A New and Efficient One-Pot Synthesis of 2-Fluoroalkyl Substituted Indoles

Article abstract of DOI:10.1002/jhet.2290

A new simple and efficient one-pot synthesis of 2-fluoroalkyl substituted indoles from 2-aminobenzyl alcohols with fluorine-containing carboxylic acids in the presence of Ph₃P, CCl₄, and NEt₃ is described. Various kinds of 2-fluoroalkyl substituted indole derivatives can be conveniently prepared.

Full text of DOI:10.1002/jhet.2290

November 2015 A New and Efficient One-Pot Synthesis of 2-Fluoroalkyl Substituted
1893
Indoles
Zengxue Wang* and Qingwen Ma
Lunan Pharmaceutical Group Corporation, No. 209, Hongqi Rd, Linyi, Shandong, 276005, China
*
E-mail: wangzx0912@126.com
Received March 4, 2014
DOI 10.1002/jhet.2290
Published online 20 November 2014 in Wiley Online Library (wileyonlinelibrary.com).
A new simple and efficient one-pot synthesis of 2-fluoroalkyl substituted indoles from 2-aminobenzyl
alcohols with fluorine-containing carboxylic acids in the presence of Ph P, CCl , and NEt is described.
3
4
3
Various kinds of 2-fluoroalkyl substituted indole derivatives can be conveniently prepared.
J. Heterocyclic Chem., 52, 1893 (2015).
INTRODUCTION
substituted benz-fused six-membered ring compound
-(trifluoromethyl)-4H-benzo[d][1,3] oxazine 5 using 2-
2
Indoles and their derivatives are common heterocyclic
compounds in nature. The indole ring system is an
important structural component in many drugs [1]. The
transition metal catalyzed ring closure methodology
provides a direct access to the indole ring component with
fewer steps and became a key strategy for the synthesis of
indole ring system in last 40 years [2]. However, few
synthetic methods provide efficient, scalable, and direct
access to the biologically significant 2-fluoroalkyl
substituted indoles. Therefore, the discovery of novel
and facile routes to the construction of such a nitrogen-
containing bicyclic system is still one of the important
issues in organic synthesis.
aminobenzyl alcohol via the aforementioned procedure,
Instead, the cyclized 2-trifluoromethylindole 4a was ob-
tained in 55% yield (Scheme 2).
This unexpected result drew our attention to explore the
mechanism of this one-pot cyclization process. It is clearly
observed that during the model reaction with trifluoroacetic
acid, the imidoyl chloride intermediate N-[2-(hydroxy-
methyl)phenyl]-2,2,2-trifluoroacetimidoyl chloride 2a was
formed at the initial stage, and with time going, 2a
disappeared gradually and instead the cyclized product 4a
was obtained as the final product. Decreasing the quantity
of NEt that was used in this reaction to one-third of nor-
3
mal dosage could effectively prevent the subsequential
cyclization from being complete. Thus, the intermediate
2
a was successfully isolated as a major and stable
RESULTS AND DISCUSSION
compound from the reaction mixture. But the further
cyclization of 2a could be achieved only in the presence
of Ph P, CCl , and NEt , which is different from the
The synthetic strategy we disclose here is a one-pot
cyclization of 2-aminobenzyl alcohols with fluorine-
containing carboxylic acids in the presence of Ph P, CCl ,
3
4
3
3
4
previous reports [4,5] (Scheme 3).
and NEt . This process provides a convenient modular, scal-
3
All imidoyl chloride intermediates, such as 2a, were
clearly detected in all examined cases and formed indole
compounds except using 1-(2-aminophenyl)ethanol 1j as
the starting material, which formed N-(2-(1-chloroethyl)
phenyl)-2,2,2-trifluoroacetimidoyl chloride 3j instead of
the corresponding indole compound (Scheme 4).
able, and well-suited approach for the direct synthesis of
various 2-fluoroalkyl substituted indole compounds in one
step (Scheme 1).
Prof. Hao and his team had reported the synthesis of 2-
fluoroalkyl substituted indoles via the Grignard cyclization
reaction of either fluorinated N-[2-(bromoalkyl)phenyl]
imidoyl chlorides or N-[2-(chloroalkyl)phenyl]imidoyl
chlorides with moderate to good yields [3]. They had also
reported the synthesis of fluorine-containing benzoxazole
+
–
3
As we all known, [Ph P Cl] CCl can be generated in situ
3
from the reaction of Ph P with a large excess amount of CCl ,
3
4
which can convert the hydroxyl group to chlorine. N-[2-(hy-
droxymethyl)phenyl]-2,2,2-trifluoroacetimidoyl chloride 2a,
which could be detected formed N-[2-(hydroxymethyl)phe-
nyl]-2,2,2-trifluoroacetimidoyl chloride 3a firstly in the
[4] and indoline derivatives [5] from 2-aminophenol or 2-
aminophenethyl alcohol via the Uneyama procedure [6], in
this case, we wonder if we could obtain the fluoroalkyl-
presence of Ph P, CCl , and NEt , So we supposed that
3 4 3
©
2014 HeteroCorporation

1
894
Z. Wang and Q. Ma
Vol 52
Scheme 1
Table 1
Synthesis of various 2-fluoroalkyl substituted indole.
a
Entry
R
1
R
2
R
f
Yield of 4 (%)
1
2
3
4
5
6
7
8
9
H
H
H
H
H
H
H
H
H
H
H
H
CF
CF
C F
3 7
CF
CF
CF
CF
CF
3
2
4a 55%
4b 47%
4c 62%
4d 73%
4e 55%
4f 49%
4g 41%
4h 66%
4i 67%
3j 52%
H
4-OCH
4-F
4-Cl
4-NO2
5-OCH
5-OCH3
H
3
3
3
3
3
3
3
Scheme 2
C3F7
CF
10
CH
3
3
a
The yields listed in this table are isolated yields.
Ph P attacked 3a and formed a phosphonium salt I [7],
3
the phosphonium salt I treated with NEt and given a
3
ylide II, which was very active and instable, once it
formed, the subsequent cyclization could occur immedi-
ately and converted to 4 (Scheme 5). As 3j is a second-
ary alkyl halide, the phosphonium salt intermediate I is
hard to form, for this reason, we failed to obtain the
corresponding indole.
Scheme 3
This one-pot process is generally suitable to prepare
various 2-fluoroalkyl substituted indoles with different
fluorine-containing carboxylic acids and 2-aminobenzyl
alcohols even in the hundreds of grams (Table 1). Most
of the starting 2-aminobenzyl alcohols are commercially
available, for specific structure demands, such as 1j, the
desired product can also be simply prepared by the reduc-
tion of 2-aminobenzoic acid or 2-nitrobenzoic acid [8].
It was found that the yields of 4 were affected by the
electronic effects of substituent group R on the benzene
2
ring. Without substituent group (R = H) or with electron-
donating group, such as methoxyl group, the products are
2
Scheme 4
obtained in good yields, while with electron-deficient
substituent, such as NO , the yields decreased to the
2
moderate. When the substituent group at side-chain, such
as (R = CH ), the reaction cannot occur.
1
3
Scheme 5
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

November 2015
A Unique and Concise One-Pot Synthesis of 2-Fluoroalkyl Substituted Indoles
1895
3
19
JC–F = 6.9 Hz, CH = C-CF H); F-NMR (470 MHz) δ ꢀ109.83
CONCLUSIONS
2
(
d, JF–H = 54.9 Hz, 2 F); IR (neat) 3395 (NH), 2924, 1621, 1371,
ꢀ
1
In conclusion, a unique and concise one-pot synthesis of
1
9 7 2
069, 1015, 810, 750cm ; Anal. Calcd for C H F N: C, 64.67;
2
-fluoroalkyl substituted indoles from of 2-aminobenzyl
H, 4.22; N, 8.38. Found: C, 64.66; H, 4.19; N, 8.35.
alcohols, and fluorine-containing carboxylic acids has been
developed. This new approach provides an efficient, scal-
able, low-cost, and direct access to the biologically impor-
tant indoles.
2-Heptafluoropropylindole (4c). In 62% yield, 4c was
1
obtained as a light yellow solid: mp 63–64°C; H-NMR (500 MHz)
δ 8.32 (br, 1H), 7.64 (d, J= 8.0Hz, 1H), 7.37 (d, J=8.0Hz, 1H),
7
.28 (t, J= 7.5 Hz, 1H), 7.16 (t, J= 7.5 Hz, 1H), 6.87 (s, 1H);
13
C-NMR (125 MHz) δ 136.1, 127.5, 124.4 (t, JC–C–F = 29.4 Hz),
18.0 (qt, JC–F = 286.2 Hz, JC–C–F = 33.8 Hz),124.1,121.1, 117.7,
112.8 (tt, JC–F = 251.9 Hz, J = 31.2 Hz), 111.7,108.8 (m),
1
EXPERIMENTAL
C–C–F
19
1
3
06.0 (t, J=5.0Hz); F-NMR (470 MHz) δ ꢀ80.20 (t, J=9.4Hz,
General. All melting points were taken on a WRS-1A or
F), ꢀ109.47 (q, J=9.4Hz, 2F), ꢀ126.70 (s, 2 F); IR (neat) 3308,
WRS-1B Digital Melting Point Apparatus without correction.
ꢀ
1
1
13
19
2953, 1628, 1548, 1459, 1343, 1232, 1080, 814, 760 cm ; Anal.
H-NMR, C-NMR, and F-NMR spectra were recorded in
CDCl on a Bruker AV-500 spectrometer. Chemical shifts for
H-NMR spectra are reported in ppm downfield from TMS,
Calcd for C H F N: C, 46.33; H, 2.12; N, 4.91. Found: C, 46.36;
11 6 7
3
l
H, 2.09; N, 4.85.
1
3
6-Methoxy-2-trifluoromethyl indole (4d). In 73% yield, 4d
was obtained as a colorless solid: mp 88–90°C; H-NMR
(500 MHz) δ 8.28 (br, 1H, NH), 7.48 (d, J = 8.5 Hz, 1H), 7.10
chemical shifts for C-NMR spectra are reported in ppm
relative to internal chloroform (δ 77.0 ppm for C), and
chemical shifts for
downfield from external fluorotrichloro-methane (CFCl
Coupling constants (J) are given in Hertz (Hz). The terms
m, s, d, t, and q refer to multiplet, singlet, doublet, triplet,
and quartlet; br refers to a broad signal. Infrared spectra (IR)
were recorded on AVATAR 370 FT-IR spectrometer.
Elemental analyses were carried out on a VARIO EL111
elemental analyzer.
1
1
3
1
9
F-NMR spectra are reported in ppm
(
d, J = 2.5 Hz, 1H), 6.89 (dd, J = 9.0, 2.5 Hz, 1H), 6.86 (s, 1H,
3
).
13
CH = C-CF ), 3.85 (s, 3H); C-NMR (125 MHz) δ 158.2, 137.3,
3
2
1
1
26.2 (q, JC–F =38.4Hz, C-CF
CF
4.8, 55.7 (Ar-OCH
s, 3 F); IR (neat) 3302 (NH), 2959, 1599, 1560, 1254,
3
), 122.7, 121.2 (q, JC–F =265.9Hz,
3
3
), 119.7, 111.6, 104.3 (q,
J
C–F = 3.3 Hz, CH = C-CF
F-NMR (470 MHz) δ
3
),
1
9
9
(
1
5
3
);
ꢀ60.45
ꢀ
1
174, 1117, 1001 cm ; Anal. Calcd for C H F NO: C,
10 8 3
5.82; H, 3.75; N, 6.51; O, 7.44. Found: C, 55.86; H, 3.77;
General procedure.
bottomed flask equipped with a condenser and a magnetic stir
bar was added Ph (7.86 g, 30 mmol), NEt (4.2 mL,
0 mmol), CCl (40 mL, 419 mmol), and carboxylic acid
10 mmol) at 0°C under nitrogen atmosphere and the solution
was then stirred for 10 min, following 2-aminobenzyl alcohols
(10 mmol) was added to the reaction mixture. Once the
To a 100-mL three-necked round-
N, 6.45; O, 7.46.
-Fluoro-2-trifluoromethylindole (4e).
6
In 55% yield, 4e
3
P
3
was obtained as a yellow viscous liquid: mp 125°C (dec.);
3
(
4
1
H-NMR (500 MHz) δ 8.38 (br, 1H, NH), 7.57 (dd, J =8.8,
5
CF
.2 Hz, 1H), 7.06 (m, 1H), 6.96 (m, 1H), 6.88 (s, 1H, CH =C-
13
1
3
); C-NMR (125MHz) δ 161.1 (d, JC–F = 240.0 Hz), 136.2
1
3
2
(
(
(
(
d, JC–F = 12.5Hz), 126.2 (q,
d, J = 10.0 Hz), 122.9, 121.1(q, J = 265.8 Hz, CF ), 110.2
J
= 39.2 Hz, C-CF ), 123.2
C–F 3
1
addition was completed, the reaction mixture was allowed to
reflux for 3–12 h_k;. After cooling, the solvent was removed
by rotary evaporator, the residue was then carefully washed
with mixture solvent (4:1 hexane:ethyl acetate) three times,
and the precipitate was removed via filtration. The filtrate was
combined and concentrated by rotary evaporator. The residue
was then purified by column chromatography to offer the
product 4a–4i and 3j.
3
C–F
C–F
3
2
3
d, JC–F = 25.0 Hz), 104.3 (q, JC–F = 3.3 Hz, CH = C-CF
3
), 97.8
d, JC–F = 26.2 Hz); F-NMR (470 MHz) δ ꢀ60.56 (s, 3 F, CF ),
116.7 (m, 1 F, Ar-F); IR (neat) 3457 (NH), 2938, 1566, 1305,
2
19
3
ꢀ
ꢀ1
1
249, 1169, 831 cm ; Anal. Calcd for C H F N: C, 53.21; H,
9 5 4
2
.48; N, 6.90. Found: C, 53. 17; H, 2.50; N, 6.91.
-Chloro-2-trifluoromethylindole (4f). In 49% yield, 4f
was obtained as a yellow viscous liquid: mp 147°C (dec.);
6
1
Characterizations of products.
H-NMR (500 MHz)
δ
8.40(br, 1H, NH), 7.56
2-Trifluoromethylindole (4a). In 55% yield, 4a was obtained as
(d, J = 8.5 Hz, 1H), 7.43–7.16 (m, 2H, Ar-H), 6.91 (s, 1H,
1
3
a light yellow solid by column chromatography (4:1 hexane:ethyl
acetate) on neutral aluminum oxide: mp 107–108°C; H-NMR
CH = C-CF ); C-NMR (125 MHz) δ 136.3, 130.8, 126.2
3
1
2
(q, 1 JC–F = 38.8 Hz, C-CF3), 124.8, 122.7, 3122.1, 120.6
(500 MHz) δ 8.31 (br, 1H, NH), 7.66 (d, J= 8.0 Hz, 1H), 7.37
(q, JC–F = 266.3 Hz, CF ), 111.5, 103.8 (q, JC–F = 3.5 Hz,
3
1
9
(d, J= 8.0 Hz, 1H), 7.28 (t, J= 7.5 Hz, 1H), 7.20 (t, J=7.5Hz, 1H),
CH = C-CF3); F-NMR (470 MHz) δ ꢀ60.61 (s, 3 F); IR
13
6
.92 (s, 1H); C-NMR (125 MHz) δ 136.1, 126.5, 125.7 (q,
(neat) 3425 (NH), 1554, 1416, 1357, 1310, 1125, 922,
2
1
ꢀ1
J
C–F =38.8Hz, C-CF
CF ), 121.1, 111.7, 104.3 (q, JC–F =3.3Hz, CH = C-CF
470 MHz) δ ꢀ60.50 (s, 3 F); IR (neat) 3389 (NH), 2921, 1375,
3
), 124.7, 121.9, 121.2 (q, JC–F = 266.2 Hz,
826 cm ; Anal. Calcd for C H ClF N: C, 49.23; H, 2.30;
9
5
3
3
19
3
3
); F-NMR
N, 6.38. Found: C, 49.35; H, 2.28; N, 6.40.
(
6-Nitro-2-trifluoromethylindole (4g). In 41% yield, 4g
was obtained as a yellow solid: mp 143–144°C; H-NMR
(500 MHz) δ 8.45(br, 1H, NH), 8.26 (d, J = 8.5 Hz, 1H),
ꢀ
1
1
1306, 1168, 1103, 940, 818, 754 cm ; Anal. Calcd for C H F N:
9
6 3
C, 58.38; H, 3.27; N, 7.57. Found: C, 58.40; H, 3.31; N, 7.55.
1
3
2
-Difluoromethylindole (4b). In 47% yield, 4b was
7.50–7.55 (m, 2H), 6.95 (s, 1H, CH = C-CF
3
);
C–F = 38.6Hz, C-CF
C–F = 266.3 Hz, CF ), 118.5,
C-NMR
1
2
obtained as a yellow solid: mp 56–58°C; H-NMR (500 MHz)
δ 8.31 (br, 1H, NH), 7.65 (d, J = 8.0 Hz, 1H, Ar-H), 7.35 (d,
J = 8.0 Hz, 1H), 7.28 (t, J = 7.5 Hz, 1H), 7.17 (t, J = 7.5 Hz,
(125 MHz) δ 140.3, 138.8, 127.9 (q,
J
3
),
1
123.7 122.7, 122.1, 120.8 (q,
J
3
3
19
102.4 (q, J = 3.5 Hz, CH = C-CF3); F-NMR (470 MHz) δ
C–F
1
H), 6.81 (t, JH–F = 54.5 Hz, 1H, CF H), 6.74 (d,
ꢀ60.81 (s, 3 F); IR (neat) 3380 (NH), 1654, 1515, 1456,
2
1
3
ꢀ1
J
1
1
H–F = 2.0 Hz, 1H, CH = C-CF
2
H);
C-NMR (125 MHz) δ
H), 126.9, 124.1, 121.6,
C–F = 233.4Hz, CF H), 103.9 (t,
1300, 1025, 927, 835 cm ; Anal. Calcd for C
9
H
5
F
3
N
2
O
2
: C,
2
36.2, 130.0 (t, JC–F = 24.2 Hz, C-CF
2
46.97; H, 2.19; N, 12.17; O, 13.90. Found: C, 46.92; H,
2.17; N, 12.18; O, 13.93.
1
20.6, 111.6, 110.5 (t,
J
2
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

1
896
Z. Wang and Q. Ma
Vol 52
2
5
-Methoxy-2-trifluoromethyl indole (4h). In 66% yield, 4h
JC–F = 42.9 Hz, C-CF ), 128.8, 127.7, 126.5, 119.2, 116.7 (q,
3
1
1
19
was obtained as a light yellow solid: mp 50–51°C; H-NMR
500 MHz) δ 8.30 (br, 1H, NH), 7.33 (d, J= 8.5 Hz, 1H), 7.11
d, J= 2.5 Hz, 1H), 7.00 (dd, J=9.0, 2.5Hz, 1H), 6.84 (s, 1H,
JC–F = 275.8 Hz, CF ), 56.4, 26.1; F-NMR (470 MHz) δ ꢀ71.60
3
(
(
(s, 3 F); IR (neat) 2980, 1697 (C¼N), 1486, 1288, 1209, 1165, 951,
ꢀ
1
8 2 3
765 cm ; Anal. Calcd for C10H Cl F N: C, 44.47; H, 2.99; N, 5.19.
1
3
CH=C-CF
3
), 3.86 (s, 3H, Ar-OCH
3
); C-NMR (125 MHz)
Found: C, 44.50; H, 3.01; N, 5.21.
2
δ 154.7, 131.3, 127.1, 126.2 (q, JC–F = 38.4 Hz, C-CF ), 121.2
3
1
3
C–F 3 C–F
(
q, J = 265.9 Hz, CF ), 115.6, 112.4, 103.8 (q, J =3.3Hz,
19
CH = C-CF
3
), 102.7, 55.5 (Ar-OCH
3
);
F-NMR (470 MHz)
δ ꢀ60.45 (s, 3 F); IR (neat) 3402 (NH), 2949, 1559, 1461, 1224,
Acknowledgments. The authors also thank Dr. J. Hao and The
Instrumental Analysis & Research Center of Shanghai University
for structural analysis.
–1
1
174, 1117, 801 cm ; Anal. Calcd for C H F NO: C, 55.82; H,
10 8 3
3
.75; N, 6.51; O, 7.44. Found: C, 55.85; H, 3.76; N, 6.48; O, 7.56.
5
-Methoxy-2-heptafluoropropylindole (4i).
In 67% yield,
1
4
i was obtained as a light yellow solid: mp 44–45°C; H-NMR
(
(
500 MHz) δ 8.52 (br, 1H, NH), 7.27 (d, J = 9.0 Hz, 1H), 7.10
d, J = 2.0 Hz, 1H), 7.01 (dd, J = 8.8, 2.3 Hz, 1H), 6.87 (s, 1H,
REFERENCES AND NOTES
1
3
CH = C-C F ), 3.84 (s, 3H); C-NMR (125 MHz) δ 155.1,
3 7
[
1] (a) Humphrey, G. R.; Kuethe, J. T. Chem Rev 2006, 106,
2875; (b) Horton, D. A.; Bourne, G. T.; Smythe, M. L. Chem Rev
2003, 103, 893.
2
1
32.0, 127.5, 124.3 (t,
JC–F = 286.2 Hz, J = 33.8 Hz, CF CF CF ), 116.1, 112.8 (tt,
JC–F = 251.9 Hz, JC–F = 31.2 Hz, CF CF CF ), 112.7, 108.8
J
C–F = 29.4 Hz, C-C
3
F
7
), 118.0 (qt,
1
2
C–F
2
2
3
1
2
[2] For recent reviews on the synthesis of indoles, see: (a) Lu, B. Z.;
Zhao, W.; Wei, H. X.; Dufour, M.; Farina, V.; Senanayake, C. H. Org Lett
2006, 8, 3271; (b) Mclaughlin, M.; Palucki, M.; Davies, I. W. Org Lett
006, 8, 3307.
3] Ge, F.; Wang, Z.; Wan, W.; Jiang, H.; Hao, J. J Fluorine Chem
2007, 128: 1143.
[4] Ge, F.; Wang, Z.; Wan, W.; Lu, W.; Hao, J. Tetrahedron Lett
2007, 48, 3251.
2
2
3
3
(
5
3
m, CF
2
CF
5.8 (Ar-OCH
F, CF CF CF
126.70 (s, 2 F, CF CF CF ); IR (neat) 3318 (NH), 2956,
2
-CF
3
), 106.0 (t, J = 5.0 Hz, CH = C-C
3
F
7
), 102.7,
); F-NMR (470 MHz) δ ꢀ80.20 (t, J = 9.4 Hz,
), ꢀ109.47 (q, J = 9.4 Hz, 2 F, CF CF CF ),
1
9
3
2
2
2
3
2
2
3
[
ꢀ
2
2
3
–
1
1
545, 1450, 1345, 1232, 1181, 967, 790 cm ; Anal. Calcd for
NO: C, 45.73; H, 2.56; N, 4.44; O, 5.08. Found: C,
12 8 7
C H F
4
[
5] Wang, Z.; Wan, W.; Jiang, H.; Hao, J. J Org Chem 2007,
5.75; H, 2. 60; N, 4.42; O, 5.11.
N-[2-(1-Chloroethyl)phenyl]-2,2,2-trifluoroacetimidoyl chloride
7
2, 9364.
[
6] Tamura, K.; Mizukami, H.; Maeda, K.; Watanabe, H.;
Uneyama, K. J Org Chem 1993, 58, 32.
7] Miyashita, K.; Tsuchiya, K.; Kondoh, K.; Miyabe, H.; Imanishi, T.
J Chem Soc, Perkin Trans 1 1996, 11, 1261.
[8] Evans, D. A.; Peterson, G. S.; Johnson, J. S.; Barnes, D. M.;
Campos, K. R.; Woerpel, K. A. J Org Chem 1998, 63, 4541.
(3j). In 52% yield, 3j was obtained as a colorless oil by flash column
1
chromatography on neutral Al
500 MHz) δ 7.65 (dd, J=7.5, 2.0Hz, 1H), 7.40–7.31 (m, 2H, Ar-H),
.95 (dd, J=7.5, 1.2Hz, 1H), 5.45 (q, J= 7.0 Hz, 1H), 2.15 (d,
2 3
O : bp 80–82°C/9 mmHg; H-NMR
[
(
6
13
J=7.0Hz, 3H); C-NMR (125 MHz) δ 141.1, 134.9, 134.2 (q,
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet