Synthesis of 3-Fluoroindoles via Photoredox Catalysis

Article abstract of DOI:10.1021/acs.joc.6b02344

A method for the synthesis of 3-fluoroindoles from N-arylamines substituted with the CF₂I group is described. The reaction is mediated by a ruthenium photocatalyst in the presence of a substoichiometric amount of triphenylphosphine upon irradiation with blue light. The starting N-arylamines are readily obtained by nucleophilic iododifluoromethylation of iminium ions.

Full text of DOI:10.1021/acs.joc.6b02344

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Note
Synthesis of 3-Fluoroindoles via Photoredox Catalysis
Liubov I. Panferova, Vladimir O. Smirnov, Vitalij V. Levin, Vladimir
A. Kokorekin, Marina I. Struchkova, and Alexander D. Dilman
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.6b02344 • Publication Date (Web): 12 Dec 2016
Downloaded from http://pubs.acs.org on December 13, 2016
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Synthesis of 3-Fluoroindoles via Photoredox Catalysis
Liubov I. Panferova,† Vladimir O. Smirnov,† Vitalij V. Levin,† Vladimir A. Kokorekin,†,‡ Marina I.
Struchkova,† Alexander D. Dilman†,*
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†N. D. Zelinsky Institute of Organic Chemistry, 119991 Moscow, Leninsky prosp. 47, Russian
Federation
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‡ First I. M. Sechenov Moscow State Medical University, 119991 Moscow, Trubetskaya st. 8ꢀ2,
Russian Federation
adil25@mail.ru
R3
Ru(bpy)3(BF4)2 (0.5 mol%)
PPh3 (20 mol%)
R2
R1
R2
R1
R3
N
blue LED
N
I
then silica gel
F
F
F
Abstract A method for the synthesis of 3ꢀfluoroindoles from Nꢀarylamines substituted with the
CF2I group is described. The reaction is mediated by a ruthenium photocatalyst in the presence of
substoichiometric amount of triphenylphosphine upon irradiation with blue light. The starting Nꢀ
arylamines are readily obtained by nucleophilic iododifluoromethylation of iminium ions.
Importance of organofluorine compounds for medicinal chemistry1 has stimulated the
development of methods for their synthesis.2 Of particular interest are reactions allowing for
assembling of molecules bearing single fluorine atom or a fluorinated group in a specified position
from simple building blocks.1a,3 Despite significant progress in this field, synthesis of heterocycles
substituted with the fluorine in a specific position still may be problematic.4 For example, there are
no general methods for the synthesis of 3ꢀfluoroindoles. Thus, all reported approaches to 3ꢀ
fluoroindoles rely on electrophilic fluorination reactions which either are accompanied by
overfluorination,5 or require biased substrates such 3ꢀstannylindoles6 or orthoꢀalkynylanilines.7 In
this work, we describe a straightforward access to 3ꢀfluoroindoles starting from Nꢀaryliminium salts
with the fluorine substituent originating from difluorocarbene8 (Scheme 1).
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Recently, we reported facile methods of nucleophilic fluoroalkylation of carbonyl compounds
and iminium ions affording products containing CF2X groups,9,10 where X is either halogen (Br, I)
or a triphenylphosphonium fragment (Scheme 1). It is also known that fluorinated iodides11 and
phosphonium salts12 can serve as sources of fluorinated radicals under photoredox conditions.13
Herein, we demonstrate the application of photoredox catalysis to effect cyclization of Nꢀarylꢀ
substituted amines 1 (R3 = Ar). Difluorinated indolines 2 are the primary products of photoredox
processes, whereas subsequent elimination of hydrogen fluoride would lead to the indole system.14
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Scheme 1. Approach to the synthesis of 3-fluoroindoles.
Previous work:
R2
R3
R2
R1
R3
R2
R1
R3
N
N
N
X
X
R1
Y
C
F
F
1
F
F
X = Br, I, +PPh3
This work:
R2
R1
R2
N
R2
N
Cat, hν
N
X
R1
R1
– HX
– HF
F
F
F
F
F
2
3
1
A series of substrates 1a-X were evaluated in the presence of photocatalyst (0.5 mol%)
irradiating either with blue LED for ruthenium or with UV LED for iridium complexes (Table 1).
Reactions were performed in acetonitrile using sodium acetate as basic scavenger, and the mixtures
were analyzed by 19F NMR. In reaction of phosphonium salt no product was formed with ruthenium
catalyst, whereas facꢀIr(ppy)3 was markedly more efficient (entries 1 and 2). When iodosubstituted
substrate 1a-I was used, traces of product 2a were observed, with the starting iodide being virtually
unconsumed (entries 4 and 5). Surprisingly, addition of 20 mol % of triphenylphosphine to both
ruthenium and iridium catalysts had profound effect, and product 2a was formed in high yields
(entries 6 and 10). Ruthenium system was particularly effective affording the product in a virtually
quantitative yield. Bromoꢀsubstituted starting compound 1a-Br was less efficient compared to an
iodoꢀcounterpart (entries 12 and 13). When Hünig's base, a typical reductive additive in photoredox
processes,15 was used instead of phosphine, the product was formed in low yield (entry 7).
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However, with 2 equiv of Hünig's base, complete conversion of starting substrate was noted along
with high yield of the product (entry 8). It is likely that acetic acid formed during the reaction
scavenges the amine base (pKa = 11.51), whereas less basic phosphine (pKa = 2.73) remains
unprotonated and can be employed in substoichiometric amounts.
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Table 1. Optimization studies.
cat (0.5 mol%),
AcONa (2 equiv)
Me
Me
R1
additive
N
N
X
R1
MeCN, light, rt, 12 h
F
F
F
F
1a-X, R1 = 4-ClC6H4
2a
no
X
cat.a
Additive
yield of
2a, %b
–
1
+PPh3 Ru(bpy)3(BF4)2
+PPh3 Ir(ppy)3
–
–
2
27
–
3
+PPh3 Ru(bpy)3(BF4)2
PPh3 (0.2 equiv)
4
I
I
I
I
I
I
I
I
Ru(bpy)3(BF4)2
Ir(ppy)3
–
–
5
–
< 5
98
6
Ru(bpy)3(BF4)2
Ru(bpy)3(BF4)2
Ru(bpy)3(BF4)2
Ru(bpy)3(BF4)2
Ir(ppy)3
PPh3 (0.2 equiv)
7
iꢀPr2NEt (0.2 equiv) 23
iꢀPr2NEt (2.0 equiv) 89
8
9
PPh3 (0.05 equiv)
PPh3 (0.2 equiv)
PPh3 (1 equiv)
16
79
79
–
10
11
Ir(ppy)3
12 Br
13 Br
Ru(bpy)3(BF4)2
Ir(ppy)3
PPh3 (0.2 equiv)
PPh3 (0.2 equiv)
65
a For Ruꢀcatalyst, blue LED; for Irꢀcatalyst, 400ꢀnm LED.
b Determined by 19F NMR of reaction mixtures with 4ꢀfluorotoluene as an internal standard.
The isolation of difluoroindoline 2a by chromatography on silica gel was unsuccessful, since a
significant portion of the product underwent elimination of hydrogen fluoride leading to
corresponding 3ꢀfluroindole. Surprisingly, numerous attempts to intentionally cause
dehydrofluorination by treatment of 2a with mild bases or acids did not furnish complete
conversion. Finally, for the isolation of indole, dehydrofluorination was performed by simple
stirring of a solution of the crude indoline with silica gel for 4–16 hours at room temperature.
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Accordingly, under the optimized conditions, a series of idododifluoromethylated amines 1 were
converted into 3ꢀfluoroindoles 3 (Table 2). Starting substrates 1 were obtained by
iododifluoromethylation of in situ generated iminium ions using a combination of Me3SiCF2Br and
NaI as a source of CF2I carbanion.9c,16 Various substrates bearing aromatic, heteroaromatic, as well
as aliphatic substituents, worked well in this reaction. Substrates having methoxy or halogen groups
provided indoles 3 in high yields. Tetrahydroquinoline derivative furnished tricyclic product 3n.
Table 2. Synthesis of 3-fluoroindoles 3.
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Me3SiCF2Br (2 equiv)
NaI (3-5 equiv)
(a) Ru(bpy)3(BF4)2 (0.5 mol%)
PPh3 (0.2 equiv)
Y
R2
R3
R2 OTf
N
H
R2
Me
R1
Y
HMPA (1.5-2 equiv)
R3
N
AcONa (2 equiv)
N
or
N
O
I
R1
blue LED, rt, 12–16 h
R1
F
R1
3
F
F
(b) work-up
1
then silica gel, rt, 4–16 h
starting
product
yield,
%
starting
product
yield,
%
a
a
Me
Ph
F
Br
3a 98
3h
3i
98
92
81
Me
N
Br
N
N
I
N
Ph
F
I
F
F
Ph
F
Cl
F
Cl
Me
Ph
Ph
Br
3b 98
N
Me
Br
N
N
I
N
Ph
F
F
I
F
F
F
F
Me
Ph
3c
89
Ph
3j
N
Me
N
N
N
N
N
I
I
I
F
F
F
F
F
F
F
F
MeO
Cl
MeO
Cl
OMe
3d 90
Ph
F
3k
3l
90
87
Me
OMe
N
Me
N
I
F
Br
F
F
Br
MeO
MeO
MeO
Me
Ph
OMe
O
3e
3f
97
80
Me
N
O
N
OMe
MeO
MeO
I
MeO
N
MeO
Cl
N
F
F
I
F
F
F
F
OMe
MeO
Cl
OMe
N
Me
Ph
OMe
O
3m
3n
86
88
N
Me
O
OMe
I
MeO
N
MeO
N
F
F
I
F
F
F
F
OMe
3g 85
Me
S
OMe
N
Me
N
N
N
I
I
F
F
F
F
F
F
S
MeO
MeO
a Isolated yield for the conversion of 1 to 3.
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To probe the reaction mechanism, the light/dark experiment for the reaction of 1a-I under
standard conditions was performed (Figure 1). The reaction stops during periods when the light is
turned off, and restores when irradiation is resumed. This result excludes a lightꢀinitiated chain
process and suggests the involvement of the photocatalyst in the reaction.
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Figure 1. Conversion of 1a-I in the light/dark sequence. Dark periods are shown in grey.
To evaluate the feasibility of electron transfer steps, the redox potentials of compound 1a-I were
measured by cyclic voltammetry (CV). Thus, the reduction potential of –1.15 V corresponding to
the CF2Iꢀfragment and oxidation potential of +1.10 V corresponding to the aniline fragment were
obtained (all values are given vs. S.C.E., see Supporting Information for CV curves). The oxidation
potential of triphenylphosphine was measured to be +0.77 V. Taken together, these data allow to
propose the mechanism shown in Scheme 2. The reductive quenching of exited photocatalyst by
triphenylphosphine provides Ru(I), which reduces the substrate generating difluorinated radical.
Subsequent intramolecular attack of the radical onto aromatic ring followed by oxidation by
phosphine radical cation and elimination of the proton affords product 2.
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Scheme 2. Proposed mechanism.
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Concerning the mechanism of hydrogen fluoride elimination from indolines 2, we may propose
that it starts from cleavage of the carbonꢀfluorine bond, which is facilitated by mesomeric donation
from orthoꢀnitrogen. Finally, elimination of a proton assisted by the fluoride anion leads to a stable
indole system (Scheme 3).
Scheme 3. Proposed mechanism for indole formation.
R2
R1
R2
R2
R1
N
N
N
R1
– HF
H
F
F
F
F
2
3
F
In summary, a method for the synthesis of 3ꢀfluoroindoles from difluoroiodomethylꢀsubstituted
amines under photoredox conditions is described. The use of ruthenium (II) photocatalyst in
combination with triphenylphosphine to generate difluorinated radical is the key feature responsible
for the reaction efficiency.
Experimental section
General Methods. All reactions were performed under an argon atmosphere. Acetonitrile was
distilled from CaH2. High resolution mass spectra (HRMS) were measured using electrospray
ionization (ESI) and timeꢀofꢀflight (TOF) mass analyzer. The measurements were done in a positive
ion mode (interface capillary voltage – 4500 V) or in a negative ion mode (3200 V); mass range
from m/z 50 to m/z 3000. For blue light irradiation, a strip of light emitting diodes (2835ꢀ120LEDꢀ
1MꢀBLUE 12V) was used. Column chromatography was carried out employing silica gel (230ꢀ400
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mesh). Precoated silica gel plates Fꢀ254 were used for thinꢀlayer analytical chromatography
visualizing with UV and/or aq. KMnO4 solution. (Bromodifluoromethyl)trimethylsilane16a was
obtained according to a literature procedure.
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Measurement of redox potentials by cyclic voltammetry (CV). Voltammetric studies were
carried out in a temperatureꢀcontrolled (25 °C) cell (V = 10 mL) with the scan rate of 0.1 V·s–1. A
platinum wire (diameter 1 mm) in a Teflon casing was used as the working electrode. A saturated
calomel electrode (S.C.E.) separated from the solution being studied by a salt bridge filled with the
supporting electrolyte (0.1 М Et4NClO4 in MeCN) was used as the reference electrode. A platinum
plate (S = 3 cm2) was used as the counter electrode.
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Tris(2,2'-bipyridine)ruthenium(II) tetrafluoroborate was obtained by modified literature
procedure.17 A mixture of ruthenium chloride hydroxide (2 g, 9 mmol), hydrocloric acid (5 mL of
aqueous 30% solution) and ethanol (10 mL) was refluxed for 3 hours. Then, volatiles were
evaporated under vacuum. Chloroform (5 mL) was added to the residue, and volatiles were
evaporated under vacuum. The residue was treated with ethylene glycol (30 mL) and 2,2'ꢀbipyridine
(4.2 g, 27 mmol), and the mixture was refluxed for 3 hours. The heating was discontinued, and a
solution of NaBF4 (4.9 g, 45 mmol) in water (2 mL) was added. The mixture was cooled and kept
overnight in a refrigerator at 0 °C to effect crystallization. The precipitate was filtered off, washed
1
with ethanol (3×10 mL), and dried affording 5.5 g of red powder (82%). Mp >200 °C. H NMR
(300 MHz, (CD3)2SO) δ: 8.82 (d, J = 8.3 Hz, 6H), 8.22–8.10 (m, 6H), 7.73 (d, J = 5.0 Hz, 6H),
7.57–7.48 (m, 6H). 13C{1H} NMR (50 MHz, (CD3)2SO), δ: 156.6, 151.2, 138.0, 127.9, 124.5, 96.8.
N-[2-Bromo-1-(4-chlorophenyl)-2,2-difluoroethyl]-N-methyl-N-phenylamine
(1a-Br).
Prepared according to a literature procedure9b from pꢀchlorobenzaldehyde (2.0 mmol) and Nꢀ
methylaniline (2.2 mmol); yield 526 mg (73 %). Colorless oil. Chromatography: hexane. Rf 0.24
(hexane). 1H NMR (300 MHz, CDCl3) δ: 7.37 (s, 4H), 7.34 (dd, J = 8.7 Hz, 7.3 Hz, 2H), 6.98 (d, J
13
= 8.2 Hz, 2H), 6.92 (t, J = 7.3 Hz, 1H), 5.60 (dd, J = 14.0, 12.6 Hz, 1H), 2.77 (s, 3H). C{1H}
NMR (75 MHz, CDCl3), δ: 149.9, 134.7, 132.0 (t, J = 1.4 Hz), 130.2 (t, J = 2.3 Hz), 129.6, 129.0,
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123.9 (dd, J = 316.1, 314.4 Hz), 119.5, 114.5, 71.4 (dd, J = 22.7 Hz, 20.1 Hz), 33.8 (t, J = 2.3 Hz).
19F NMR (282 MHz, CDCl3), δ: –49.1 (dd, J = 165.3, 12.6 Hz, 1F), –50.1 (dd, J = 165.3, 14.0 Hz,
1F). HRMS (ESI): calcd for C15H14BrClF2N (M+H) 361.9940; found 361.9954.
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Synthesis of iododifluoromethyl-susbtituted amines.
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General procedure 1. Methyl triflate (274 µL, 2.5 mmol) was added to a solution of imine (2
mmol) in acetonitrle (3 mL), and the mixture was stirred at room temperature for 2 h. The mixture
was cooled with ice/water bath, and NaI (900 mg, 6 mmol), Me3SiCF2Br (650 µL, 4 mmol) and
HMPA (696 µL, 4 mmol) were successively added. The cooling bath was removed, and the mixture
was stirred at room temperature for 8 h. For the workꢀup, saturated aq. Na2CO3 (2 mL) was added,
and the mixture was washed with EtOAc/hexane (1/1, 3×5 mL). The combined organic layers were
filterred through Na2SO4, concentrated under vacuum, and the residue was purified by column
chromatography.
General procedure 2. Me3SiCl (0.51 mL, 4.0 mmol) was added dropwise to a vigorously stirred
mixture of NaI (1.50 g, 10.0 mmol), 1,8ꢀbis(dimethylamino)naphthalene (428 mg, 2.0 mmol), Nꢀ
alkylꢀNꢀarylamine (2.0 mmol), aldehyde (2.0 mmol), and acetonitrile (4 mL) at 0 °C. Then, the
cooling bath was removed, and the reaction mixture was stirred at room temperature for one hour.
The reaction flask was immersed into ice/water cooling bath, Me3SiCF2Br (610 mg, 3.0 mmol) and
HMPA (523 µL, 3.0 mmol) were added successively. The cooling bath was removed, and the
mixture was stirred at room temperature for one hour. The reaction mixture was workedꢀup by
successive addition of hexane/CH2Cl2 mixture (4/1, 8 mL), saturated aqueous Na2CO3 (4 mL) and
water (4 mL). Organic layer was separated, aqueous layer was washed with hexane/CH2Cl2 mixture
(4/1, 2×8 mL). The combined organic layers were washed with 1.0 M aqueous NaHSO4 (4 mL),
while acidic aqueous layer was washed with hexane/CH2Cl2 mixture (4/1, 2×8 mL). All organic
layers were combined, filtered through Na2SO4, concentrated under vacuum, and the residue was
purified by column chromatography.
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Me
Ph
F
N
I
F
Cl
1a-I
5
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Nꢀ(1ꢀ4ꢀChorophenyl)ꢀ2,2ꢀdifluoroꢀ2ꢀiodoethyl)ꢀNꢀmethylaniline (1a-I). According to General
procedure 1, from Nꢀ[(4ꢀchlorophenyl)methylene]ꢀNꢀphenylamine, yield 415 mg (51%).Yellow oil.
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1
Chomatography: hexanes/EtOAc, 20/1. Rf 0.60 (hexanes/EtOAc, 20/1). H NMR (300 MHz,
CDCl3) δ: 7.50–7.31 (m, 6H), 7.10–6.90 (m, 3H), 5.63 (t, J = 14.5 Hz, 1H), 2.84 (s, 3H). 13C{H}
NMR (75 MHz, CDCl3) δ: 149.7, 134.6, 131.7, 130.4 (t, J = 2.3 Hz), 129.5, 129.0, 119.4, 114.5,
19
105.1 (dd, J = 323.6, 322.8 Hz), 73.7 (dd, J = 20.7, 19.5 Hz), 34.0 (t, J = 2.3 Hz). F NMF (282
MHz, CDCl3) δ: –42.7 (dd, J = 180.1, 14.5 Hz, 1F), –43.6 (dd, J = 182.3, 14.5 Hz, 1F). HRMS
(ESI): calcd for C15H14ClF2IN (M+H) 407.9822; found 407.9812.
Me
Ph
N
I
Ph
F
F
1b
Nꢀ(2,2ꢀDifluoroꢀ2ꢀiodoꢀ1ꢀphenylethyl)ꢀNꢀmethylaniline (1b). According to General procedure 1,
from Nꢀ(phenylmethylene)ꢀNꢀphenylamine, yield 522 mg (70%). Yellow oil. Chromatography:
1
hexanes/EtOAc, 20/1. Rf 0.26 (hexanes/EtOAc, 20/1). H NMR (300 MHz, CDCl3) δ: 7.53–7.29
(m, 7H ), 7.01 (d, J = 8.0 Hz, 2H), 6.92 (t, J = 6.8 Hz, 1H), 5.63 (t, J = 14.8 Hz, , 1H), 2.81 (s, 3H).
13C{H} NMR (75 MHz, CDCl3) δ: 149.9, 133.3, 129.5, 129.1 (t, J = 2.3 Hz), 128.8, 128.6, 119.1,
19
114.4, 105.6 (dd, J = 323.6 Hz, 319.0 Hz) , 74.1 (dd, J = 21.8, 19.5 Hz), 34.1 (t, J = 2.3 Hz). F
NMF (282 MHz, CDCl3) δ: –42.2 (dd, J = 180.2, 14.8 Hz, 1F), –43.3 (dd, J = 180.2, 14.8 Hz, 1F).
HRMS (ESI): calcd for C15H15F2IN (M+H) 374.0212; found 374.0207.
Me
Ph
N
I
F
F
MeO
1c
Nꢀ(2,2ꢀDifluoroꢀ 2ꢀiodoꢀ1ꢀ(4ꢀmethoxyphenyl)ethyl)ꢀNꢀmethylaniline (1c). According to General
procedure 1, from Nꢀ[(4ꢀmethoxyphenyl)methylene]ꢀNꢀphenylamine, yield 500 mg (62%). Yellow
1
oil. Chromatography: from hexanes/EtOAc, 20/1. Rf 0.46 (hexanes/EtOAc, 20/1). H NMR (300
MHz, CDCl3) δ: 7.53–7.33 (m, 4H), 7.07 (d, J = 8.0 Hz, 2H), 7.02–6.88 (m, 3H ), 5.66 (dd, J =
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14.1, 14.1 Hz, 1H), 3.88 (s, 3H), 2.87 (s, 3H). 13C{H} NMR (75 MHz, CDCl3) δ: 159.6, 149.9,
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130.4 (t, J = 2.2 Hz), 129.4, 125.2 (t, J = 1.9 Hz), 119.0, 114.4, 114.0, 106.1 (dd, J = 324.0, 323.2
19
Hz), 73.7 (dd, J = 20.7, 18.4 Hz), 55.6, 34.0. F NMF (282 MHz, CDCl3) δ: –42.0 (dd, J = 180.1,
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14.1 Hz, 1F), –43.8 (dd, J = 178.0, 14.1 Hz, 1F). HRMS (ESI): calcd for C16H17F2INO (M+H)
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404.0317; found 404.0310.
OMe
Me
N
I
F
F
MeO
1d
Nꢀ(2,2ꢀDifluoroꢀ2ꢀiodoꢀ1ꢀ(4ꢀmethoxyphenyl)ethyl)ꢀ4ꢀmethoxyꢀNꢀmethylaniline (1d). According
to General procedure 1, from Nꢀ(4ꢀmethoxyphenyl)ꢀNꢀ[(4ꢀmethoxyphenyl)methylene]amine, yield
450 mg (52%). Yellow oil. Chromatography: hexanes/EtOAc, 15/1. Rf 0.26 (hexanes/EtOAc, 15/1).
1H NMR (300 MHz, CDCl3) δ: 7.32 (d, J = 8.5 Hz, 2H), 7.05–6.81 (m, 6H ), 5.34 (t, J = 15.1 Hz,
1H), 3.84 (s, 3H), 3.82 (s, 3H), 2.76 (s, 3H). 13C{H} NMR (75 MHz, CDCl3) δ: 159.7, 153.5, 144.7,
130.6 (t, J = 2.3 Hz), 125.0, 117.4, 114.7, 114.0, 107.2 (dd, J = 323.6, 323.0 Hz), 76.1 (dd, J = 21.8,
18.4 Hz), 55.7, 55.4, 34.8. 19F NMF (282 MHz, CDCl3) δ: –42.8 (dd, J = 178.0, 15.1 Hz, 1F), –44.0
(dd, J = 178.0, 15.1 Hz, 1F). HRMS (ESI): calcd for C17H19F2INO2 (M+H) 434.0423; found
434.0410.
Me
Ph
N
MeO
MeO
I
F
F
1e
OMe
Nꢀ[2,2ꢀdifluoroꢀ2ꢀiodoꢀ1ꢀ(3,4,5ꢀtrimethoxyphenyl)ethyl]ꢀNꢀmethylꢀNꢀphenylamine
(1e).
According to General procedure 2 from 3,4,5ꢀtrimethoxybenzaldehyde and Nꢀmethylaniline, yield
485 mg (52%). Colorless oil. Chromatography: hexane/EtOAc, 7/1. Rf 0.31 (hexane/EtOAc, 5/1).
1H NMR (300 MHz, CDCl3) δ: 7.32 (t, J = 7.8 Hz, 2H), 6.98 (d, J = 8.2 Hz, 2H), 6.89 (t, J = 7.3 Hz,
1H), 6.60 (s, 2H), 5.50 (t, J = 14.4 Hz, 1H), 3.88 (s, 3H), 3.82 (s, 6H), 2.82 (s, 3H). 13C{1H} NMR
(75 MHz, CDCl3), δ: 153.3, 150.0, 138.5, 129.5, 128.6, 119.3, 114.7, 106.7, 105.5 (t, J = 323.2 Hz),
74.2 (dd, J = 20.7, 18.9 Hz), 61.0, 56.4, 34.2. 19F NMR (282 MHz, CDCl3), δ: –41.9 (dd, J = 180.1,
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14.4 Hz, 1F), –43.4 (dd, J = 180.1, 14.4 Hz, 1F). HRMS (ESI): calcd for C18H20F2INO3Na (M+Na)
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486.0348; found 486.0324.
Me
Ph
N
I
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F F
1f
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Nꢀ[2,2ꢀDifluoroꢀ2ꢀiodoꢀ1ꢀ(1ꢀnaphthyl)ethyl]ꢀNꢀmethylꢀNꢀphenylamine (1f).
According to General procedure 2 from 1ꢀnaphthaldehyde and Nꢀmethylaniline, yield 637 mg,
(75 %). White crystals. Mp 125–126 °C. Chromatography: CH2Cl2/hexane, from 1/7 to 1/3. Rf 0.31
1
(CH2Cl2/hexane, 1/7). H NMR (300 MHz, CDCl3) δ: 8.05 (d, J = 7.3 Hz, 1H), 7.92 (t, J = 7.6 Hz,
2H), 7.62–7.32 (m, 6H), 7.08 (d, J = 8.2 Hz, 2H), 6.95 (d, J = 7.3 Hz, 1H), 6.27 (dd, JHꢀF = 23.3 Hz,
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J = 5.5 Hz, 1H), 2.72 (d, J = 0.9 Hz, 3H). C{1H} NMR (75 MHz, CDCl3), δ: 148.9, 134.1, 132.4
(t, J = 1.7 Hz), 129.9 (dd, J = 5.2 Hz, 2.3 Hz), 129.6, 129.2, 128.0, 127.9, 127.2, 126.1, 124.8,
123.3, 118.8, 113.39, 113.37, 105.3 (dd, J =327.6 Hz, 316.7 Hz), 69.3 (t, J = 18.4 Hz,), 34.2 (d, J =
19
2.9 Hz). F NMR (282 MHz, CDCl3), δ: –39.0 (dd, J = 180.6, 5.5 Hz, 1F), –50.0 (dd, J = 180.6,
23.3 Hz, 1F). HRMS (ESI): calcd for C19H17F2IN (M+H) 424.0368; found 424.0346.
OMe
Me
N
I
F
F
S
1g
Nꢀ(2,2ꢀDifluoroꢀ2ꢀiodoꢀ1(thiophenꢀ2ꢀyl)ethyl)ꢀ4ꢀmethoxyꢀNꢀmethylaniline (1g).
According to General procedure 1 from Nꢀ(4ꢀmethoxyphenyl)ꢀNꢀ[thienꢀ2ꢀylmethylene]amine,
o
yield 417 mg (51%).Yellow crystals. Mp 29–30 C. Chromatography: hexanes/EtOAc, 20/1. Rf
0.33 (hexanes/EtOAc, 20/1). 1H NMR (300 MHz, CDCl3) δ: 7.34 (d, J = 5.6 Hz, 1H), 7.22–7.17 (m,
1H), 7.06 (t, J = 4.7 Hz, 1H), 6.98 (d, J = 9.2 Hz, 2H), 6.92 (d, J = 9.0 Hz, 2H), 5.57 (dd, J = 14.7,
13.3 Hz, 1H), 3.82 (s, 3H), 2.86 (s, 3H). 13C{H} NMR (75 MHz, CDCl3) δ: 153.8, 144.1, 134.1,
128.3 (t, J = 2.3 Hz), 127.0, 126.1, 117.8, 114.7, 105.5 (dd, J = 323.6, 323.6 Hz), 72.8 (dd, J = 21.8,
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19.5 Hz), 55.7, 34.6 (t, J = 2.3 Hz). F NMF (282 MHz, CDCl3) δ: –43.0 (dd, J = 180.2, 13.3 Hz,
1F), –44.7 (dd, J = 180.1, 14.7 Hz, 1F). HRMS (ESI): calcd for C14H14F2INOS (M+) 408.9803;
found 408.9821.
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Br
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Ph
1h
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Nꢀ(4ꢀBromophenyl)ꢀNꢀ(2,2ꢀdifluoroꢀ2ꢀiodoꢀ1ꢀphenylethyl)ꢀNꢀpropylamine (1h). According to
General procedure 2 from benzaldehyde and Nꢀ(4ꢀbromophenyl)ꢀNꢀpropylamine, yield 551 mg
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(57%). Pale yellow crystals. Mp 90–91 °C. Chromatography: hexane. Rf 0.32 (hexane). H NMR
(300 MHz, CDCl3) δ: 7.39 (d, J = 9.1 Hz, 2H), 7.38 (s, 4H), 6.87 (d, J = 9.1 Hz, 2H), 5.45 (dd, J =
16.9, 12.8 Hz, 1H), 3.15 (ddd, J = 14.9, 9.4, 5.5 Hz, 1H), 2.98 (ddd, J = 14.7, 9.5, 5.2 Hz, 1H),
1.54–1.37 (m, 1H), 1.34–1.13 (m, 1H), 0.72 (t, J = 7.3 Hz, 3H). C{1H} NMR (75 MHz, CDCl3),
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δ: 147.4, 133.8 (t, J = 2.3 Hz), 132.2, 129.3 (dd, J = 2.9, 1.7 Hz), 128.8, 128.7, 118.5, 112.0, 105.4
(dd, J = 324.7, 320.7 Hz), 75.6 (dd, J = 20.7, 17.8 Hz), 48.2, 20.1, 11.3. 19F NMR (282 MHz,
CDCl3), δ: –42.1 (dd, J = 179.5, 12.8 Hz, 1F), –45.5 (dd, J = 179.5, 16.9 Hz, 1F). HRMS (ESI):
calcd for C17H18BrF2IN (M+H) 481.9610; found 481.9622.
Br
N
I
F
F
1i
Nꢀ(4ꢀBromophenyl)ꢀNꢀ[2,2ꢀdifluoroꢀ2ꢀiodoꢀ1ꢀ(4ꢀmethylphenyl)ethyl]ꢀNꢀpropylamine
(1i).
According to General procedure 2 from 4ꢀmethylbenzaldehyde and Nꢀ(4ꢀbromophenyl)ꢀNꢀ
1
propylamine, yield 672 mg (68%). Colorless oil. Chromatography: hexane. Rf 0.29 (hexane). H
NMR (300 MHz, CDCl3) δ: 7.39 (d, J = 9.2 Hz, 2H), 7.27 (d, J = 8.2 Hz, 2H), 7.18 (d, J = 8.2 Hz,
2H), 6.87 (d, J = 9.2 Hz, 2H), 5.41 (dd, J = 17.4, 12.4 Hz, 1H), 3.15 (ddd, J = 15.1, 9.5, 5.6 Hz,
1H), 2.99 (ddd, J = 14.6, 9.5, 5.1 Hz, 1H), 2.38 (s, 3H), 1.54–1.37 (m, 1H), 1.34–1.15 (m, 1H), 0.73
(t, J = 7.6 Hz, 3H). C{1H} NMR (75 MHz, CDCl3), δ: 147.5, 138.6, 132.1, 130.7 (t, J = 2.3 Hz),
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129.4, 129.2 (dd, J = 2.3, 1.7 Hz), 118.5, 111.9, 105.7 (dd, J = 324.4, 320.9 Hz), 75.5 (dd, J = 20.7,
18.4 Hz), 48.2, 21.3, 20.1, 11.4. 19F NMR (282 MHz, CDCl3), δ: –41.8 (dd, J = 180.1, 12.4 Hz, 1F),
–45.7 (dd, J = 180.1, 17.4 Hz, 1F). HRMS (ESI): calcd for C18H20BrF2IN (M+H) 495.9767; found
495.9792.
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N
I
F
1j
Cl
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7
Nꢀ[1ꢀ(4ꢀChlorophenyl)ꢀ2,2ꢀdifluoroꢀ2ꢀiodoethyl]ꢀNꢀisobutylꢀNꢀphenylamine (1j).
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According to General procedure 2 from 4ꢀchlorobenzaldehyde and Nꢀisobutylaniline, yield 555
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mg (62 %). Colorless oil. Chromatography: hexane. Rf 0.29 (hexane). H NMR (300 MHz, CDCl3)
δ: 7.40–7.34 (m, 6H), 7.08 (d, J = 7.8 Hz, 2H), 7.00 (t, J = 7.3 Hz, 1H), 5.31 (dd, JHꢀF = 18.5 Hz, J =
11.7 Hz, 1H), 2.90 (dd, J = 13.5, 8.0 Hz, 1H), 2.73 (dd, J = 13.5, 6.2 Hz, 1H), 1.66–1.85 (m, 1H),
0.89 (d, J = 6.4 Hz, 3H), 0.60 (d, J = 6.4 Hz, 3H). 13C{1H} NMR (75 MHz, CDCl3), δ: 149.1, 134.5,
132.3, 131.0, 129.2, 128.8, 121.8, 120.5, 105.6 (dd, J = 323.5, 320.7 Hz), 78.8 (t, J = 19.2 Hz),
19
54.3, 25.5, 20.6, 20.3. F NMR (282 MHz, CDCl3), δ: –41.3 (dd, J = 178.0, 11.7 Hz, 1F), –46.0
(dd, J = 178.0, 18.5 Hz, 1F). HRMS (ESI): calcd for C18H20ClF2IN (M+H) 450.0292; found
450.0273.
Ph
N
I
F
F
Br
1k
Nꢀ[1ꢀ(4ꢀBromophenyl)ꢀ2,2ꢀdifluoroꢀ2ꢀiodoethyl]ꢀNꢀisobutylꢀNꢀphenylamine (1k). According to
General procedure 2 from 4ꢀbromobenzaldehyde and Nꢀisobutylaniline, yield 635 mg (64 %).
Colorless oil. Chromatography: hexane. Rf 0.30 (hexane). 1H NMR (300 MHz, CDCl3) δ: 7.50 (d, J
= 8.2 Hz, 2H), 7.31 (t, J = 7.6 Hz, 2H), 7.20 (d, J = 8.2 Hz, 2H), 7.07 (d, J = 8.2 Hz, 2H), 7.00 (t, J
= 7.1 Hz, 1H), 5.27 (dd, JHꢀF = 18.3, J = 11.9 Hz, 1H), 2.88 (dd, J = 13.5, 8.0 Hz, 1H), 2.72 (dd, J =
13.7, 6.0 Hz, 1H), 1.66–1.83 (m, 1H), 0.88 (d, J = 6.4 Hz, 3H), 0.60 (d, J = 6.9 Hz, 3H). C{1H}
13
NMR (75 MHz, CDCl3), δ: 149.1, 132.8 (t, J = 2.6 Hz), 131.8, 131.3 (t, J = 2.0 Hz), 129.3, 122.8,
121.9, 120.7, 105.6 (dd, J = 324.1, 320.7 Hz), 78.9 (dd, J = 20.1, 17.8 Hz), 54.4 (t, J = 1.7 Hz),
25.5, 20.6, 20.3. 19F NMR (282 MHz, CDCl3), δ: –41.3 (dd, J = 178.0, 11.9 Hz, 1F), –46.0 (dd, J =
178.0, 18.3 Hz, 1F). HRMS (ESI): calcd for C18H20BrF2IN (M+H) 495.9767; found 495.9740.
OMe
O
MeO
Cl
N
I
F
F
1l
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Methyl Nꢀ[1ꢀ(4ꢀchlorophenyl)ꢀ2,2ꢀdifluoroꢀ2ꢀiodoethyl]ꢀNꢀ(4ꢀmethoxyphenyl)ꢀβꢀalaninate (1l).
According to General procedure 2 from 4ꢀchlorobenzaldehyde and methyl Nꢀ(4ꢀmethoxyphenyl)ꢀβꢀ
alaninate, yield 701 mg (69%). Pale yellow oil. Chromatography: from CH2Cl2/hexane (1/2) to
CH2Cl2. Rf 0.54 (CH2Cl2). 1H NMR (300 MHz, CDCl3) δ: 7.32 (d, J = 8.2 Hz, 2H), 7.21 (d, J = 8.2
Hz, 2H), 6.95 (d, J = 9.2 Hz, 2H), 6.83 (d, J = 9.2 Hz, 2H), 4.98 (dd, J = 15.6 Hz, 14.2 Hz, 2H),
3.79 (s, 3H), 3.61 (s, 3H), 3.60–3.47 (m, 1H), 3.28 (dd, J = 13.7, 8.2, 5.5 Hz, 1H), 2.48–2.24 (m,
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2H). C{1H} NMR (75 MHz, CDCl3), δ: 172.4, 155.8, 140.6, 134.7, 131.8, 131.0 (t, J = 2.0 Hz),
128.8, 123.6, 114.6, 106.6 (dd, J = 322.7 Hz, 321.0 Hz), 78.2 (dd, J = 20.9 Hz, 18.1 Hz), 55.6, 51.7,
45.0, 33.2. 19F NMR (282 MHz, CDCl3), δ: –42.5 (dd, J = 179.1, 14.2 Hz, 1F), –45.9 (dd, J = 179.1,
15.6 Hz, 1F). HRMS (ESI): calcd for C19H19ClF2INO3Na (M+Na) 531.9958; found 531.9940.
OMe
O
MeO
N
I
1m
F
F
Methyl Nꢀ{1ꢀ[difluoro(iodo)methyl]ꢀ2ꢀmethylpropyl}ꢀNꢀ(4ꢀmethoxyphenyl)ꢀβꢀalaninate (1m).
According to General procedure 2 from isobutyraldehyde and methyl Nꢀ(4ꢀmethoxyphenyl)ꢀβꢀ
alaninate, yield 287 mg (33 %). Colorless oil. Chromatography: CH2Cl2/hexane, from 1/2 to
CH2Cl2. Rf 0.53 (CH2Cl2). 1H NMR (300 MHz, CDCl3) δ: 6.92–6.82 (m, 4H), 3.78 (s, 3H), 3.71 (t,
J = 7.8 Hz, 2H), 3.69 (s, 3H), 3.58 (dd, JHꢀF = 18.8 Hz, J = 9.4, 6.6 Hz, 1H), 2.74–2.55 (m, 2H),
13
2.44–2.26 (m, 1H), 1.17–1.10 (m, 3H), 0.98 (d, J = 6.4 Hz, 3H). C{1H} NMR (75 MHz, CDCl3),
δ: 172.7, 153.4, 141.9, 117.9, 114.8, 109.8 (dd, J = 327.3, 325.0 Hz), 78.0 (t, J = 19.8 Hz), 55.7,
51.8, 40.8 (d, J = 2.9 Hz), 32.7, 29.6, 21.7, 20.6 (dd, J = 6.0, 2.0 Hz). 19F NMR (282 MHz, CDCl3),
δ: –30.7 (d, J = 178.0 Hz, 1F), –40.7 (dd, J = 178.0, 18.8 Hz, 1F). HRMS (ESI): calcd for
C16H23F2INO3 (M+H) 442.0685; found 442.0669.
N
I
F
F
1n
MeO
1ꢀ[2,2ꢀDifluoroꢀ2ꢀiodoꢀ1ꢀ(4ꢀmethoxyphenyl)ethyl]ꢀ1,2,3,4ꢀtetrahydroquinoline (1n). According
to General procedure 2 from 4ꢀmethoxybenzaldehyde and 1,2,3,4ꢀtetrahydroquinoline, yield 439 mg
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(51%). Pale yellow oil. Chromatography: CH2Cl2/hexane, 1/2. Rf 0.42 (CH2Cl2/hexane, 1/2). H
NMR (300 MHz, CDCl3) δ: 7.39 (d, J = 8.7 Hz, 2H), 7.15 (t, J = 7.8 Hz, 1H), 7.02 (d, J = 7.3 Hz,
1H), 6.97 (d, J = 8.7 Hz, 1H), 6.90 (d, J = 8.7 Hz, 2H), 6.73 (t, J = 7.3 Hz, 1H), 5.65 (dd, J = 17.4,
12.4 Hz, 1H), 3.84 (s, 3H), 3.32 (ddd, J = 11.2, 8.1, 3.1 Hz, 1H), 3.05 (ddd, J = 11.2, 7.7, 3.5 Hz,
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1H), 2.85–2.63 (m, 2H), 1.94–1.79 (m, 1H), 1.68–1.54 (m, 1H). C{1H} NMR (75 MHz, CDCl3),
δ: 159.7, 144.9, 130.7 (dd, J = 2.9 Hz, 1.7 Hz), 130.0, 127.3, 125.5 (t, J = 2.3 Hz), 123.8, 117.8,
114.1, 112.1 (d, J = 2.3 Hz), 106.0 (dd, J = 324.7, 322.4 Hz), 71.6 (dd, J = 20.7, 18.4 Hz), 55.4,
44.8 (t, J = 2.0 Hz), 28.3, 21.8. 19F NMR (282 MHz, CDCl3), δ: –41.4 (dd, J = 180.1, 12.4 Hz, 1F),
–44.8 (dd, J = 178.0, 17.4 Hz, 1F). HRMS (ESI): calcd for C18H19F2INO (M+H) 430.0474; found
430.0463.
Synthesis of indoles 3 (General procedure 3). A test tube containing sodium acetate (82 mg, 1
mmol) and triphenylphosphine (26.2 mg, 0.1 mmol) was evacuated and filled with argon. Then, a
solution of iodide 1 (0.5 mmol) in acetonitrile (2 mL) was injected, and Ru(bpy)3(BF4)2 (2 mg) was
added, and the mixture was irradiated with a strip of blue LED during 12–16 h (since diods provide
heat when working, the reaction tube was immersed into a glass vessel cooled with circulating room
temperature water; the cooling vessel was wrapped with the LED strip). For the workꢀup, water (2
mL) was added, and the mixture was washed with EtOAc/hexane (1/2, 3×5 mL). The organic
phases were combined, silica gel (5 g) was added, and the mixture was stirred for 4–14 h at room
temperature (TLC control). The solvent was evaporated to dryness under vacuum, the residual silica
gel was transferred onto packed chromatography column followed by elution.
Me
N
F
Cl
3a
2ꢀ(4ꢀChlorophenyl)ꢀ3ꢀfluoroꢀ1ꢀmethylꢀ1Hꢀindole (3a). Reaction time 12 h; treatment with silica
gel 4 h; yield 126 mg (97%). White crystals. Mp 112–114 °C. Chromatography: hexanes/EtOAc,
1
15/1. Rf 0.35 (hexanes/EtOAc). H NMR (300 MHz, CDCl3) δ: 7.66 (d, J = 7.8 Hz, 1H), 7.57–7.41
13
(m, 4H), 7.40–7.24 (m, 2H), 7.24–7.14 (m, 1H), 3.68 (s, 3H). C{H} NMR (75 MHz, CDCl3) δ:
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142.2 (d, J = 245.5 Hz), 134.3 (d, J = 3.4 Hz), 131.1 (d, J = 2.3 Hz), 127.5 (d, J = 3.4 Hz), 125.2,
122.5 (d, J = 20.7 Hz), 121.5 (d, J = 15.0 Hz), 120.1, 117.1 (d, J = 2.3 Hz), 116.8, 109.8 (d, J = 2.3
Hz), 31.2. 19F NMF (282 MHz, CDCl3) δ: –175.6 (s, 1F). HRMS (ESI): calcd for C15H12FClN
(M+H) 260.0623; found 260.0637.
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N
Ph
F
3b
3ꢀFluoroꢀ1ꢀmethylꢀ2ꢀphenylꢀ1Hꢀindol (3b). Reaction time 12 h; treatment with silica gel 4 h;
yield 110 mg (98%). White crystals. Mp 73–75 °C. Chromatography: hexanes/EtOAc, 15/1. Rf 0.33
(hexanes/EtOAc, 15/1). H NMR (300 MHz, CDCl3) δ: 7.88–7.12 (m, 9H), 3.73 (s, 3H). 13C{H}
1
NMR (75 MHz, CDCl3) δ: 141.9 (d, J = 245.5 Hz), 134.0 (d, J = 5.7 Hz), 129.9, 129.0 (d, J = 3.4
Hz), 128.8, 128.2, 123.7 (d, J = 20.7 Hz), 122.8, 119.9, 117.1, 116.8 (d, J = 3.4 Hz), 109.7 (d, J =
19
2.3 Hz), 31.1. F NMF (282 MHz, CDCl3) δ: –176.3 (s, 1F). HRMS (ESI): calcd for C15H13FN
(M+H) 226.1017; found 226.1027.
Me
N
F
3c
MeO
3ꢀFluoroꢀ2ꢀ(4ꢀmethoxyphenyl)ꢀ1ꢀmethylꢀ1Hꢀindole (3c). Reaction time 12 h; treatment with
silica gel 4 h; yield 114 mg (89%). White crystals. Mp 110–112 °C. Chromatography:
1
hexanes/EtOAc, 20/1. Rf 0.46 (hexanes/EtOAc, 20/1). H NMR (300 MHz, CDCl3) δ: 7.65 (d, J =
8.5 Hz, 1H), 7.47 (d, J = 8.9 Hz, 2H), 7.39–7.12 (m, 3H), 7.06 (d, J = 8.2 Hz, 2H), 3.89 (s, 3H),
13
3.67 (s, 3H). C{H} NMR (75 MHz, CDCl3) δ: 159.7, 141.4 (d, J = 243.2 Hz), 133.7 (d, J= 5.7
Hz), 131.3 (d, J = 2.3 Hz), 123.6 (d, J = 21.8 Hz), 122.5, 121.4 (d, J = 3.4 Hz), 119.8, 117.0 (d, J =
16.1 Hz), 116.7 (d, J = 3.5 Hz), 114.4, 109.6, 55.5, 31.0. 19F NMF (282 MHz, CDCl3) δ: –177.3 (s,
1F). Calcd for C16H14FNO (255.29) C, 75.28; H, 5.53; N, 5.49. Found: C, 75.39; H, 5.53; N, 5.50.
Me
OMe
N
F
MeO
3d
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3ꢀFluoroꢀ5ꢀmethoxyꢀ2ꢀ(4ꢀmethoxyphenyl)ꢀ1ꢀmethylꢀ1Hꢀindole (3d). Reaction time 12 h;
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treatment with silica gel 4 h; yield 128 mg (90%). White crystals. Mp 99–100 °C. Chromatography:
1
hexanes/EtOAc, 10/1. Rf 0.26 (hexanes/EtOAc, 10/1). H NMR (300 MHz, CDCl3) δ: 7.46 (d, J =
8
9
8.2 Hz, 2H), 7.29–7.18 (m, 1H), 7.13–7.00 (m, 3H), 6.88 (d, J = 9.0 Hz, 1H), 3.90 (s, 3H), 3.89 (s,
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3H), 3.64 (s, 3H). C{H} NMR (50 MHz, CDCl3) δ: 159.6, 154.4, 141.6 (d, J = 241.3 Hz), 131.2,
129.3 (d, J = 5.7 Hz), 124.3 (d, J = 21.3 Hz), 121.5 (d, J = 4.3 Hz), 116.9 (d, J = 15.6 Hz), 114.3,
19
113.2, 110.7, 97.8 (d, J = 2.8 Hz), 56.0, 55.4, 31.0. F NMF (282 MHz, CDCl3) δ: –177.6 (s, 1F).
Calcd for C17H16FNO2 (285.31) C, 71.56; H, 5.65; N, 4.91; Found: C, 71.62; H, 5.63; N, 5.00.
Me
N
MeO
MeO
F
3e
OMe
3ꢀFluoroꢀ1ꢀmethylꢀ2ꢀ(3,4,5ꢀtrimethoxyphenyl)ꢀ1Hꢀindole (3e). Reaction time 12 h; treatment
with silica gel 4 h; yield 153 mg (97%). White crystals. Mp 136–137 °C. Chromatography:
hexanes/EtOAc, 5/1. Rf 0.34 (hexanes/EtOAc, 5/1). 1H NMR (300 MHz, CDCl3) δ: 7.65 (d, J = 8.6
Hz, 1H),7.39–7.24 (m, 2H), 7.21–7.14 (m, 1H), 6.74 (s, 2H), 3.94 (s, 3H), 3.93 (s, 6H), 3.70 (s,
3H). 13C{H} NMR (50 MHz, CDCl3) δ: 153.5, 141.6 (d, J = 244.4 Hz), 124.3 (d, J = 3.5 Hz),
123.9, 123.6 (d, J = 20.7 Hz), 122.8, 116.8 (d, J = 16.1 Hz), 116.6 (d, J = 2.3 Hz), 109.6 (d, J = 2.3
19
Hz), 109.1, 107.4, 105.8, 61.0, 56.3, 31.0. F NMF (282 MHz, CDCl3) δ: –175.9 (s, 1F). HRMS
(ESI): calcd for C18H19FNO3 (M+H) 316.1343; found 316.1338.
Me
N
F
3f
3ꢀFluoroꢀ1ꢀmethylꢀ2ꢀ(naphthalenꢀ1ꢀyl)ꢀ1Hꢀindole (3f). Reaction time 16 h; treatment with silica
gel 14 h; yield 110 mg (80%). Light yellow crystals. Mp 111–112 °C. Chromatography:
1
hexanes/CH2Cl2, 10/1. Rf 0.32 (hexanes/CH2Cl2, 10/1). H NMR (300 MHz, CDCl3) δ: 8.11–7.89
(m, 2H), 7.77 (d, J = 7.5 Hz, 2H), 7.71–7.19 (m, 7H), 3.50 (s, 3H). 13C{H} NMR (75 MHz, CDCl3)
δ: 142.3 (d, J = 245.5 Hz), 133.9, 133.8, 132.9, 130.0, 129.7, 128.6, 127.0, 126.4 (d, J = 2.3 Hz),
126.3, 126.0, 125.4, 122.7, 121.9 (d, J = 23.0 Hz), 119.9, 117.0 (d, J = 2.3 Hz), 116.9 (d, J = 16.1
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Hz), 109.7, 30.7. F NMF (282 MHz, CDCl3) δ: –174.3 (s, 1F). HRMS (ESI): calcd for C19H15FN
3
4
5
(M+H) 276.1186; found 276.1183.
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7
8
9
Me
S
OMe
N
F
3g
10
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3ꢀFluoroꢀ5ꢀmethoxyꢀ1ꢀ(tiophenꢀ2ꢀyl)ꢀ1Hꢀindole (3g). Reaction time 12 h; treatment with silica
gel 4 h; yield 111 mg (85%). Yellow crystals. Mp 80–81 °C. Chromatography: hexanes/EtOAc,
15/1. Rf 0.30 (hexanes/EtOAc, 15/1). 1H NMR (300 MHz, CDCl3) δ: 7.49 (d, J = 5.1 Hz, 1H), 7.31
(d, J = 3.3 Hz, 1H), 7.25ꢀ7.18 (m, 2H), 7.08 (d, J = 1.8 Hz, 1H), 6.96 (dd, J = 9.0, 2.5 Hz, 1H), 3.91
(s, 3H), 3.76 (s, 3H). 13C{H} NMR (50 MHz, CDCl3) δ: 154.4, 142.2 (d, J = 245.5 Hz), 129.8 (d, J
= 5.0 Hz), 129.5 (d, J = 5.7 Hz), 127.9 (d, J = 3.4 Hz), 127.6, 126.8, 118.0 (d, J = 20.7 Hz), 116.4
19
(d, J = 14.9 Hz), 114.2, 110.7, 97.8 (d, J = 2.3 Hz), 55.9, 31.1. F NMF (282 MHz, CDCl3) δ: –
172.0 (s, 1F). HRMS (ESI): calcd for C14H13FNOS (M+H); 262.0696; found 262.0692.
Br
N
Ph
3h
F
5ꢀBromoꢀ3ꢀfluoroꢀ2ꢀphenylꢀ1ꢀpropylꢀ1Hꢀindole (3h). Reaction time 12 h; treatment with silica
gel 4 h; yield 163 mg (98%). Yellow oil. Chromatography: hexanes/CH2Cl2, 20/1. Rf 0.32
1
(hexanes/CH2Cl2, 20/1). H NMR (300 MHz, CDCl3) δ: 7.81 (d, J = 1.9 Hz, 1H), 7.63–7.42 (m,
5H), 7.35 (dd, J = 8.0 Hz, 2.2 Hz, 1H ), 7.25 (dd, J = 9.2, 2.8 Hz, 1H), 4.06 (t, J = 7.2 Hz, 2H), 1.65
13
(sext, J = 7.8 Hz, 2H), 0.75 (t, J = 7.2 Hz, 3H). C{H} NMR (75 MHz, CDCl3) δ: 141.0 (d, J =
245.5 Hz), 131.8 (d, J = 4.6 Hz), 139.9, 128.9, 128.8, 128.6, 125.5, 124.8 (d, J = 19.5 Hz), 119.4 (d,
J = 3.4 Hz), 118.6 (d, J = 16.1 Hz), 113.0, 111.8, 45.7, 23.3, 11.3. 19F NMF (282 MHz, CDCl3) δ: –
175.8 (s, 1F). HRMS (ESI): calcd for C17H16FNBr (M+H) 334.0425; found 334.0420.
Br
N
F
3i
5ꢀBromoꢀ3ꢀfluoroꢀ1ꢀpropylꢀ2ꢀ(pꢀtolyl)ꢀ1Hꢀindole (3i). Reaction time 12 h; treatment with silica
gel 4 h; yield 159 mg (92%). Yellow oil. Chromatography: hexanes/CH2Cl2, 20/1. Rf 0.36
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(hexanes/CH2Cl2, 20/1). 1H NMR (300 MHz, CDCl3) δ: 7.83 (d, J = 2.4 Hz, 1H), 7.48ꢀ7.31 (m, 5H
), 7.25 (dd, J = 8.6 Hz, 2.0 Hz, 1H), 4.07 (t, J = 7.7 Hz, 2H), 2.49 (s, 3H), 1.67 (sext, J = 7.4 Hz,
13
2H), 0.78 (t, J = 6.8 Hz, 3H). C{H} NMR (75 MHz, CDCl3) δ: 140.6 (d, J = 244.4 Hz), 138.6,
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131.7 (d, J = 5.7 Hz), 129.8, 129.6, 125.8 (d, J = 3.4 Hz), 125.3, 124.9 (d, J = 20.7 Hz), 119.2 (d, J
= 3.4 Hz), 118.7 (d, J = 14.9 Hz), 112.9, 111.7, 45.6, 23.3, 21.4, 11.2. 19F NMF (282 MHz, CDCl3)
δ: –176.0 (s, 1F). HRMS (ESI): calcd for C18H18FNBr (M+H) 346.0601; found 346.0599.
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N
F
3j
Cl
2ꢀ(4ꢀCholorophenyl)ꢀ3ꢀfluoroꢀ1ꢀisobutylꢀ1Hꢀindole (3j). Reaction time 14 h; treatment with
silica gel 4 h; yield 122 mg (81%). Pale yellow oil. Chromatography: hexanes. Rf 0.25 (hexanes).
1H NMR (300 MHz, CDCl3) δ: 7.75 (d, J = 8.3 Hz, 1H), 7.62–7.16 (m, 7H), 4.01 (d, J = 7.6 Hz,
13
2H), 2.11ꢀ1.93 (m, 1H), 0.73 (d, J = 6.6 Hz, 6H). C{H} NMR (75 MHz, CDCl3) δ: 142.3 (d, J =
245.5 Hz), 134.2, 133.7 (d, J = 5.7 Hz), 131.3, 129.1, 128.0 (d, J = 3.4 Hz), 122.9, 122.5 (d, J =
19.5 Hz), 120.0, 117.0 (d, J = 16.1 Hz), 116.9 (d, J = 2.3 Hz), 110.6, 51.2, 29.2, 20.1. 19F NMF (282
MHz, CDCl3) δ: –175.7 (s, 1F). HRMS (ESI): calcd for C18H17FClN (M) 301.1028; found
301.1029.
N
F
3k
Br
2ꢀ(4ꢀBromophenyl)ꢀ3ꢀfluoroꢀ1ꢀisobutylꢀ1Hꢀindole (3k). Reaction time 15 h; treatment with silica
gel 4 h; yield 156 mg (90%). Yellow oil. Chromatography: hexanes/CH2Cl2, 20/1. Rf 0.38
1
(hexanes/CH2Cl2, 20/1). H NMR (300 MHz, CDCl3) δ: 7.78–7.62 (m, 3H), 7.48–7.38 (m, 3H ),
7.33 (t, J = 6.7 Hz, 1H), 6.23 (t, J = 7.7 Hz, 1H), 4.00 (d, J = 7.4 Hz, 2H), 2.10–1.91 (m, 1H), 0.71
13
(d, J = 6.0 Hz, 6H). C{H} NMR (75 MHz, CDCl3) δ: 142.3 (d, J = 245.5 Hz), 133.7 (d, J = 5.7
Hz), 132.0, 131.4, 128.5 (d, J = 3.4 Hz), 122.9, 122.4 (d, J = 20.6 Hz), 122.4, 120.0, 117.0 (d, J =
19
16.1 Hz), 116.9 (d, J = 2.3 Hz), 110.6, 51.1, 29.1, 20.0. F NMF (282 MHz, CDCl3) δ: –175.6 (s,
1F). HRMS (ESI): calcd for C18H18FNBr (M+H) 346.0601; found 346.0607.
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OMe
MeO
Cl
N
F
3l
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Methyl 3ꢀ[2ꢀ(chlorophenyl)ꢀ3ꢀfluoroꢀ5ꢀmethoxyꢀ1Hꢀindolꢀ1ꢀyl]propanoate (3l). Reaction time
9
12 h; treatment with silica gel 4 h; yield 157 mg (87%). Yellow crystals. Mp 66–67 °C.
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Chromatography: hexanes/EtOAc, 5/1. Rf 0.27 (hexanes/EtOAc, 5/1). H NMR (300 MHz, CDCl3)
δ: 7.40–7.28 (m, 4H), 7.16 (dd, J = 9.2, 2.7 Hz, 1H), 6.95 (d, J = 2.8 Hz, 1H), 6.83 (dd, J = 9.2, 2.8
Hz, 1H), 4.27 (t, J = 7.3 Hz, 2H), 3.75 (s, 3H), 3.44 (s, 3H), 2.37 (t, J = 7.3 Hz, 2H). 13C{H} NMR
(75 MHz, CDCl3) δ: 171.1, 154.6, 142.6 (d, J = 246.7 Hz), 134.4, 130.8 (d, J = 2.3 Hz), 129.2,
128.8 (d, J = 5.7 Hz), 127.3 (d, J = 3.4 Hz), 122.3 (d, J = 19.5 Hz), 117.7 (d, J = 15.0 Hz), 114.2,
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111.2, 98.1 (d, J = 2.3 Hz), 55.7, 51.8, 39.8, 34.1. F NMF (282 MHz, CDCl3) δ: –174.4 (s, 1F).
HRMS (ESI): calcd for C19H18ClFNO3 (M+H) 362.0954; found 362.0943.
O
OMe
MeO
N
3m
F
Methyl 3ꢀ(3ꢀfluoroꢀ2ꢀisopropylꢀ5ꢀmethoxyꢀ1Hꢀindolꢀ1ꢀyl)propanoate (3m). Reaction time 12 h;
treatment with silica gel was omitted since the indole was formed directly after the reaction; yield
126 mg (86%). Yellow oil. Chromatography: hexanes/EtOAc, 10/1. Rf 0.28 (hexanes/EtOAc, 10/1).
1H NMR (300 MHz, CDCl3) δ: 7.16 (dd, J = 9.1, 2.3 Hz, 1H), 6.76 (d, J = 2.3 Hz, 1H), 6.71 (dd, J =
9.1, 2.6 Hz, 1H), 4.35 (t, J = 7.3 Hz, 2H), 3.85 (s, 3H), 3.69 (s, 3H), 3.15–3.99 (m, 1H), 2.69 (t, J =
7.8 Hz, 2H), 1.43 (d, J = 7.5 Hz, 6H). 13C{H} NMR (75 MHz, CDCl3) δ: 171.5, 154.2, 141.7 ( d, J
= 239.8 Hz), 128.2, 127.9, 126.8 (d, J = 5.7 Hz), 117.8 (d, J = 16.1 Hz), 112.3, 110.2 (d, J = 2.3
19
Hz), 97.8, 55.9, 52.0, 39.0, 25.2 (d, J = 3.4 Hz), 21.8 (d, J = 3.4 Hz). F NMF (282 MHz, CDCl3)
δ: –175.5 (s, 1F). HRMS (ESI): calcd for C16H20FNO3Na (M+Na) 316.1319; found 316.1317.
N
F
3n
MeO
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1ꢀFluoroꢀ2ꢀ(4ꢀmethoxyphenyl)ꢀ5,6ꢀdihydroꢀ4Hꢀpyrrolo[3,2,1ꢀij]quimoline (3n). Reaction time
3
4
5
6
7
12 h; treatment with silica gel 4 h; yield 124 mg (88%). White crystals. Mp 126–127 °C.
1
Chromatography: hexanes/EtOAc, 15/1. Rf 0.35 (hexanes/EtOAc, 15/1). H NMR (300 MHz,
8
9
CDCl3) δ: 7.57–7.40 (m, 3H), 7.14–7.00 (m, 3H), 6.95 (d, J = 7.1 Hz, 1H), 4.09 (t, J = 5.5 Hz, 2H),
3.89 (s, 3H), 3.03 (t, J = 6.0 Hz, 2H), 2.23 (quint, J = 6.0 Hz, 2H). 13C{H} NMR (75 MHz, CDCl3)
δ: 159.5, 141.3 (d, J = 244.2 Hz), 130.5 (d, J = 2.3 Hz), 122.3 (d, J = 21.3 Hz), 121.7 (d, J = 2.3
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Hz), 121.6, 119.9, 119.3, 114.4, 114.2 (d, J = 2.3 Hz), 55.5, 43.1, 25.1, 23.1. F NMF (282 MHz,
CDCl3) δ: –177.0 (s, 1F). HRMS (ESI): calcd for C18H17FNO (M+H) 282.1289; found 282.1299.
Acknowledgement
This work was supported by the Russian Science Foundation (project 14ꢀ13ꢀ00034). We thank Mr.
D. Agababyan and Mr. A. Zemtsov for preparation of the photocatalyst.
Supporting Information
Copies of NMR spectra for all compounds and CV curves for 1a-I, Ru(bpy)3(BF4)2 and PPh3. This
material is available free of charge via the Internet at http://pubs.acs.org.
References
(1) (a) Purser, S.; Moore, P. R.; Swallow, S.; Gouverneur, V. Chem. Soc. Rev. 2008, 37, 320–330.
(b) Wang, J.; SanchezꢀRoselló, M.; Aceña, J. L.; del Pozo, C.; Sorochinsky, A. E.; Fustero,
S.; Soloshonok, V. A.; Liu, H. Chem. Rev. 2014, 114, 2432–2506. (c) Zhou, Y.; Wang, J.; Gu,
Z.; Wang, S.; Zhu, W.; Aceña, J. L.; Soloshonok, V. A.; Izawa, K.; Liu, H. Chem. Rev. 2016,
116, 422–518.
(2) (a) Liang, T.; Neumann, C. N.; Ritter, T. Angew. Chem. Int. Ed. 2013, 52, 8214–8264. (b)
Shimizu, M.; Hiyama, T. Angew. Chem. Int. Ed. 2005, 44, 214–231. (c) See special issue of
Chem. Rev. devoted to fluorine chemistry: Chem. Rev. 2015, 115, 563–1306.
(3) Campbell, M. G.; Ritter, T. Org. Proc. Res. Dev. 2014, 18, 474–480.
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(4) (a) Fluorine in Heterocyclic Chemistry, Volumes 1,2; Nenajdenko, V., Ed.; Springer
International Publishing: Cham, 2014. (b) Petrov, V. A. Fluorinated Heterocyclic
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