Environmentally benign, microwave-assisted chemoselective Nhydroxyalkylation of indoles with trifluoroacetaldehyde methyl hemiacetal

Article abstract of DOI:10.24820/ark.5550190.p010.286

The chemoselective microwave-activated N-hydroxyalkylation of indoles using trifluoroacetaldehyde methylhemiacetal as the alkylating agent under mild conditions is described. The chemoselectivity of this reaction is determined by the solvent used. In dimethyl sulfoxide, the reaction occurs without the use of a strong base or a metal catalyst. This approach can be applied to a variety of different substituted indoles to obtain the corresponding N-alkylated products with high selectivity. The product 2,2,2-trifluoro-1-(1-H-indol-1-yl)ethanols combine two moieties of frequent pharmacological interest: the indole core and a CF₃-group containing a hydroxyalkyl substituent.

Full text of DOI:10.24820/ark.5550190.p010.286

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Arkivoc 2018, part ii, 122-130
Organic Chemistry
Environmentally benign, microwave-assisted chemoselective N-
hydroxyalkylation of indoles with trifluoroacetaldehyde methyl hemiacetal
Christian Schäfer,*a Clifford J. Ellstrom,a Abha Sood,b Judith Alonzo,a Shainaz M. Landgeb Chris D. Tran,a and
Béla Török*a
a Department of Chemistry, University of Massachusetts Boston, 100 Morrissey Blvd,
Boston, MA 02125-3393, USA
b Department of Chemistry and Biochemistry, Georgia Southern University, 521 College of Education Drive,
Statesboro, GA 30460-8064, USA
E-mail: christian.schaefer@umb.edu, bela.torok@umb.edu
Dedicated to Prof. Kenneth Laali on the occasion of his 65th birthday and life-long contributions to chemistry
Received 07-31-2017
Accepted 10-27-2017
Published on line 11-05-2017
Abstract
The chemoselective microwave-activated N-hydroxyalkylation of indoles using trifluoroacetaldehyde
methylhemiacetal as the alkylating agent under mild conditions is described. The chemoselectivity of this
reaction is determined by the solvent used. In dimethyl sulfoxide, the reaction occurs without the use of a
strong base or a metal catalyst. This approach can be applied to a variety of different substituted indoles to
obtain the corresponding N-alkylated products with high selectivity. The product 2,2,2-trifluoro-1-(1-H-indol-1-
yl)ethanols combine two moieties of frequent pharmacological interest: the indole core and a CF3-group
containing a hydroxyalkyl substituent.
Keywords: Indole, hydroxyalkylation, trifluoroalkylation, microwave activation, solvent effect
DOI: https://doi.org/10.24820/ark.5550190.p010.286
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Introduction
Indole as a structural moiety can be found in a broad range of natural products (i.e. alkaloids and peptides).1
As these compounds are often biologically active they serve as a core in many drugs and potential
pharmaceutical synthons. Thus, their synthesis is of high interest for the pharmaceutical industry.1-3 Indoles
are also known as potential inhibitors of various pathogenic pathways leading to fatal neurodegenerative
diseases such as prion4 or Alzheimer’s disease.5,6 While it is possible to synthesize these molecules by building
the indole core with substituents already in place,7-11 the functionalization of the existing indole core also
represents a versatile strategy. The introduction of a CF3- group to indole using trifluoromethyl group-
containing substrates can further enhance the drug like properties of bioactive compounds.12-15
The importance of organofluorine compounds has steadily increased over the last few decades due to
their frequent use in pharmaceutical and agrochemical applications, as well as in the synthesis of advanced
materials. Currently, an estimated 20 percent of pharmaceuticals prescribed or administered contain at least
one fluorine atom. Their improved potential, such as enhanced affinity towards biological targets, increased
metabolic stability, bioavailability and membrane permeability is due to the unique physiochemical and
biological properties of organofluorine compounds16-18
.
Substitution on the 5-membered ring of indoles can occur at the N1, C2 and C3 positions. With C3
being the most reactive position in aromatic electrophilic substitutions, numerous methods for the synthesis
of 3-substituted indoles are reported in literature.19-22 However, achieving a selective introduction of
substituents to the N1- or C2-position of indoles is a more challenging task.23,24 N-Substituted indoles are
mainly obtained by direct N-alkylation. This involves the initial formation of an indolyl anion, but due to its
ambident nature, both N- and C- alkylated products can form. As deprotonation makes the nitrogen atom the
most reactive nucleophilic site, procedures for N-substitution commonly involve base-catalyzed nucleophilic
substitution or conjugate addition reactions.25,26 Accordingly, there is only a limited number of broadly
applicable procedures for the synthesis of N-alkylated indole derivatives.27 In order to obtain chemoselectivity
between the reactive centers several factors have to be carefully considered, e.g. the type of metal counter
ion, the use of metal catalysts28 or phase transfer catalyst,29 the use of base30 and the type of solvent used.31
Some advances toward selective N-arylation have recently been made applying Cu-nanoparticles.32 However,
the use of a stoichiometric amount of base, harsh reaction conditions or multistep synthesis33 is commonly
required for these methods.
Extending our recent efforts on the development of sustainable synthesis methods,34-38 herein we
report the environmentally benign synthesis of 2,2,2-trifluoro-1-(1-H-indol-1-yl)ethanols by a direct N-
hydroxyalkylation of indoles with trifluoroacetaldehyde methyl hemiacetal under mild conditions without the
use of strong bases or metal catalysts.
Results and Discussion
Based on our earlier results the alkylation of indole using trifluoroacetaldehyde methyl hemiacetal occurs
preferentially at the C3 position yielding the thermodynamically favored product.39,40 The N-substituted
product can be obtained under kinetic control using a strong base or metal mediated reactions.25 However,
our recent mechanistic and DFT investigations showed that the outcome of this hydroxyalkylation reaction is
highly dependent on the choice of the reaction conditions, especially the selection of the solvent.41 It was
found that the use of non-polar solvents, such as hexane, resulted in the exclusive hydroxyalkylation at the C3
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position. As the polarity of the solvent increases, the reaction tends to favor the formation of the N-alkylated
product. Using DMSO as the solvent, almost exclusive N-alkylation was observed (Scheme 1). The product can
be obtained under completely base-free conditions, however, the use of a catalytic amount of triethylamine
led to a 2-fold increase in yield.
Scheme 1. Solvent dependence of indole hydroxyalkylation.
This solvent dependence can be applied to synthesize selectively indol-1-yl-trifluoromethyl ethanols
without the use of harsh reaction conditions and/or additional reagents. Following these findings for the
selective N-alkylation of indole we decided to broaden the scope of the reaction by using various substituted
indoles.
The reactions were performed according to our previously optimized conditions (Scheme 2).41
Scheme 2. General reaction scheme for the chemoselective synthesis of indol-1-yl trifluoromethyl ethanols.
The indoles were dissolved in DMSO, and then a catalytic amount of triethylamine (NEt3) and excess
trifluoroacetaldehyde methylhemiacetal were added. While trifluoroacetaldehyde ethylhemiacetal can also be
used for the generation of trifluoroacetaldehyde (fluoral) under acidic conditions,40 the methylhemiacetal,
appeared to be more reactive and could be used under these mild conditions to achieve the selective
conversion of the starting material. A variety of substituted indoles were submitted to these conditions and
the results are summarized in Table 1. With few exceptions, the products were obtained with complete
chemoselectivity. It is worth noting that while the yields are only moderate, the reaction resulted in the
exclusive formation of the hydroxyalkylation-product; no other byproduct formation was observed and the
unreacted starting indole was recovered and reused.
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Table 1. Reaction of different substituted indoles with trifluoroacetaldehyde methylhemiacetal
Entry
1
Substrate
Product
A
Yielda
44%
Ratio A:B
99:1
2
3
4
A
A
A
34%
22%c
19%
99:1
99:1
99:1
5
A+B
A
40%
9%
1:1
6b
99:1
7
A
32%
99:1
8
9
A
A
20
100:0
99:1
10%
10
11
12
-
B
-
0%
99%
0%
-
0:100
-
aGC yield. >99% selectivity was obtained; the starting indole was recovered after the reaction.
o
c
bReaction was performed at 60 C for 30 min; due to stability issues the product was only
identified by its El-MS spectrum.
As it can be seen in Table 1 the reaction can be performed successfully with indole and indoles bearing
an electron-donating (alkyl or oxygen-containing) substituent on the 6-membered ring of the indole (entries 1-
7). The yields obtained are generally in the range of 20-40%, which is due to the relatively low conversion of
the reaction. When the reaction is driven to achieve higher conversions (increased temperature and/or
reaction time) the selectivity of the reaction decreases and C-alkylation, as well as the formation of other
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byproducts occur. It should be noted that 5-hydroxyindole is highly reactive under the standard reaction
conditions yielding in a mixture of N- and C-substituted product (entry 5). Lowering the reaction temperature
and reaction time restored the chemoselectivity of the reaction for exclusive N-hydroxyalkylation, albeit with
lower conversion (entry 6). When indoles with an electron-withdrawing (EWD) substituent are tested (e.g. 5-
Br-indole, entry 10) under the reaction conditions, no product formation was observed, the starting material
could be recovered completely. This is probably due to the deactivating effect of the substituent reducing the
reactivity of the aromatic system.
When placing substituents to the C2 position of indole, the outcome of the reaction is strongly
dependent on the nature and size of the substituent. Similarly to the effect of electron withdrawing
substituents on the carbocyclic ring, adding EWD substituents to the five-membered ring deactivates the ring
and no product formation occurs. Submitting 2-tert-butyl substituted indole to the reaction conditions (entry
12) does not result in product formation either. Using 2-methylindole (entry 11) as a starting material results
in the formation of the C3 hydroxyalkylated product in quantitative yield. While the latter observation can be
explained by the activating effect of the methyl-group, the lack of reactivity of 2-tert-butylindole can be
interpreted by the steric strain imposed by the bulky substituent overcoming its activating effect and
preventing the reaction from taking place at either of the N1- and C3-positions. Blocking the C3 position on
the indole leads to a selective transformation yielding the N-alkylated product even with bulky substituents
such as tert-butyl (entry 8).
Conclusions
N-Hydroxyalkylated indoles were synthesized selectively using trifluoroacetaldehyde methylhemiacetal as the
hydroxyalkylating agent. The reactions can be performed under mild conditions without the use of a strong
base or a metal catalyst. The reaction can be performed with a variety of substituted indoles and the
selectivity can be strongly influenced by the choice of the solvent. DMSO was found to act as a strong directing
solvent and reactions carried out in DMSO yielded the chemoselective formation of the N-substituted
products.
While the yields are only moderate at this level of the research, the results described clearly indicate that the
method allows for the preparation of the target compounds via a simple, one-step method that is reasonably
more environmentally benign than the known literature procedures. In addition, the reaction did not yield
other byproducts, thus the unreacted starting material could be recovered and recycled.
Experimental Section
General. All reagents used were obtained from commercial sources (Alfa Aesar, Sigma-Aldrich) and used as
received. Reactions were monitored by gas chromatography – mass spectrometry (GC-MS) with an Agilent
6850 gas chromatograph-5973 mass spectrometer system (70 eV electron impact ionization) using a 30 m long
DB-5 type column (J&W Scientific). Microwave heating was performed in a CEM-Discover microwave reactor
using closed-vessel setting. Product separation was performed by preparative thin-layer chromatography
using Merck silica gel PF254 containing gypsum binder. Nuclear Magnetic Resonance (NMR) spectra were
recorded on an Agilent MR400DD2 spectrometer, with a multinuclear probe with two RF channels and
variable temperature capability. The measurements were carried out at 400 MHz (1H NMR) and 100 MHz (13C
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NMR) and 376 MHz (19F NMR). The NMR signals are reported in parts per million (ppm) relative to
tetramethylsilane (TMS) or the residual signal of the solvent. The high resolution mass spectrometry analysis
(HR-MS) was performed using a AB SCIEX Qtrap 5500 instrument in negative ion mode.
General reaction conditions. Indole (0.35 mmol, 1 eq.), trifluoroacetaldehyde methylhemiacetal (270 µL, 7
eq.), triethylamine (7 µL, 10 mol %), and DMSO (0.5 mL) were mixed together in a microwave vial (10 mL). The
solution was irradiated in the microwave reactor at 80˚C for 45 min. After cooling to room temperature the
reaction mixture was diluted with 2 mL of dichloromethane and washed with water (3x 5 mL). The solvent was
evaporated under vacuum and the crude product was purified by preparative thin layer chromatography.
2,2,2-trifluoro-1-(1-H-indol-1-yl)ethanol (Table 1, entry 1). MS (EI) m/z 215 (54%, M+), 146 (41%), 118 (85%),
1
117 (100%). H NMR (400 MHz, (CD3)2CO): δ (ppm) 7.66 (d, J 8.4 Hz, 1H), 7.58 (dt, J 8.0, 1.2 Hz, 1H), 7.47 (d, J
3.2 Hz, 1H), 7.16-7.22 (m, 1H), 7.06-7.12 (m, 1H), 6.55-6.59 (m, 1H), 4.04 (q, J 6.8 Hz, 1H), 2.94 (br s, 1H); 13C
NMR (101 MHz, (CD3)2CO): δ (ppm) 137.0, 130.0, 126.0, 124.3, 123.0, 121.7, 121.3, 111.3, 104.6, 77.0 (q, J 36.3
Hz); 19F NMR (376 MHz, (CD3)2CO): δ (ppm) -81.05 (d, J 5.2 Hz). HR-MS (ESI-TOF) (M-1): calcd. for C10H7F3NO,
214.0480; found: 214.0051.
2,2,2-trifluoro-1-(5-methyl-1H-indol-1-yl)ethan-1-ol (Table 1, entry 2). MS (EI) m/z 229 (68%, M+), 160 (32%),
1
131(71%), 130 (100%); H NMR (400 MHz,(CD3)2SO): δ (ppm), ), 8.24 (d, J 4.3 Hz, 1H), 7.59 (d, J= 6.1 Hz, 1H),
7.41 (t, J 4.3 Hz, 1H), 7.34(m, 1H), 6.98 (dd, J 8.4, 1.7 Hz, 1H), 6.85 (d, J 5.5Hz, 1H), 5.74 (s, 1H), 2.35 (s, 3H) ;
13C NMR (100 MHz, solvent): δ (ppm) 133.1, 129.1, 128.8, 128.1, 127.0, 125.5, 121.0, 111.6, 104.3, 54.4 ; 19F
NMR (376 MHz, solvent): δ (ppm) -77.99 (d, J 3.5 Hz). HR-MS (ESI-TOF) (M-1): calcd. for C11H11F3NO, 228.0636;
found: 228.0009.
2,2,2-trifluoro-1-(5-methoxy-1H-indol-1-yl)ethan-1-ol (Table 1, entry 4).6 MS (EI) m/z 245 (100%, M+), 176
1
(32%), 147 (65%), 132 (58%), 104 (50%); H NMR (400 MHz, (CD3)2SO): δ (ppm) 8.28 (s, 1H), 7.63 (m, 1H), 7.44
(d, J 5.3 Hz, 1H), 7.07 (d, J 4.8 Hz, 1H), 6.81 (dd, J 9.0, 2.5 Hz, 1H),6.55(d, J 6.6 Hz, 1H), 6.48 (dd, J 3.4, 0.5, 1H),
3.74 (s, 3H); 13C NMR (100 MHz, (CD3)2SO): δ (ppm) 154.0, 136.1, 133.9, 129.7, 124.3, 112.3, 110.5, 109.0,
104.6, 102.2, 68.9 ; 19F NMR (376 MHz, (CD3)2SO): δ (ppm) -79.43 (d, J 5.2 Hz). Known compound. Spectral
data are agreement with ref 6.
1-(2,2,2-trifluoro-1-hydroxyethyl)-1H-indol-5-ol (Table 1, entry 5). MS (EI) m/z 231 (74% M+), 133 (100%), 104
1
(37%); H NMR (400 MHz, (CD3)2SO): δ (ppm) 7.80 (d, J 5.5Hz, 1H), 7.56 (d, J 5.1 Hz, 1H), 6.99 (d, J 6.6 Hz, 1H),
6.61 (t, J 5.5 Hz, 1H), 6.59 (t, J 5.1 Hz, 1H) 6.52 (d, J 6.6Hz, 1H), 5.5 (s, 1H), 4.0 (s, 1H);13C NMR (100 MHz,
(CD3)2SO): δ (ppm): δ (ppm) 152.3, 131.5, 127.2, 124.4, 121.6, 118.8, 104.9, 103.4, 101.3, 86.4; 19F NMR (376
MHz, (CD3)2SO): δ (ppm) -82.71 (d, J 4.2 Hz). HR-MS (ESI-TOF) (M-1): calcd. for C10H9F3NO2, 230.0429; found:
230.0340.
1-(4,6-dimethoxy-3-methyl-1H-indol-1-yl)-2,2,2-trifluoroethan-1-ol (Table 1, entry 7). MS (EI) m/z 289 (45%,
1
M+), 191 (100%), 176 (99%); H NMR (400 MHz, (CD3)2SO): 8.08 (d, J 4.5 Hz, 1H), 6.91 (s, 1H), 6.86 (d, J 1.6 Hz,
1H), 6.44 – 6.40 (m, 1H), 6.18 (d, J 1.6 Hz, 1H), 3.78 (s, 3H), 3.77 (s, 3H), 3.37 (s, 3H); 13C NMR (100 MHz,
(CD3)2SO): δ (ppm) 157.6, 155.0, 138.7, 125.2, 120.1, 112.8, 112.2, 94.5, 92.2, 92.0, 75.3, 55.6; 19F NMR (376
MHz, (CD3)2SO): δ (ppm) -79.21 (d, J 5.1 Hz). HR-MS (ESI-TOF) (M-1): calcd. for C13H13F3NO3, 288.0848; found:
288.0938.
1-(3-(tert-butyl)-1H-indol-1-yl)-2,2,2-trifluoroethan-1-ol (Table 1, entry 8). MS (EI) m/z 271 (18%, M+), 256
(55%), 173 (32%), 158 (100%); 1H NMR (400 MHz, (CD3)2SO): δ (ppm) 8.17 (d, J 5.6Hz, 1H), 7.74 (d, J 7.4Hz, 1 H),
13
7.4 (d, J 7.4 Hz, 1 H), 7.05 (m, 1 H), 6.51 (m, 1 H), 5.75 (s, 1H), 5.04 (m, 1H), 2.53 (s, 9H); C NMR (100 MHz,
19
(CD3)2SO): δ (ppm) 136.7, 128.4, 125.7, 121.7, 120.8, 119.2, 118.7, 109.1, 43.0, 36.3; F NMR (376 MHz,
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(CD3)2SO): δ (ppm) -79.14 (d, J 4.8 Hz). HR-MS (ESI-TOF) (M-1): calcd. for C14H15F3NO, 270.1106; found:
270.1074.
1-(2,3-dimethyl-1H-indol-1-yl)-2,2,2-trifluoroethan-1-ol (Table 1, entry 9). MS (EI) m/z 243 (30%, M+), 145
(70%), 144 (100%), 130 (56%); 1H NMR (400 MHz, (CD3)2SO): δ (ppm) 8.43 (d, J 7.2Hz, 1H), 8.13 (t, J 7.2Hz, 1H),
13
8.09 (d, J 7.2 Hz, 1H), 8.07 (t, J 3.9Hz, 1H), 6.22 (q, J 4.6Hz, 1H), 3.20 (s, 3H), 3.06 (s, 3H); C NMR (100 MHz,
19
(CD3)2SO): δ (ppm) 135.2, 132.1, 129.6, 121.1, 119.9, 118.2, 110.7, 105.5, 97.8, 76.6 (q, J 35.1 Hz), 10.7, 8.5; F
NMR (376 MHz, (CD3)2SO): δ (ppm) -84.34 (d, J 4.6 Hz). HR-MS (ESI-TOF) (M-1): calcd. for C12H11F3NO,
242.0793; found: 242.0028.
Synthesis of 3-t-butyl indole. Indole (100 mg), K-10 montmorillonite (250 mg) and 2 mL of tert-butanol were
mixed together in a microwave vial (10 mL). The solution was irradiated in the microwave reactor at 100˚C for
60 min. After cooling to room temperature the reaction mixture was diluted with 2 mL of dichloromethane
and washed with water (5 mL). The solvent was evaporated under vacuum and the crude product was purified
by preparative thin layer chromatography.
1
3-(tertbutyl)-indole42 MS (EI) m/z 173 (31%, M+) 158 (100%); H NMR (400 MHz, (CD3)2SO): δ (ppm) 10.70 (s,
1H), 7.67 (d, J 8.0 Hz, 1H), 7.32 (d, J 8.0 Hz, 1H), 7.06 – 6.87 (m, 3H), 1.38 (s, 9H); 13C NMR (100 MHz, (CD3)2SO):
δ (ppm) 137.7, 125.9, 124.9, 120.9, 120.8, 120.5, 118.3, 112.4, 31.6, 31.2 (3C). Known compound. Spectral
data are agreement with ref. 42.
Acknowledgements
Financial support from the Department of Chemistry, University of Massachusetts (UMASS), Boston and the
Department of Chemistry and Biochemistry, Georgia Southern University (GSU), is gratefully acknowledged.
References
1. Sundberg, R. J. In Indoles, Ch. 1 - Introduction; Academic: London, 1996; pp 1-6.
2. Poojitha, J.; Mounika, K. N.; Raju, G. N.; Nadendla, R. R. World J. Pharm. Res. 2015, 4, 656-666.
3. Sravanthi, T. V.; Manju, S.L. Eur. J. Pharm. Sci. 2016, 91, 1-10.
https://doi.org/10.1016/j.ejps.2016.05.025
4. Thompson, M. J.; Louth, J. C.; Ferrara, S.; Sorrell, F. J.; Irving, B. J.; Cochrane, E. J.; Meijer, A. J.; Chen, B.
ChemMedChem 2011, 6, 115-130.
https://doi.org/10.1002/cmdc.201000383
5. Török, M.; Abid, M.; Mhadgut, S. C.; Török, B. Biochemistry 2006, 45, 5377-5383.
https://doi.org/10.1021/bi0601104
6. Török, B.; Sood, A.; Bag, S.; Kulkarni, A.; Borkin, D.; Lawler, E.; Dasgupta, S.; Landge, S.; Abid, M.; Zhou,
W.; Foster, M.; LeVine, H., III ; Török, M. ChemMedChem 2012, 7, 910-919.
https://doi.org/10.1002/cmdc.201100569
7. Agasti, S.; Dey, A.; Maiti, D. Chem. Comm. 2017, 53, 6544-6556.
https://doi.org/10.1039/C7CC02053H
8. Monguchi, Y.; Sawama, Y.; Sajiki, H. Heterocycles 2015, 91, 239-264.
https://doi.org/10.3987/REV-14-811
9. Zhang, B.; Studer, A. Chem. Soc. Rev. 2015, 44, 3505-3521.
https://doi.org/10.1039/C5CS00083A
Page 128
©ARKAT USA, Inc

Arkivoc 2018, ii, 122-130
Schäfer, T. et al.
10. Abid, M.; Landge, S. M.; Török, B. Org. Prep. Proced. Int. 2006, 35, 495-500.
https://doi.org/10.1080/00304940609356444
11. Abid, M.; Spaeth, A.; Török, B. Adv. Synth. Catal. 2006, 348, 2191-2196.
https://doi.org/10.1002/adsc.200606200
12. Török, B.; Abid, M.; London, G.; Esquibel, J.; Török, M.; Mhadgut, S. C.; Yan, P.; Prakash, G. K. S. Angew.
Chem. Int. Ed. 2005, 44, 3086-3089.
https://doi.org/10.1002/anie.200462877
13. Abid, M.; Teixeira, L.; Török, B. Org. Lett. 2008, 10, 933-935.
https://doi.org/10.1021/ol703095d
14. Sood, A.; Abid, M.; Hailemichael, S.; Foster, M. Török, B.; Török, M. Bioorg. Med. Chem. Lett. 2009, 19,
6931-6934.
https://doi.org/10.1016/j.bmcl.2009.10.066
15. Rudnitskaya A.; Huynh, K.; Török, B.; Stieglitz, K. J. Med. Chem. 2009, 52, 878-882.
https://doi.org/10.1021/jm800720a
16. Muzalevskiy, V. M.; Serdyuk, O. V.; Nenajdenko, V. G. Chemistry of Fluorinated Indoles; In Fluorine in
Heterocyclic Chemistry; Nenajdenko, V. Ed.; Springer: Cham, 2014; Vol. 1, pp 117-156.
https://doi.org/10.1007/978-3-319-04346-3_3
17. Usachev, B. I. J. Fluorine Chem. 2016, 185, 118-167.
https://doi.org/10.1016/j.jfluchem.2016.02.006
18. Bégué, J.-P.; Bonnet-Delpon, D. Bioorganic and Medicinal Chemistry of Fluorine Wiley: Hoboken, New
Jersey, 2008.
https://doi.org/10.1002/9780470281895
19. Daştan, A.; Kulkarni, A.; Török, B. Green Chem. 2012, 14, 17-37.
https://doi.org/10.1039/C1GC15837F
20. Zhu,X.; Ganeshan, A. J. Org. Chem. 2002, 67, 2705-2708.
https://doi.org/10.1021/jo010996b
21. Darehkordi, A.; Rahmani, F.; Hashemi, V. Tetrahedron Lett. 2013, 54, 4689-4692.
https://doi.org/10.1016/j.tetlet.2013.06.093
22. Kulkarni, A.; Quang, P.; Török, B. Synthesis 2009, 4010-4014.
23. Nunomoto, S.; Kawakami, K.; Yamashita, Y. J. Chem. Soc. Perkin Trans. 1990, 1, 111-114.
https://doi.org/10.1039/p19900000111
24. Zhu, Y.; Rawal, V. H. J. Am. Chem. Soc. 2012, 134, 111-114.
https://doi.org/10.1021/ja2095393
25. Sundberg, R. J. In Indoles, Ch. 9 - Synthetic Modification of Indoles by Substitution at Nitrogen; Academic:
London, 1996; pp 89-93.
26. Reinecke, M. G.; Sebastian, J. F.; Johnson, H. W.; Pyun, C. J. Org. Chem. 1972, 37, 3066-3068.
https://doi.org/10.1021/jo00985a005
27. Karchava, A. V.; Melkonyan, F. S.; Yurovskaya, M. A. Chem. Heterocycl. Compd. 2012, 48, 391-407.
https://doi.org/10.1007/s10593-012-1006-2
28. Leitch, S.; Jones, A.-J., McCluskey,A. Tetrahedron Lett. 2005, 46, 2915-2918.
https://doi.org/10.1016/j.tetlet.2005.02.153
29. Santaniello, E.; Farachi, C.; Ponti, F. Synthesis 1979, 1979, 617- 618.
https://doi.org/10.1055/s-1979-28783
30. Li, Y.; Zhang, L.; Yuan, H.; Liang, F.; Zhang, J. Synlett 2015, 26, 116-122.
Page 129
©ARKAT USA, Inc

Arkivoc 2018, ii, 122-130
Schäfer, T. et al.
31. Le Noble, W. J.; Morris, H. F. J. Org. Chem. 1969, 34, 1969-1973.
https://doi.org/10.1021/jo01258a101
32. Nandi, D.; Siwal, S.; Mallick, K. New J. Chem. 2017, 41, 3082-3088.
https://doi.org/10.1039/C6NJ03584A
33. Kilic, H.; Bayindir, S.; Erdogan, E.; Saracoglu, N. Tetrahedron 2012, 68, 5619-5630.
https://doi.org/10.1016/j.tet.2012.04.066
34. Kulkarni, A.; Török, B. Green Chem. 2010, 12, 875-878.
https://doi.org/10.1039/c001076f
35. Solan, A.; Nişanci, B.; Belcher, M.; Young, J.; Schäfer, C.; Wheeler, K. A.; Török, B.; Dembinski, R. Green
Chem. 2014, 16, 1120-1124.
https://doi.org/10.1039/C3GC41898G
36. Cho, H.; Török, F.; Török, B. Green Chem. 2014, 16, 3623-3634.
https://doi.org/10.1039/C4GC00037D
37. Schäfer, C.; Ellstrom, C. J.; Cho, H.; Török, B. Green Chem. 2017, 19, 1230-1234.
https://doi.org/10.1039/C6GC03032G
38. Kokel, A.; Török, B. Green Chem. 2017, 19, 2515-2519.
https://doi.org/10.1039/C7GC00901A
39. Borkin, D.; Landge, S.; Török, B. Chirality 2011, 23, 612-616.
https://doi.org/10.1002/chir.20982
40. Landge S.; Borkin, D.; Török, B. Tetrahedron Lett. 2007, 48, 6372-6376.
https://doi.org/10.1016/j.tetlet.2007.06.170
41. Landge, S. M.; Alonzo, J.; Török, B.; Int. Conf. on Microwave Chemistry, CEM-MIT, Cambridge, 2008.
42. Budylin, V. A.; Ermolenko, M. S.; Kost, A. N.; Khim. Geterosikl. Soed. 1978, 921-924.
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