.F. Bjeldanes, Chem. Res. Toxicol. 19 (2006) 436–442.
[6] P. Hewawasam, V.K. Gribkoff, Y. Pendri, S.I. Dworetzky, N.A. Meanwell, E. Marti-
nez, C.G. Boissard, D.J. Post-Munson, J.T. Trojnacki, K. Yeleswaram, L.M. Pajor, J.
Knipe, Q. Gao, R. Perrone, J.E. Starrett Jr., Bioorg. Med. Chem. Lett. 12 (2002) 1023–
1026.
4.2.10. 5-Chloro-3-[2-(N,N-dimethylamino)ethyl]-3-fluorooxindole
(7k)
Yield: 96%; pale yellow oil; IR (neat)
cmÀ1; 1H NMR
2.13 (6H, s), 2.21–2.35 (3H, m), 2.49 (1H, m), 6.85
(1H, dd, J = 8.2, 1.8 Hz), 7.30 (1H, dt, J = 8.2, 1.8 Hz), 7.36 (1H, t,
J = 1.8 Hz), 9.29 (1H, brs); 13C NMR
32.6 (d, J = 26.8 Hz), 45.0, 52.9
(d, J = 8.6 Hz), 93.0 (d, J = 185.9 Hz), 111.7, 125.4, 127.5 (d,
J = 18.2 Hz), 128.3 (d, J = 2.9 Hz), 131.1 (d, J = 3.8 Hz), 140.4 (d,
n
2949 (NH), 1740 (C55O)
[7] (a) Y. Takeuchi, T. Shiragami, K. Kimura, E. Suzuki, N. Shibata, Org. Lett. 1 (1999)
1571–1573;
d
(b) Y. Takeuchi, N. Shibata, E. Suzuki, Y. Iimura, T. Kosasa, T. Yamanishi, H.
Sugimoto, PCT Int. Appl. WO 2002020482; Chem. Abstr. 136 (2002) 247496;
(c) H. Fujisawa, T. Fujiwara, Y. Takeuchi, K. Omata, Chem. Pharm. Bull. 53 (2005)
524–528;
(d) Y. Takeuchi, H. Fujisawa, T. Fujiwara, M. Matsuura, H. Komatsu, S. Ueno, T.
Matsuzaki, Chem. Pharm. Bull. 53 (2005) 1062–1064;
d
J = 5.8 Hz), 174.5 (d, J = 21.1 Hz); 19F NMR
d –155.92 (1F, dd,
(e) Y. Takeuchi, T. Fujiwara, T. Saito, US 20090171093; Chem. Abstr., 151, 123831,
2009.
J = 13.5, 10.3 Hz); MS (EI) m/z: 258 (M++2), 256 (M+), 238 [(M++2)–
HF], 236 (M+–HF), 223 [(M++2)–HF–CH3], 221 (M+–HF–CH3);
HRMS (EI) calcd for C12H14ClFN2O (M+): 256.0779; found
256.0764.
[8] (a) S.D. Taylor, C.C. Kotoris, G. Hum, Tetrahedron 55 (1999) 12431–12477;
(b) R.P. Singh, J.M. Shreeve, Acc. Chem. Res. 37 (2004) 31–44.
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[10] (a) T. Fujiwara, B. Yin, M. Jin, K.L. Kirk, Y. Takeuchi, J. Fluorine Chem. 129 (2008)
829–835;
(b) T. Fujiwara, T. Seki, M. Miura, Y. Takeuchi, Heterocycles 79 (2009) 427–432.
[11] For selected examples: (a) M. Dukat, C. Smith, K. Herrick-Davis, M. Teitler, R.A.
Glennon, Bioorg. Med. Chem. 12 (2004) 2545–2552.
4.2.11. 3-[2-(N,N-Dimethylamino)ethyl]-3-fluoro-5-[(1,2,4-triazol-
1-yl)methyl]oxindole (20)
(b) J. Holenz, R. Merce`, J.L. Dı´az, X. Guitart, X. Codony, A. Dordal, G. Romero, A.
Torrens, J. Mas, B. Andaluz, S. Herna´ndez, X. Monroy, E. Sa´nchez, E. Herna´ndez, R.
Pe´rez, R. Cubı´, O. Sanfeliu, H. Buschmann, J. Med. Chem. 48 (2005) 1781–1795;
(c) H. Sard, G. Kumaran, C. Morency, B.L. Roth, B.A. Toth, P. He, L. Shuster, Bioorg.
Med. Chem. Lett. 15 (2005) 4555–4559;
Yield: 75%; pale yellow oil; IR (neat)
cmÀ1; 1H NMR
2.08 (6H, s), 2.19–2.30 (3H, m), 2.48 (1H, m), 6.88
(1H, d, J = 7.8 Hz), 7.25 (1H, dt, J = 7.8, 1.8 Hz), 7.34 (1H, t,
J = 1.8 Hz), 7.98 (1H, s), 8.10 (1H, s), 8.28 (1H, brs); 13C NMR
32.6
(d, J = 26.8 Hz), 45.0, 53.0 (d, J = 7.7 Hz), 53.1, 92.7 (d, J = 185.9 Hz),
110.8, 125.0, 126.8 (d, J = 18.2 Hz), 129.4 (d, J = 2.9 Hz), 131.2 (d,
J = 2.9 Hz), 142.1 (d, J = 5.8 Hz), 143.0, 152.3, 174.2 (d, J = 21.1 Hz);
n 3119 (NH), 1737 (C55O)
d
d
(d) M. Dukat, P.D. Mosier, R. Kolanos, B.L. Roth, R.A. Glennon, J. Med. Chem. 51
(2008) 603–611.
[12] (a) K. Acosta, J.W. Cessac, P.N. Rao, H.K. Kim, J. Chem. Soc., Chem. Commun.
(1994) 1985–1986;
(b) P.A. Lartey, H.N. Nellans, R. Faghih, A. Petersen, C.M. Edwards, L. Freiberg, S.
Quigley, K. Marsh, L.L. Klein, J.J. Plattner, J. Med. Chem. 38 (1995) 1793–1798;
(c) H.G. Stenmark, A. Brazzale, Z. Ma, J. Org. Chem. 65 (2000) 3875–3876;
(d) T. Katoh, T. Watanabe, M. Nishitani, M. Ozeki, T. Kajimoto, M. Node, Tetrahe-
dron Lett. 49 (2008) 598–600.
19F NMR
d
–155.21 (1F, t, J = 12.4 Hz); MS (EI) m/z: 303 (M+), 283
(M+–HF), 268 (M+–HF–CH3); HRMS (EI) calcd for C15H18FN5O (M+):
303.1495; found 303.1491.
[13] (a) F.P. Guengerich, C.H. Yun, T.L. Macdonald, J. Biol. Chem. 271 (1996) 27321–
27329;
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