Grignard cyclization reaction of fluorinated N-arylimidoyl chlorides: A novel and facile access to 2-fluoroalkyl indoles

Article abstract of DOI:10.1055/s-2007-967950

2-Fluoroalkyl-substituted indole derivatives were simply prepared via the Grignard cyclization reaction (GCR) of corresponding fluorinated N-aryl imidoyl chlorides in good yields. This approach provides a novel and facile access to the biologically import

Full text of DOI:10.1055/s-2007-967950

LETTER
447
Grignard Cyclization Reaction of Fluorinated N-Arylimidoyl Chlorides:
A Novel and Facile Access to 2-Fluoroalkyl Indoles
A
ccess to 2-Fl
e
uoroalkyl
I
n
a
Department of Chemistry, Shanghai University, 99 Shangda Road, Shanghai 200444, P. R. of China
Fax +86(21)66133380; E-mail: jhao@mail.shu.edu.cn
b
Key Laboratory of Organofluorine Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences,
354 Fenglin Road, Shanghai 200032, P. R. of China
Received 24 August 2006
which were readily prepared from commercially available
o-alkylanilines and fluorine-containing carboxylic acids,
This approach provides a novel and facile access to
various 2-fluoroalkyl-subsituted indole derivatives spe-
cifically (Scheme 1).
Abstract: 2-Fluoroalkyl-substituted indole derivatives were simply
prepared via the Grignard cyclization reaction (GCR) of corre-
sponding fluorinated N-aryl imidoyl chlorides in good yields. This
approach provides a novel and facile access to the biologically
important 2-fluoroalkylindole derivatives.
Key words: fluorine-containing Indoles, Grignard cyclizations,
imidoyl chlorides, aryl amines, heterocycles
The 2-fluoroalkyl-substituted indole derivatives 3 were
successfully prepared through the GCR of either fluori-
nated N-(2-bromoalkyl)phenyl imidoyl chlorides 2 under
normal Grignard reaction condition in moderate to good
yields.5
Due to the many potential bioactivities, fluorine-contain-
ing heterocycles have long received wide attention from
either synthetic chemists or pharmaceutical scientists. As
one of the important heterocycles, indole ring systems are
found in many pharmaceuticals, for instance, indometha-
cin, oxypertine, and sumatriptan. Even today, the synthe-
sis and applications of various indole derivatives are key
subjects of considerable efforts.1,2 However, indole ring
systems bearing a fluoroalkyl group, especially 2- or 3-
fluoroalkyl-substituted systems, have not been well-in-
vestigated due to the lack of efficient approaches to access
the systems. Recently, Konno and his co-workers reported
the palladium(0)-catalyzed regioselective annulation of
fluorine-containing internal alkynes with o-iodoanilines,
which provided a direct access to both 2- and 3-fluoro-
alkyl-substituted indole derivatives with good yields.3
However, the application of this method is still somewhat
limited due to the use of valuable palladium catalyst and
the starting material source. Some other methods were
also developed, but most of them suffered from either
poor yields or the limitation of starting materials.4 The de-
velopment of novel and simple approach to synthesize the
fluorine-containing indole derivatives from commercially
or rapidly available materials still remains a challenge.
R1
R1
Br
Mg, THF
R2
R2
Cl
0 °C to r.t., 2 h
N
N
RF
H
RF
2
3
RF = CF3, CF2H, n-C3F7
Scheme 1 Grignard cyclization reaction (GCR) of N-aryl imidoyl
chlorides
The yields of 3 from GCR of compounds 2 were found to
be greatly affected by the electronic effect of the substitu-
ent group R2 on the benzene ring. Without the substituent
group (R2 = H) or with an electron-donating group, such
as methoxy, 3 could be obtained in good yields. With
moderately electron-withdrawing groups, such as F, or Cl,
the yields of 3 were decreased. While the presence of a
strongly electron-withdrawing substituent, such as a nitro
group, was found to inhibit the reaction and resulted in the
total recovery of starting materials (Table 1). The process
of this GCR was generally clean and no other by-products
were in all cases examined. The high yielding and simple
work-up procedure also enabled us to carry out the reac-
tions even in larger scale.
Our interest in the synthesis of 2-fluoroalkyl-substituted
indoles arose from ongoing research projects for the syn-
thesis of 2-trifluoromethyl-substituted indole 3-carbinol
and indomethacin derivatives, which all contain the indole
ring systems. In this letter, we wish to report and share our
preliminary results from the synthesis of 2-fluoroalkyl
indole derivatives via Grignard cyclization reaction
(GCR) of the corresponding N-aryl imidoyl chlorides,
The N-(2-bromoalkyl)phenyl imidoyl chlorides 2 were
prepared simply, in two steps, from o-alkylanilines via an
intermediate 1 according to Uneyama’s one-pot ap-
proach.6,7 Subsequent a-bromination at the benzylic
position of compound 1 in the presence of N-bromosuc-
cinimide (NBS)/benzoyl peroxide (BPO) resulted in the
formation of N-[2-(bromoalkyl)phenyl]imidoyl chlorides
2 in good to excellent yields (Scheme 2).8 Although N-[2-
(bromoalkyl)phenyl]imidoyl chlorides 2 were generally
SYNLETT 2007, No. 3, pp 0447–0450
1
5.
0
2.
2
0
0
7
Advanced online publication: 07.02.2007
DOI: 10.1055/s-2007-967950; Art ID: W17406ST
© Georg Thieme Verlag Stuttgart · New York

448
F. Ge et al.
LETTER
sensitive to acids, bases, and moisture, 2 can be purified derivatives. Hence, protection of the amino group of 3b
by flash column chromatography on neutral or basic alu- with 4-chlorobenzoyl chloride9 under basic conditions in
minum oxide, or by distillation under reduced pressure. DMSO–THF resulted in the formation compound 4 in
Electron-withdrawing substituents such as a nitro group, 93% yield. Following bromination of 3-methyl group of 4
substituted on the benzene ring, also decreased the yield with NBS/AIBN in refluxing CCl4 led to the formation of
of bromination reaction (entry 6, Table 1).
5 in 85% yield (Scheme 3).10 Nucleophilic substitution of
5 with NaCN was first examined in EtOH at room temper-
ature, and resulted in the formation of N-deprotected
nitrile 6 in 94% yield. This yield was obviously higher
than those without 2-trifluoromethyl substituent because
of the strong electron-withdrawing effect of the trifluoro-
methyl group. Under these reaction conditions, the
nucleophilic cyanide anion attacked both the amide group
and the bromide functionality. Subsequent hydrolysis of
cyanide group of 6 led to the formation of 2-trifluoro-
methyl-substituted heteroauxin 7 in 62% yield,11 which
has the potential to be used as a new plant growth regula-
tor or herbicide. The bioactivity of 7 is currently under
investigation.
RFCO2H
R1
Cl
R1
PPh3, Et3N
R2
R2
CCl4, reflux
83–97%
N
NH2
RF
1
R1
Br
Cl
NBS, BPO
R2
CCl4, reflux
56–92%
N
RF
2
Scheme 2 Synthesis of N-[2-(bromoalkyl)phenyl]imidoyl chlorides
Alternatively, compound 7 was also a precursor for the
synthesis of 2-trifluoromethyl-substituted indomethacin.
As described earlier, the 2-fluoroalkyl-substituted indole
derivatives 3 could be efficiently synthesized via GCR
from the corresponding fluorinated imidoyl chlorides 2 in
good yields. As one application of this synthetic method,
this approach provides us the possibility to explore the
biological activities of such 2-fluoroalkyl-substituted new
heteroauxin and indomethacin derivatives.
Hence, nucleophilic substitution reaction of 5 with
malonate carbanion successfully led to the formation of
compound 8 in 89% yield (Scheme 4).
In conclusion, a novel and facile approach for the synthe-
sis of biologically important 2-fluoroalkyl-substituted
indole derivatives via the GCR of the corresponding
fluorinated imidoyl chlorides has been established. The
nucleophilic substitutions of 5 have been demonstrated as
one of the efficient ways to access new generation of
interesting fluorine-containing indole derivatives, which
may lead to the discovery of new and valuable biologi-
cally active molecules.
On the basis of this consideration, 3-methyl-2-trifluoro-
methylindole (3b) was selected as a substrate for the syn-
thesis of 2-trifluoromethyl-substituted heteroauxin and
indomethacin derivatives due to the easy modification of
its 3-methyl group. Such modification could also lead to
the formation of other interesting 3-substituted indole
Table 1 Synthesis of 2-Fluoroalkyl-Substituted Indole Derivatives 3 from o-Alkylanilines
Entry
RF
R1
H
R2
Yield of 1 (%)a
1a 89
Yield of 2 (%)a
2a 91
Yield of 3 (%)a
3a 78
1
CF3
H
2
CF3
Me
H
H
1b 86
2b 92
3b 82
3
CF3
4-OMe
5-F
1c 92
2c 88
3c 75
4
CF3
H
1d 97
2d 82
3d 62
5
CF3
H
5-Cl
4-NO2
H
1e 97
2e 68
3e 45
b
6
CF3
H
1f 88
2f 56
–
7
CF2H
CF2H
n-C3F7
n-C3F7
H
1g 83
2g 85
3g 77
3h 78
3i 79
3j 76
8
H
4-OMe
H
1h 90
2h 82
9
Me
H
1i 89
2i 92
10
4-OMe
1j 90
2j 83
a Isolated yields.
b Recovery of starting material.
Synlett 2007, No. 3, 447–450 © Thieme Stuttgart · New York

LETTER
Access to 2-Fluoroalkyl Indoles
449
Me
(3) Konno, T.; Chae, J.; Ishihara, T.; Yamanaka, H. J. Org.
Chem. 2004, 69, 8258.
(4) (a) Latham, E. J.; Stanforth, S. P. J. Chem. Soc., Perkin
Trans. 1 1997, 2059. (b) Miyashita, K.; Kondoh, K.;
4-chlorobenzoyl
NBS
AIBN
chloride
N
CF3
3b
NaH, DMSO
THF, 93%
CCl4, reflux
85%
Tsuchiya, K.; Miyabe, H.; Imanishi, T. J. Chem. Soc., Perkin
Trans. 1 1996, 1261. (c) Kobayashi, M.; Sadamune, K.;
Mizukami, H.; Uneyama, K. J. Org. Chem. 1994, 59, 1909.
(d) Chen, Q.-Y.; Li, Z.-T. J. Chem. Soc., Perkin Trans. 1
1993, 645. (e) Huang, W.-Y. J. Fluorine Chem. 1992, 58, 1.
(f) Yoshida, M.; Yoshida, T.; Kobayashi, M.; Kamigata, N.
J. Chem. Soc., Perkin Trans. 1 1989, 909. (g) Girard, Y.;
Atkinson, J. G.; Belanger, P. C.; Fuentes, J. J.; Rokach, J.;
Rooney, C. S. J. Org. Chem. 1983, 48, 3220.
O
4
Cl
Br
CN
N
CF3
NaCN
EtOH
r.t., 94%
O
N
H
CF3
(h) Kobayashi, Y.; Kumadaki, I.; Hirose, Y.; Hanzawa, Y. J.
Org. Chem. 1974, 39, 1836.
Cl
6
5
(5) General Procedure for the Synthesis of 2-Fluoroalkyl-
Substituted Indoles 3.
CO2H
3 N HCl
To a flame-dried 100 mL three-necked round-bottomed
flask equipped with condenser and magnetic stir bar was
added magnesium ribbon (0.3 g, 12.1 mmol) and anhydrous
THF (25 mL) under a nitrogen atmosphere. A solution of the
appropriate fluorinated N-[(2-bromoalkyl)phenyl]imidoyl
chloride 2 (10.1 mmol) dissolved in THF (6 mL) was added
dropwise at 0 °C. The reaction started within a few minutes.
After addition, the reaction mixture was stirred for 2 h at
0 °C (monitored by TLC). Upon completion of the reaction,
the reaction mixture was quenched with 10 mL sat. solution
of NH4Cl and extracted with EtOAc (15 mL, 3 ×). The
combined organic layer was washed with brine, dried over
Mg2SO4, and concentrated by rotary evaporator. The residue
was then purified by column chromatography (20:1 hexane–
EtOAc) on neutral Al2O3 to yield products 3.
80% AcOH
reflux, 62%
N
H
CF3
7
Scheme 3 Synthesis of new trifluoromethyl-substituted hetero-
auxin 7
CH(CO2Me)2
t-BuOK
CH2(CO2Me)2
N
CF3
5
O
THF, 0 °C
89%
Cl
2-Trifluoromethylindole (3a).
8
Compound 3a was obtained as a light yellow solid in 78%
yield; mp 107–108 °C. 1H NMR (500 MHz): d = 8.30 (br, 1
H), 7.68 (d, J = 8.0 Hz, 1 H), 7.40 (d, J = 8.0 Hz, 1 H), 7.32
(t, J = 7.5 Hz, 1 H), 7.20 (t, J = 7.5 Hz, 1 H), 6.92 (s, 1 H).
Scheme 4 Nucleophilic substitution of 5 with malonate carbanion
13C NMR (125 MHz): d = 136.1, 126.6, 125.7 (q, JC–C–F
=
Acknowledgment
38.8 Hz), 124.8, 122.1, 121.2 (q, JC–F = 266.2 Hz), 121.1,
111.7, 104.3 (q, JC–C–C–F = 3.3 Hz). 19F NMR (470 MHz):
d = –60.50 (s, 3 F). IR (neat): 3389, 2921, 1375, 1306, 1196,
1168, 1103, 940, 818, 754 cm–1. Anal. Calcd for C9H6F3N:
C, 58.38; H, 3.27; N, 7.57. Found: C, 58.39; H, 3.32; N, 7.55.
HRMS: m/z calcd for C9H6F3N [M+]: 185.0452; found:
185.0452.
This work was financially supported by the National Natural
Science Foundation of China (No.20472049) and Key Laboratory
of Organofluorine Chemistry, Chinese Academy of Sciences. The
authors also thank the Instrumental Analysis & Research Center of
Shanghai University for structural determination.
3-Methyl-2-trifluoromethylindole (3b).
Compound 3b was obtained as a yellow solid in 82% yield,
using 1.5 equiv of magnesium ribbon; mp 73–74 °C. 1H
NMR (500 MHz): d = 8.16 (br, 1 H) 7.64 (d, J = 8.0 Hz, 1
H), 7.38 (d, J = 8.5 Hz, 1 H), 7.32 (t, J = 7.7 Hz, 1 H), 7.19
(t, J = 7.5 Hz, 1 H), 2.44 (q, J = 1.7 Hz, 3 H). 13C NMR (125
MHz): d = 135.2, 128.1, 124.8, 122.1 (q, JC–F = 266.3 Hz),
References and Notes
(1) For recent reviews on the synthesis of indoles, see:
(a) Humphrey, G. R.; Kuethe, J. T. Chem. Rev. 2006, 106,
2875. (b) Lu, B. Z.; Zhao, W.; Wei, H.-X.; Dufour, M.;
Farina, V.; Senanayake, C. H. Org. Lett. 2006, 8, 3271.
(c) Mclaughlin, M.; Palucki, M.; Davies, I. W. Org. Lett.
2006, 8, 3307. (d) Cacchi, S.; Fabrizi, G. Chem. Rev. 2005,
105, 2873. (e) Ackermann, L. Org. Lett. 2005, 7, 439.
(f) Balme, G.; Bouyssi, D.; Lomberget, T.; Monteiro, N.
Synthesis 2003, 2115. (g) Gribble, G. W. J. Chem. Soc.,
Perkin Trans. 1 2000, 1045.
121.6 (q, JC–C–F = 36.7 Hz), 120.4, 120.1, 114.1 (q, JC–C–C–F
=
2.9 Hz), 111.6, 8.3. 19F NMR (470 MHz): d = –58.61 (s, 3 F).
IR (neat): 3393, 2925, 1454, 1321, 1263, 1166, 1116, 756
cm–1. HRMS: m/z calcd for C10H8F3N [M+]: 199.0609;
found: 199.0610.
5-Methoxy-2-trifluoromethylindole (3c).
(2) For leading references on the biological activities of indoles,
see: (a) Kuethe, J. T.; Wong, A.; Qu, C.; Smitrovich, J.;
Davies, I. W.; Hughes, D. L. J. Org. Chem. 2005, 70, 2555.
(b) Van Zandt, M. C.; Jones, M. L.; Gunn, D. E.; Geraci, L.
S.; Jones, J. H.; Sawicki, D. R.; Sredy, J.; Jacot, J. L.;
Dicioccio, A. T.; Petrova, T.; Mitschler, A.; Podjarny, A. D.
J. Med. Chem. 2005, 48, 3141. (c) Li, J. J.; Gribble, G. W.
Palladium in Heterocyclic Chemistry, Vol. 20; Pergamon
Press: New York, 2000, 73. (d) Glennon, R. A. J. Med.
Chem. 1987, 30, 1.
Compound 3c was obtained as a light yellow solid in 75%
yield; mp 50–51 °C. 1H NMR (500 MHz): d = 8.30 (br, 1 H),
7.32 (d, J = 8.5 Hz, 1 H), 7.10 (d, J = 2.5 Hz, 1 H), 7.00 (dd,
J = 9.0, 2.5 Hz, 1 H), 6.85 (s, 1 H), 3.86 (s, 3 H). 13C NMR
(125 MHz): d = 154.8, 131.3, 127.1, 126.2 (q, JC–C–F = 38.4
Hz), 121.2 (q, JC–F = 265.9 Hz), 115.7, 112.6, 103.8 (q,
JC–C–C–F = 3.3 Hz), 102.8, 55.7. 19F NMR (470 MHz): d =
–60.45 (s, 3 F). IR (neat): 3402, 2949, 1559, 1461, 1384,
1224, 1174, 1117, 1023, 801 cm–1. HRMS: m/z calcd for
C10H8F3NO [M+]: 215.0558; found: 215.0557.
Synlett 2007, No. 3, 447–450 © Thieme Stuttgart · New York

450
F. Ge et al.
LETTER
6-Fluoro-2-trifluoromethylindole (3d).
yield, using 1.5 equiv of magnesium ribbon; mp 44–46 °C.
1H NMR (500 MHz): d = 8.54 (br, 1 H), 7.27 (d, J = 9.0 Hz,
1 H), 7.10 (d, J = 2.0 Hz, 1 H), 6.99 (dd, J = 8.8, 2.3 Hz, 1
H), 6.87 (s, 1 H), 3.84 (s, 3 H). 13C NMR (125 MHz): d =
155.0, 132.0, 127.5, 124.4 (t, JC–C–F = 29.4 Hz), 118.0 (qt,
Compound 3d was obtained as a yellow viscous liquid in
62% yield; mp 126 °C (dec.). 1H NMR (500 MHz): d = 8.40
(br, 1 H), 7.58 (dd, J = 8.8, 5.2 Hz, 1 H), 7.06 (dd, J = 9.0,
1.8 Hz, 1 H), 6.96 (td, J = 9.0, 2.2 Hz, 1 H), 6.88 (s, 1 H). 13
C
NMR (125 MHz): d = 161.2 (d, JC–F = 240.0 Hz), 136.2 (d,
JC–F = 286.2 Hz, JC–C–F = 33.8 Hz), 116.1, 112.8 (tt, JC–F =
J
C–C–C–F = 12.5 Hz), 126.2 (q, JC–C–F = 39.2 Hz), 123.2 (d,
C–C–C–F = 10.0 Hz), 123.1, 121.0 (q, JC–F = 265.8 Hz), 110.4
251.9 Hz, JC–C–F = 31.2 Hz), 112.7, 108.8 (m), 106.0 (t,
J
J = 5.0 Hz), 102.7, 55.8. 19F NMR (470 MHz): d = –80.20 (t,
J = 9.4 Hz, 3 F), –109.47 (q, J = 9.4 Hz, 2 F), –126.70 (s, 2
F). IR (neat): 3308, 2953, 1628, 1548, 1459, 1343, 1222,
1180, 976, 792 cm–1. HRMS: m/z calcd for C12H8F7NO
[M+]: 315.0494; found: 315.0496.
(d, JC–C–F = 25.0 Hz), 104.4 (q, JC–C–C–F = 3.3 Hz), 97.9 (d,
J
C–C–F = 26.2 Hz). 19F NMR (470 MHz): d = –60.66 (s, 3 F),
–116.7 (m, 1 F). IR (neat): 3463, 2929, 1567, 1323, 1258,
1174, 835 cm–1. HRMS: m/z calcd for C9H5F4N [M+]:
203.0358; found: 203.0361.
(6) Tamura, K.; Mizukami, H.; Maeda, K.; Watanabe, H.;
Uneyama, K. J. Org. Chem. 1993, 58, 32.
6-Chloro-2-trifluoromethylindole (3e).
Compound 3e was obtained as a yellow viscous liquid in
45% yield, using 1.5 equiv of magnesium ribbon; mp 145 °C
(dec.). 1H NMR (500 MHz): d = 8.41 (br, 1 H), 7.59 (d,
J = 8.5 Hz, 1 H), 7.43–7.16 (m, 2 H), 6.91 (s, 1 H). 13C NMR
(125 MHz): d = 136.4, 130.7, 126.4 (q, JC–C–F = 38.8 Hz),
125.1, 123.0, 122.1, 120.9 (q, JC–F = 266.3 Hz), 111.6, 104.3
(q, JC–C–C–F = 3.5 Hz). 19F NMR (470 MHz): d = –60.71 (s, 3
F). IR (neat): 3425, 2965, 1554, 1417, 1356, 1313, 1239,
1125, 922, 826 cm–1. HRMS: m/z calcd for C9H5ClF3N [M+]:
219.0063; found: 219.0059.
(7) General Procedure for the Synthesis of Fluorinated N-(2-
Alkylphenyl)Imidoyl Chlorides (1).
To a 200 mL three-necked round-bottomed flask equipped
with condenser and magnetic stir bar was added Ph3P (34.5
g, 132 mmol), Et3N(7.3 mL, 53 mmol), CCl4 (21.1 mL, 220
mmol), and TFA, difluoroacetic acid or perfluorocarboxylic
acid (44 mmol) at 0 °C under a nitrogen atmosphere and
stirred for 10 min. A solution of o-alkylaniline (44 mmol)
dissolved in CCl4 (21.1 mL, 220 mmol) was added dropwise
to the reaction mixture. Upon completion of the addition, the
reaction mixture was allowed to reflux for 3 h. After cooling,
the solvent was removed by rotary evaporator, the residue
was then carefully washed with PE (3 ×), and the
precipitation was removed via filtration. The filtrate was
combined and concentrated by rotary evaporator. The
residue was then purified by flash column chromatography
(10:1 hexane–EtOAc) or distillation under reduced pressure
to offer the products 1.
2-Difluoromethyl-5-methoxyindole (3h).
Compound 3h was obtained as a yellow solid in 78% yield,
using 1.5 equiv of magnesium ribbon; mp 76–78 °C. 1H
NMR (500 MHz): d = 8.33 (br, 1 H), 7.24 (d, J = 9.0 Hz, 1
H), 7.08 (d, J = 2.5 Hz, 1H), 6.95 (dd, J = 9.0, 2.5 Hz, 1 H),
6.77 (t, JH–F = 55.0 Hz, 1 H), 6.66 (d, J = 2.0 Hz, 1 H), 3.84
(s, 3 H). 13C NMR (125 MHz): d = 154.6, 131.5, 130.6 (t,
J
C–C–F = 24.2 Hz), 127.4, 114.8, 112.4, 110.4 (t, JC–F = 233.8
Hz), 103.6 (t, JC–C–C–F = 6.8 Hz), 102.7, 55.7. 19F NMR (470
MHz): d = –109.8 (d, JF–H = 55.0 Hz, 2 F). IR (neat): 3459,
2959, 1561, 1456, 1372, 1206, 1173, 1134, 1070, 983, 809
cm–1. HRMS: m/z calcd for C10H9F2NO [M+]: 197.0652;
found: 197.0654.
(8) General Procedure for the Synthesis of Fluorinated N-
[(2-Bromoalkyl)phenyl]imidoyl Chlorides (2).
To a 200 mL three-necked round-bottomed flask equipped
with condenser and magnetic stir bar was added the
appropriate fluorinated N-arylimidolyl chloride 1 (46
mmol), NBS (8.6 g, 48 mmol), benzoyl peroxide (0.6 g, 2.3
mmol), and anhydrous CCl4 (80 mL) under a nitrogen
atmosphere. This reaction mixture was stirred and heated to
reflux for 2–5 h (monitored by TLC) until a complete
conversion of 1. After cooling down to r.t., the precipitate
was removed via filtration. Then, the filtrate was combined
and concentrated by rotary evaporator. The residue was then
purified by flash column chromatography (10:1 hexane–
EtOAc) or distillation under reduced pressure to yield
products 2.
3-Methyl-2-perfluoropropylindole (3i).
Compound 3i was obtained as a light yellow solid in 79%
yield, using 1.5 equiv of magnesium ribbon; mp 73–75 °C.
1H NMR (500 MHz): d = 8.18 (br, 1 H), 7.67 (d, J = 8.0 Hz,
1 H), 7.41 (d, J = 8.0 Hz, 1 H), 7.35 (m, 1 H), 7.22 (m, 1 H),
2.45 (t, J = 2.2 Hz, 3 H). 13C NMR (125 MHz): d = 136.0,
128.3, 124.9, 120.4, 120.1, 119.3 (t, JC–C–F = 28.1 Hz), 118.0
(qt, JC–F = 286.2 Hz, JC–C–F = 33.8 Hz), 116.6 (t, JC–C–C–F
=
3.8 Hz), 114.1 (tt, JC–F = 253.1 Hz, JC–C–F = 31.9 Hz), 111.5,
109.2 (m), 8.5 (q, J = 2.1 Hz). 19F NMR (470 MHz): d =
–80.26 (t, J = 9.4 Hz, 3 F), –109.60 (q, J = 9.4 Hz, 2 F),
–126.66 (s, 2 F). IR (neat): 3387, 2928, 1343, 1225, 1196,
1112, 903, 748 cm–1. HRMS: m/z calcd for C12H8F7N [M+]:
299.0545; found: 299.0548.
(9) Kalgutkar, A. S.; Marnett, A. B.; Crews, B. C.; Remmel, R.
P.; Marnett, L. J. J. Med. Chem. 2000, 43, 2860.
(10) Zhang, P.; Liu, R.; Cook, J. M. Tetrahedron Lett. 1995, 36,
7411.
(11) Miyashita, K.; Kondoh, K.; Tsuchiya, K.; Miyabe, H.;
Imanishi, T. Chem. Pharm. Bull. 1997, 45, 932.
5-Methoxy-2-perfluoropropylindole (3j).
Compound 3j was obtained as a light yellow solid in 76%
Synlett 2007, No. 3, 447–450 © Thieme Stuttgart · New York