Friedel-Crafts Fluoroacetylation of Indoles with Fluorinated Acetic Acids for the Synthesis of Fluoromethyl Indol-3-yl Ketones under Catalyst- and Additive-Free Conditions

Article abstract of DOI:10.1021/acs.joc.6b00580

A simple and efficient protocol for the fluoroacetylation of indoles is reported. The reaction uses fluorinated acetic acids as the fluoroacetylation reagents to synthesize diverse fluoromethyl indol-3-yl ketones in good yields under catalyst- and additive-free conditions. In addition, the only byproduct is water in this transformation. The synthetic utility of this reaction was also demonstrated by the concise synthesis of α-(trifluoromethyl)(indol-3-yl)methanol and indole-3-carboxylic acid.

Full text of DOI:10.1021/acs.joc.6b00580

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Article
Friedel-Crafts Fluoroacetylation of Indoles with Fluorinated
Acetic Acids for the Synthesis of Fluoromethyl Indol-3-
yl Ketones under Catalyst- and Additive-free Conditions
Shun-Jiang Yao, Zhi-Hui Ren, Yao-Yu Wang, and Zheng-Hui Guan
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.6b00580 • Publication Date (Web): 21 Apr 2016
Downloaded from http://pubs.acs.org on April 24, 2016
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Friedel-Crafts Fluoroacetylation of Indoles with Fluorinated Acetic Acids for the
Synthesis of Fluoromethyl Indol-3-yl Ketones under Catalyst- and Additive-free
Conditions
Shun-Jiang Yao, Zhi-Hui Ren, Yao-Yu Wang, and Zheng-Hui Guan*
Key Laboratory of Synthetic and Natural Functional Molecule Chemistry of Ministry of Education,
Department of Chemistry & Materials Science, Northwest University, Xi’an 710127, P. R. China
guanzhh@nwu.edu.cn
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ABSTRACT: A simple and efficient protocol for the fluoroacetylation of indoles is reported. The
reaction performs using fluorinated acetic acids as the fluoroacetylation reagents to synthesize
diverse fluoromethyl indol-3-yl ketones in good yields under catalyst- and additive-free conditions.
Also, the only by-product is water in this transformation. The synthetic utility of this reaction was
also demonstrated by the concise synthesis of α-trifluoromethyl-(indol-3-yl)methanol and
indole-3-carboxylic acid.
INTRODUCTION
Increased attention is being focused on organofluorine chemistry because the incorporation of
fluorine-containing groups into organic molecules can dramatically alter physical, chemical, and
1
biological properties such as binding affinity, metabolic stability, and lipophilicity. In recent years,
a number of highly effective methods have been developed for the incorporation of fluorine atoms
2
,3
or fluoromethyl groups into organic molecules. Among numerous fluoromethyl-containing
compounds, indolyl fluoromethyl ketones are an important structural motif of many biologically
4
active compounds and intermediates for the synthesis of other fluoromethyl-substituted
5
compounds. Traditional methods for the preparation of indolyl fluoromethyl ketones largely
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involve either: Friedel-Crafts acylation (strong electrophiles in combination with reactive Lewis
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acids) or oxidation of α-fluoromethyl alcohols (multistep conversions). A general, efficient
method for the preparation of indolyl fluoromethyl ketones from easily available reagents is
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highly desirable.
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Scheme 1. Acylation Reactions of Indoles
Recently, 3-chlorodifluoroacylation of N-alkylindoles for the synthesis of indolyl
chlorodifluoromethyl ketones through an elegant self-activation of sodium chlorodifluoroacetate
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has been developed by Greaney and Williams (Scheme 1, eq 1). However, the approachs for the
ready preparation of diverse indolyl fluoromethyl ketones, such as, indolyl trifluoromethyl ketones,
indolyl bromodifluoromethyl ketones, and indolyl difluoromethyl ketones, are still urgently
needed and remain a significant challenge. More recently, an electrophilic sulfenylation of indoles
with arylsulfinic acids in water under catalyst- and additive-free conditions has been developed by
1
0
Wang and co-workers (Scheme 1, eq 2). To the best of our knowledge, the Friedel-Crafts
acylation with carboxylic acids under catalyst- and additive-free conditions has never been
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reported. Inspired by Greaney and Wang’s results, we envisaged that the fluoroacetylation of
indoles may occur by using fluorinated acetic acids as the fluoroacetylation reagents. In this paper,
we report a Friedel-Crafts fluoroacetylation of indoles with commercially available fluorinated
acetic acids for the synthesis of indolyl fluoromethyl ketones under catalyst- and additive-free
conditions (Scheme 1, eq 3). Moreover, water is the sole by-product in this transformation. This
process not only addresses the issues of corrosion (without addition of Lewis acids as catalysts
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during the reaction) but also circumvents the problems of strict exclusion of moisture (insensitive
to water and air). This method also provides a facile and convenient method for the construction
f
of C-COR bond.
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RESULTS AND DISCUSSION
To explore the fluoroacetylation, the reaction of 1,2-dimethylindole 1a and trifluoroacetic
acid (TFA) was conducted as a model reaction. Gratifyingly, the desired 3-trifluoroacetylated
indole 2a was observed in 8% yield when CH
This result encouraged us to optimize the reaction conditions. Screening of various solvents, such
as CH Cl , 1,4-dioxane, CH OH, CH NO , toluene, N,N-dimethyl formamide (DMF), and
,2-dichloroethane (DCE), suggested that DCE was the optimal solvent for the transformation
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CN was employed as the solvent (Table 1, entry 1).
2
2
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3
2
1
(
Table 1, entries 2-8). Extra trifluoroacetic acid was added to the reaction to enhance the
10,11a
protonation the trifluoroacetic acid to trifluoroacetyl cation intermediate.
We found that
raising the equivalents of TFA enhanced the reaction, with 3 equiv providing a 89% isolated yield
of 2a (Table 1, entry 9). Further increasing or lowering the reaction temperature resulted in lower
yields (Table 1, entries 10-11).
a
Table 1. Optimization of Reaction Conditions
o
b
entry
1
solvent
CH CN
CH Cl
T ( C)
yield (%)
3
100
100
100
100
100
100
100
100
100
120
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42
0
c
2
2
2
3
1,4-dioxane
CH OH
CH NO
c
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0
3
2
toluene
DMF
DCE
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0
c
8
57
89
72
c,d
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DCE
DCE
c,d
1
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DCE
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Reaction conditions: 1a (0.2 mmol), TFA (2.0 equiv), solvent (2.0 mL), 3 h under air. Isolated yield. The
d
reaction was reflux in oil bath. TFA (3.0 equiv).
a
Table 2. Trifluoroacetylation of Various Indoles
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Reaction conditions: indoles (0.2 mmol), TFA (3.0 equiv), DCE (2.0 mL), the reaction was reflux in a 100 C
b
c
oil bath, 3-10 h under air; isolated yields. TFA (5.0 equiv). Toluene was used as solvent.
With the optimized conditions in hand, we next investigated the substrate scope of the
reaction (Table 2). The 2-methylindoles with N-methyl, ethyl, allyl, and benzyl were smoothly
converted to the trifluoromethyl ketones in good to high yields (2a-2d). However,
2
-phenyl-substituted N-methylindole gave the corresponding trifluoromethyl ketone 2f in 52%
yield, likely due to steric hindrance of the phenyl group. When N-methylindole was used as
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substrate, the corresponding trifluoromethyl ketone 2g was obtained in 70% yields. It was
noteworthy that the N-methylindoles bearing electron-donating groups or electron-withdrawing
groups, such as methoxyl, methyl, chloro, and bromo groups on the aromatic rings reacted with
trifluoroacetic acid to afford the corresponding trifluoroacetylated products in moderate to good
yields (2h-2k). Compared with electron-donating groups, electron-withdrawing groups substituted
indoles afforded modestly lower yields presumably because of the reduced nucleophilicity. It was
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notable that the free (N-H) indoles worked under the standard conditions and gave the desired
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-trifluoroacetylindoles in good yields (2e and 2l). Unfortunately, no reaction occurred when N-Ac
indole, N-Boc indole, N-Ts indole, or 1-methyl-1H-pyrrolo[2,3-b]pyridine was employed as the
substrate.
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a
Table 3. Chlorodifluoroacetylation of Various Indoles
F
F
F
F
O
O
O
O
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
F
F
F
F
Ph
N
N
N
N
H
Bn
3e, 79%b
3f, 68%b
3a, 83%
3d, 71%b
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F
F
F
O
O
O
O
Cl
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F
F
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O
N
3g, 70%c
O
N
N
N
H
3l, 42%b,c
3i, 70%
3h, 89%
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F
F
F
O
O
O
Cl
F
F
F
F
O
N
N
N
N
O
3o, 38%b,c
3p, 82%c
3
m, 79%
3n
,
87%
O
F
F
F
O
O
Cl
F
F
F
N
N
N
Bn
, 65%b
3r
3s, 67%b
3
q, 80%
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Reaction conditions: indoles (0.2 mmol), CDFA (3.0 equiv), DCE (2.0 mL), the reaction was reflux in a 100
o
b
c
C oil bath, 2-10 h under air; isolated yields. CDFA (5.0 equiv). Toluene was used as solvent.
In comparison to TFA, chlorodifluoroacetic acid (CDFA) has been reported to undergo ready
decarboxylation to form difluoromethylene or chlorodifluoromethyl radicals, which were used in
1
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situ for difluoromethylation or chlorodifluoromethylation. However, chlorodifluoroacetic acid
has not been reported to directly provide the chlorodifluoroacetyl group. Encouraged by our
previous success, we were prompted to attempt the straightforward chlorodifluoroacetylation
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reaction of indoles with chlorodifluoroacetic acid under our optimized conditions.
A wide range of indoles bearing substituents on the aromatic rings and nitrogen atom were
investigated, and the results are summarized in Table 3. 2-Methyl-N-methylindole,
2
-methyl-N-benzylindole, and 2-methylindole afforded the desired chlorodifluoroacetylated
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products in good yields (3a, 3d-3e). In addition, 1-methyl-2-phenyl-1H-indole was well tolerated
and the corresponding product 3f was obtained in 68% yield. N-Methylindoles bearing methoxyl
and methyl on the carbon skeleton showed good reactivity in the generation of the desired
chlorodifluoromethyl ketones (3h-3i, 3m-3n). It is important to note that methyl
1-methyl-1H-indole-6-carboxylate gave the corresponding chlorodifluoromethyl ketone 3o in 38%
yield. Furthermore, N-ethylindole, N-allylindole, N-propargylindole, and N-benzylindole proved to
be suitable substrates and offered the desired products in 65-82% yields (3p-3s).
a
Table 4. Bromodifluoroacetylation of Various Indoles
F
O
Br
F
BrDFA (3.0 equiv)
R2
R2
o
N
DCE, 100 C
N
R1
R1
1
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Reaction conditions: indoles (0.2 mmol), BrDFA (3.0 equiv), DCE (2.0 mL), the reaction was reflux in a 100
o
b
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C oil bath, 2-10 h under air; isolated yields. BrDFA (5.0 equiv). Toluene was used as solvent.
2
We next focused on the bromodifluoroacetylation of indoles because the BrCF COR moiety
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can serve as a CF
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radical precursor and there are no reports of the preparation of
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bromodifluoromethyl indol-3-yl ketones. Satisfactorily, bromodifluoroacetic acid (BrDFA) was
also applicable to this reaction, and afforded the bromodifluoromethyl ketones in good to high
yields (Table 4). Notably, indoles bearing methyl or phenyl substitution at the C-2 position reacted
with BrDFA to give the corresponding bromodifluoromethyl ketones in 77-85% yields (4a, 4e-4f).
N-Methylindoles bearing methoxyl and methyl on the aromatic rings performed smoothly in the
reaction to produce the desired 3-bromodifluoroacetyl indoles in 65-88% yields (4h-4i, 4m-4n).
When NH indole was used, a 3-bromodifluoroacetylated product 4l was generated in 46% yield.
Furthermore, methoxycarbonyl group was well tolerated and the corresponding product 4o was
obtained in 41% yield. Finally, the different substitution groups on the indole nitrogen were
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studied. The C -C alkyl groups, such as ethyl, allyl, butyl, and pentyl groups, afforded
corresponding bromodifluoromethyl ketones in 70-82% yields (4p-4q, 4t-4u).
a
Table 5. Difluoroacetylation of Indoles
a
o
Reaction conditions: indoles (0.2 mmol), DFA (3.0 equiv), DCE (2.0 mL), the reaction was reflux in a 100 C
b
oil bath, 4-9 h under air; isolated yields. DFA (5.0 equiv).
To further expand the scope of the fluoroacetylation reaction, we turned our attention to
difluoroacetylation of indoles with difluoroacetic acid (DFA) since the difluoromethyl ketones
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display good biological and reactive activities. Pleasingly, in this difluoroacetylation protocol, a
series of indoles reacted with difluoroacetic acid to produce the desired difluoromethyl indol-3-yl
ketones in 26-76% yields (Table 5).
Scheme 2. Synthetic Utility of Trifluoromethyl Indol-3-yl Ketones
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To demonstrate the synthetic utility of the trifluoroacetylation reaction, several examples are
illustrated in Scheme 2. First, direct reduction of 2g using NaBH
4
smoothly gave
2,2,2-trifluoro-1-(1-methyl-1H-indol-3-yl)ethanol 6 in 85% yield. This has been shown to be a
vital intermediate for synthesis of high active Cell death inhibitor and 1-trifluoromethylated
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cyclopenta[b]indole alkaloids. Under the simple hydrolysis conditions, 2g was easily
transformed into N-methylindole-3-carboxylic acid 7 that has been widely applied in various
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pharmaceutical and organic syntheses. Furthermore, 2a could be used to synthesize the
photochromic fulgimide 8 and fulgide 9. These results are particularly useful as optical switches in
information storage devices and biological sensors owing to reversible change between two
1
8
thermally stable states with different structures and colors.
Scheme 3. Plausible Reaction Mechanism
On the basis of the above results, a plausible reaction mechanism for this trifluoroacetylation
reaction is proposed (Scheme 3). First, the reaction was initiated by a protonation of trifluoroacetic
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acid to form species A under acidic conditions. The intermediate A underwent a dehydration to
release trifluoroacetyl cation B. Subsequently, electrophilic addition of trifluoroacetyl cation B to
1
,2-dimethylindole 1a gave indole iminium ion C. Finally, deprotonation from C afforded
trifluoromethyl indol-3-yl ketone 2a. Reactions of chlorodifluoroacetic acid, bromodifluoroacetic
acid, and difluoroacetic acid with indoles were explained as following a similar mechanistic
pathway.
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CONCLUSION
In summary, we have developed a simple and efficient methodology for trifluoro-,
chlorodifluoro-, bromodifluoro-, and difluoroacetylation of indoles using commercially available
trifluoroacetic acid, chlorodifluoroacetic acid, bromodifluoroacetic acid, and difluoroacetic acid as
the fluoroacetylating reagents under catalyst- and additive-free conditions. The new approach
displays a powerful method for the direct construction of diverse fluoromethyl ketones. Also,
water is the sole by-product in this transformation. The unique transformation is complementary
for the traditional Friedel-Crafts acylation and has significant potential for application to a series
of organic syntheses. Detailed mechanistic and further scope studies of this fluoroacetylation are
currently underway in our laboratory.
Experimental Section:
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General Information. H, C, and F NMR spectra were recorded at (400 MHz), (100 MHz),
and (376 MHz). The following abbreviations (or combinations thereof) were used to explain
multiplicities: s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, b = broad. Coupling
constants, J were reported in Hertz unit (Hz). All products were characterized by HRMS
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(
ESI-TOF-Q); copies of their H, C, and F NMR spectra are provided in Supporting
Information. Preparative TLC was performed on TLC plate, analytical thin layer chromatography
was performed on 10-25um silica gel GF254, visualization was carried out with UV light. Flash
2
column chromatography was performed with SiO (Silica Gel (200-300 mesh)). Unless otherwise
stated, all reagents and solvents were purchased from commercial suppliers and used without
further purification. All the N-substituted indoles were prepared according to literature
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procedures.
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Typical Procedure for Synthesis of Trifluoromethyl Indol-3-yl Ketones 2.
o
Indoles (0.2 mmol) and trifluoroacetic acid (3 equiv) were reflux at 100 C oil bath in 2 mL
of DCE under an air atmosphere, and progress of the reaction was monitored by TLC. After
completion of the reaction, as determined by TLC, the reaction was cooled to room temperature.
Water (2×5 mL) was added, and the product was extracted with ethyl acetate (20 mL), the organic
layers were washed with saturated brine and it was removed in a rotary evaporator. The product
was purified by silica gel chromatography (petroleum ether/EtOAc = 20:1-15:1) to afford
corresponding products 2.
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0
9
1-(1,2-dimethyl-1H-indol-3-yl)-2,2,2-trifluoroethan-1-one (2a): pink solid (42.8 mg, 89%,
1
mp 108-109 °C); H NMR (CDCl
3
, 400 MHz): δ 8.04-8.02 (m, 1 H), 7.30-7.27 (m, 3 H), 3.68 (s, 3
, 100 MHz): δ 175.0 (q, JCF = 35.6 Hz), 150.2, 136.7, 125.0,
13
H), 2.73 (s, 3 H); C NMR (CDCl
123.1, 121.5, 120.6 (q, JCF = 4.3 Hz), 117.2 (q, JCF = 288.0 Hz), 109.7, 107.6, 29.7, 12.9;
NMR (CDCl , 376 MHz) δ -74.3 (s, 3 F); HRMS Calcd (ESI) m/z for C12
264.0607, found: 264.0612.
3
1
9
F
+
3
10 3
H F NNaO: [M+Na]
1-(1-ethyl-2-methyl-1H-indol-3-yl)-2,2,2-trifluoroethan-1-one (2b): yellow oil (40.9 mg,
1
80%); H NMR (CDCl
3
, 400 MHz): δ 8.05-8.03 (m, 1 H), 7.34-7.32 (m, 1 H), 7.31-7.26 (m, 2 H),
1
3
4.20-4.15 (m, 2 H), 2.74 (s, 3 H), 1.37 (t, J = 7.6 Hz, 3 H); C NMR (CDCl
3
, 100 MHz): δ 175.2
(q, JCF = 35.6 Hz), 149.5, 135.7, 125.2, 123.1, 123.1, 120.9 (q, JCF = 4.6 Hz), 117.2 (q, JCF = 288.1
19
3
Hz), 109.8, 107.8, 38.2, 14.3, 12.8; F NMR (CDCl , 376 MHz) δ -74.3 (s, 3 F); HRMS Calcd
+
(ESI) m/z for C13
H
12
F
3
NNaO: [M+Na] 278.0763, found: 278.0754.
1-(1-allyl-2-methyl-1H-indol-3-yl)-2,2,2-trifluoroethan-1-one (2c): yellow oil (40 mg, 70%);
H NMR (CDCl , 400 MHz): δ = 8.06 (d, J = 7.2 Hz, 1 H), 7.33-7.28 (m, 3 H), 5.97-5.89 (m, 1
H), 5.22 (d, J = 10.4 Hz, 1 H), 4.89 (d, J = 17.2 Hz, 1 H), 4.79-4.80 (m, 2 H), 2.75 (s, 3 H);
NMR (CDCl , 100 MHz): δ 175.4 (q, JCF = 35.7 Hz), 150.0, 136.2, 130.7, 125.1, 123.3, 123.2,
1
3
13
C
3
19
120.9 (q, JCF = 4.4 Hz), 117.5, 117.1 (q, JCF = 288.1 Hz), 110.0, 108.1, 45.4, 12.8; F NMR
+
(CDCl
3 12 3
, 376 MHz) δ -74.4 (s, 3 F); HRMS Calcd (ESI) m/z for C14H F NNaO: [M+Na]
290.0763, found: 290.0751.
1-(1-benzyl-2-methyl-1H-indol-3-yl)-2,2,2-trifluoroethan-1-one (2d): white solid (45.5 mg,
1
68%, mp 112-113 °C); H NMR (CDCl
3
, 400 MHz): δ 8.09 (d, J = 7.6 Hz, 1 H), 7.31-7.23 (m, 6
1
3
3
H), 7.00 (d, J = 6.4 Hz, 2 H), 5.38 (s, 2 H), 2.73 (s, 3 H); C NMR (CDCl , 100 MHz): δ 175.5
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(
q, JCF = 35.7 Hz), 150.1, 136.6, 135.0, 129.1, 128.0, 125.8, 125.1, 123.4, 123.3, 120.9 (q, JCF
=
19
4
.4 Hz), 117.1 (q, JCF = 288.1 Hz), 110.2, 108.3, 46.7, 13.1; F NMR (CDCl
3
, 376 MHz) δ -74.3
+
(
s, 3 F); HRMS Calcd (ESI) m/z for C18
H
14
F
3
NNaO: [M+Na] 340.0920, found: 340.0914.
7
2
,2,2-trifluoro-1-(2-methyl-1H-indol-3-yl)ethan-1-one (2e): white solid (30.9 mg, 68%, mp
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1
6
149-151 °C); H NMR (DMSO-d , 400 MHz): δ 7.92-7.90 (m, 1 H), 7.48-7.47 (m, 1 H),
1
3
6
7.26-7.23 (m, 2 H), 2.70 (s, 3 H); C NMR (DMSO-d , 100 MHz): δ 173.6 (q, JCF = 34.7 Hz),
150.6, 135.2, 125.7, 123.1, 122.8, 120.0 (q, JCF = 3.3 Hz), 117.1 (q, JCF = 288.5 Hz), 112.1,
1
9
6
106.6, 15.1; F NMR (DMSO-d , 376 MHz) δ -73.8 (s, 3 F); HRMS Calcd (ESI) m/z for
+
C
11
H
8
F
3
NNaO: [M+Na] 250.0450, found: 250.0442.
2,2,2-trifluoro-1-(1-methyl-2-phenyl-1H-indol-3-yl)ethan-1-one (2f): yellow solid (31.5 mg,
1
52%, mp 87-89 °C); H NMR (CDCl
3
, 400 MHz): δ 8.33-8.31 (m, 1 H), 7.53-7.48 (m, 3 H),
, 100 MHz): δ 175.8 (q, JCF = 36.0 Hz), 149.6,
1
3
7.40-7.35 (m, 5 H), 3.51 (s, 3 H); C NMR (CDCl
136.8, 130.3, 130.1, 129.7, 128.2, 126.3, 124.1, 123.8, 121.8 (q, JCF = 1.9 Hz), 116.5 (q, JCF
3
=
19
288.1 Hz), 110.2, 108.8, 31.1; F NMR (CDCl
3
, 376 MHz) δ -72.5 (s, 3 F); HRMS Calcd (ESI)
+
m/z for C17
H
12
F
3
NNaO: [M+Na] 326.0763, found: 326.0767.
7
2,2,2-trifluoro-1-(1-methyl-1H-indol-3-yl)ethan-1-one (2g): colorless solid (31.6 mg, 70%,
1
mp 101-103 °C); H NMR (CDCl
3
, 400 MHz): δ 8.40-8.37 (m, 1 H), 7.89 (s, 1 H), 7.39-7.36 (m,
, 100 MHz): δ 174.7 (q, JCF = 34.5 Hz), 138.4 (q, JCF = 4.9
1
3
3 H), 3.88 (s, 3 H); C NMR (CDCl
3
19
Hz), 137.3, 126.9, 124.6, 123.9, 122.4, 117.1 (q, JCF = 289.3 Hz), 110.2, 109.3, 34.0; F NMR
+
(CDCl
3 8 3
, 376 MHz) δ -72.2 (s, 3 F); HRMS Calcd (ESI) m/z for C11H F NNaO: [M+Na]
250.0450, found: 250.0453.
3,3'-(2,2,2-trifluoro-1-(1-methyl-1H-indol-2-yl)ethane-1,1-diyl)bis(1-methyl-1H-indole) (2g’):
1
Red solid, mp 276-277 °C; H NMR (CDCl
3
, 400 MHz): δ 7.29-7.23 (m, 6 H), 7.14-7.10 (m, 3
23 3 3
H), 6.97 (s, 3 H), 6.87-6.84 (m, 3 H), 3.70 (s, 9 H). HRMS Calcd (ESI) m/z for C29H F N :
+
[M-H] 470.1839, found: 470.1821.
2,2,2-trifluoro-1-(5-methoxy-1-methyl-1H-indol-3-yl)ethan-1-one (2h): colorless solid (41.7
1
mg, 81%, mp 93-95 °C); H NMR (CDCl
3
, 400 MHz): δ 7.86 (d, J = 2.0 Hz, 1 H), 7.83 (s, 1 H),
1
3
7.26 (d, J = 8.8 Hz, 1 H), 7.00 (dd, J = 2.4, 2.0 Hz, 1H), 3.90 (s, 3 H), 3.86 (s, 3 H); C NMR
(CDCl , 100 MHz): δ 174.5 (q, JCF = 34.4 Hz), 157.3, 138.0 (q, JCF = 4.9 Hz), 132.0, 127.9,
17.1 (q, JCF = 289.3 Hz), 114.6, 110.9, 108.9, 103.8, 55.7, 34.0; F NMR (CDCl
3
19
1
3
, 376 MHz) δ
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2
2
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3
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3
3
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3
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4
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5
5
5
5
5
5
5
5
6
+
-
72.2 (s, 3 F); HRMS Calcd (ESI) m/z for C12
10 3 2
H F NNaO : [M+Na] 280.0556, found:
2
80.0555.
1
-(1,4-dimethyl-1H-indol-3-yl)-2,2,2-trifluoroethan-1-one (2i): colorless solid (32.1 mg, 67%,
1
mp 110-112 °C); H NMR (CDCl
3
, 400 MHz): δ 7.91 (s, 1 H), 7.27 (t, J = 8.0 Hz, 1 H), 7.19 (d,
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
13
J = 8.0 Hz, 1 H), 7.12 (d, J = 7.2 Hz, 1 H), 3.86 (s, 3 H), 2.86 (s, 3 H); C NMR (CDCl
3
, 100
MHz): δ 173.7 (q, JCF = 33.4 Hz), 139.5 (q, JCF = 5.4 Hz), 138.2, 133.7, 125.8, 125.5, 124.6,
19
3
117.6 (q, JCF = 290.8 Hz), 110.3, 107.6, 34.0, 23.0; F NMR (CDCl , 376 MHz) δ -70.3 (s, 3 F);
+
HRMS Calcd (ESI) m/z for C12
H
10
F
3
NNaO: [M+Na] 264.0607, found: 264.0608.
1-(6-chloro-1-methyl-1H-indol-3-yl)-2,2,2-trifluoroethan-1-one (2j): colorless solid (25.1 mg,
1
48%, mp 135-137 °C); H NMR (CDCl
3
, 400 MHz): δ 8.30 (d, J = 8.8 Hz, 1 H), 7.89 (s, 1 H),
13
7.39 (d, J = 1.6 Hz, 1 H), 7.34 (dd, J = 2.0 Hz, 2.0 Hz, 1 H), 3.88 (s, 3 H); C NMR (CDCl
3
, 100
MHz): δ 174.7 (q, JCF = 34.9 Hz), 138.7 (q, JCF = 4.8 Hz), 137.8, 130.7, 125.3, 124.5, 123.5,
1
9
3
116.9 (q, JCF = 289.1 Hz), 110.4, 109.4, 34.1; F NMR (CDCl , 376 MHz) δ -72.4 (s, 3 F).
+
HRMS Calcd (ESI) m/z for C11
H
7
ClF
3
NNaO: [M+Na] 284.0060, found: 284.0054.
1-(5-bromo-1-methyl-1H-indol-3-yl)-2,2,2-trifluoroethan-1-one (2k): colorless solid (31.1 mg,
1
51%, mp 178-180 °C); H NMR (CDCl
3
, 400 MHz): δ 8.47 (s, 1 H), 7.85 (s, 1 H), 7.42 (d, J =
13
8.8 Hz, 1 H), 7.21 (d, J = 4.8 Hz, 1 H), 3.88 (s, 3 H); C NMR (CDCl
3
, 100 MHz): δ 174.5 (q,
J
CF = 35.0 Hz), 138.8 (q, JCF = 4.9 Hz), 135.9, 128.3, 127.5, 124.9, 117.6, 116.8 (q, JCF = 289.1
19
3
Hz), 111.5, 108.7, 34.1; F NMR (CDCl , 376 MHz) δ -72.5 (s, 3 F); HRMS Calcd (ESI) m/z for
+
C
11
H
7
BrF
3
NNaO: [M+Na] 327.9555, found: 327.9552.
6
2,2,2-trifluoro-1-(1H-indol-3-yl)ethan-1-one (2l): white solid (17.2 mg, 40%, mp
1
6
153-155 °C); H NMR (DMSO-d , 400 MHz): δ 12.75 (s, 1 H), 8.49 (s, 1 H), 8.20 (d, J = 5.6 Hz,
1
3
6
1 H), 7.60 (d, J = 6.4 Hz, 1 H), 7.36-7.30 (m, 2 H); C NMR (DMSO-d , 100 MHz): δ 174.0 (q,
J
CF = 33.6 Hz), 137.6 (q, JCF = 4.8 Hz), 136.7, 125.8, 124.4, 123.5, 121.2, 117.0 (q, JCF = 289.8
19
6
Hz), 113.1, 108.9; F NMR (DMSO-d , 376 MHz) δ -71.3 (s, 3 F); HRMS Calcd (ESI) m/z for
+
C
10
H
6
F
3
NNaO: [M+Na] 236.0294, found: 236.0286.
Typical Procedure for Synthesis of Chlorodifluoromethyl Indol-3-yl Ketones 3.
o
Indoles (0.2 mmol) and chlorodifluoroacetic acid (3 equiv) were reflux at 100 C oil bath in 2
mL of DCE under an air atmosphere, and progress of the reaction was monitored by TLC. After
completion of the reaction, as determined by TLC, the reaction was cooled to room temperature.
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Water (2×5 mL) was added, and the product was extracted with ethyl acetate (20 mL), the organic
layers were washed with saturated brine and it was removed in a rotary evaporator. The product
was purified by silica gel chromatography (petroleum ether/EtOAc = 20:1-15:1) to afford
corresponding products 3.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
9
2-chloro-1-(1,2-dimethyl-1H-indol-3-yl)-2,2-difluoroethan-1-one (3a): red solid (42.7 mg,
1
83%, mp 95-96 °C); H NMR (CDCl
3
, 400 MHz): δ 8.06 (d, J = 4.8 Hz, 1 H), 7.31-7.28 (m, 3 H),
, 100 MHz): δ 177.0 (t, JCF = 30.0 Hz), 150.7, 136.8,
1
3
3.70 (s, 3 H), 2.76 (s, 3 H); C NMR (CDCl
3
19
124.8, 123.0, 122.9, 121.7 (t, JCF = 5.4 Hz), 121.0 (t, JCF = 301.7 Hz), 109.7, 106.9, 30.0, 13.5; F
+
NMR (CDCl
3
, 376 MHz) δ -62.4 (s, 2 F). HRMS Calcd (ESI) m/z for C12
H
10ClF
2
NNaO: [M+Na]
280.0311, found: 280.0305.
9
1-(1-benzyl-2-methyl-1H-indol-3-yl)-2-chloro-2,2-difluoroethan-1-one (3d): yellow solid
1
(47.5 mg, 71%, mp 102-104 °C); H NMR (CDCl
3
, 400 MHz): δ 8.12 (d, J = 8.4 Hz, 1 H),
13
7.32-7.23 (m, 6 H), 7.01-6.99 (m, 2 H), 5.38 (s, 2 H), 2.74 (s, 3 H); C NMR (CDCl
3
, 100 MHz):
δ 177.4 (t, JCF = 30.1 Hz), 150.6, 136.7, 135.1, 129.1, 128.0, 125.8, 124.9, 123.3, 123.1, 121.9 (t,
19
J
3
CF = 5.5 Hz), 121.0 (t, JCF = 302.0 Hz), 110.2, 107.5, 46.8, 13.6; F NMR (CDCl , 376 MHz) δ
+
-62.4 (s, 2 F). HRMS Calcd (ESI) m/z for C18
356.0612.
H14ClF
2
NNaO: [M+Na] 356.0624, found:
2-chloro-2,2-difluoro-1-(2-methyl-1H-indol-3-yl)ethan-1-one (3e): white solid (38.5 mg,
1
6
79%, mp 109-111 °C); H NMR (DMSO-d , 400 MHz): δ 12.66 (s, 1 H), 7.93-7.91 (m, 1 H),
1
3
6
7.48-7.46 (m, 1 H), 7.25-7.23 (m, 2 H), 2.71 (s, 3 H); C NMR (DMSO-d , 100 MHz): δ 175.1 (t,
J
CF = 29.4 Hz), 150.6, 134.7, 124.9, 122.5, 122.1, 120.3 (t, JCF = 4.4 Hz), 120.2 (t, JCF = 300.7 Hz),
19
6
111.6, 105.0, 15.3; F NMR (DMSO-d , 376 MHz) δ -62.2 (s, 2 F). HRMS Calcd (ESI) m/z for
+
C
11
H
8
ClF
2
NNaO: [M+Na] 266.0155, found: 266.0145.
2-chloro-2,2-difluoro-1-(1-methyl-2-phenyl-1H-indol-3-yl)ethan-1-one (3f): white solid (43.7
1
mg, 68%, mp 71-73 °C; H NMR (CDCl
3
, 400 MHz): δ 8.28-8.26 (m, 1 H), 7.51 (d, J = 6.0 Hz, 3
13
H), 7.41-7.36 (m, 5 H), 3.52 (s, 3 H); C NMR (CDCl
3
, 100 MHz): δ 177.4 (t, JCF = 30.5 Hz),
149.9, 136.9, 130.9, 130.1, 129.6, 128.3, 126.0, 123.9, 123.5, 122.3 (t, JCF = 3.3 Hz), 120.8 (t, JCF
1
9
3
= 302.6 Hz), 110.2, 107.9, 31.2; F NMR (CDCl , 376 MHz) δ -61.0 (s, 2 F). HRMS Calcd (ESI)
+
m/z for C17
H12ClF
2
NNaO: [M+Na] 342.0468, found: 342.0454.
9
2
-chloro-2,2-difluoro-1-(1-methyl-1H-indol-3-yl)ethan-1-one (3g): off-white solid (34.2 mg,
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2
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2
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4
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5
5
5
5
5
5
5
5
5
5
6
1
7
3
0%, mp 94-96 °C); H NMR (CDCl , 400 MHz): δ 8.40-8.38 (m, 1 H), 7.92 (s, 1 H), 7.38-7.35
13
(
m, 3 H), 3.87 (s, 3 H); C NMR (CDCl
3
, 100 MHz): δ 176.2 (t, JCF = 28.8 Hz), 138.1 (t, JCF
=
19
6
.8 Hz), 137.1, 127.2, 124.4, 123.8, 122.5, 120.8 (t, JCF = 302.9 Hz), 110.1, 107.8, 33.9; F NMR
+
(CDCl
3
, 376 MHz) δ -60.5 (s, 2 F). HRMS Calcd (ESI) m/z for C11
H
8
ClF
2
NNaO: [M+Na]
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
266.0155, found: 266.0151.
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2-chloro-2,2-difluoro-1-(5-methoxy-1-methyl-1H-indol-3-yl)ethan-1-one (3h): white solid
1
(48.6 mg, 89%, mp 85-87 °C); H NMR (CDCl
3
, 400 MHz): δ 7.90-7.88 (m, 2 H), 7.27 (d, J =
13
10.8 Hz, 1 H), 7.00 (dd, J = 1.6, 2.0 Hz, 1 H), 3.91 (s, 3 H) , 3.88 (s, 3 H); C NMR (CDCl
3
, 100
MHz): δ 176.1 (t, JCF = 28.7 Hz), 157.3, 137.8 (t, JCF = 6.8 Hz), 132.0, 128.3, 120.9 (t, JCF = 303.0
19
3
Hz), 114.6, 110.9, 107.5, 103.8, 55.7, 34.1; F NMR (CDCl , 376 MHz) δ -60.4 (s, 2 F). HRMS
+
Calcd (ESI) m/z for C12
H10ClF
2
NNaO
2
: [M+Na] 296.0260, found: 296.0257.
2-chloro-1-(1,4-dimethyl-1H-indol-3-yl)-2,2-difluoroethan-1-one (3i): white solid (36.0 mg,
1
70%, mp 128-130 °C); H NMR (CDCl
3
, 400 MHz): δ 7.97 (s, 1 H), 7.26 (t, J = 7.6 Hz,, 1 H),
1
3
7.18 (d, J = 8.4 Hz, 1 H), 7.11 (d, J = 7.2 Hz, 1 H), 3.85 (s, 3 H), 2.84 (s, 3 H); C NMR (CDCl
3
,
100 MHz): δ 175.5 (t, JCF = 27.7 Hz), 139.1 (t, JCF = 7.3 Hz), 138.0, 133.8, 125.9, 125.8, 124.6,
19
3
121.5 (t, JCF = 304.4 Hz), 108.9, 107.6, 34.1, 23.0; F NMR (CDCl , 376 MHz) δ -58.4 (s, 2 F).
+
HRMS Calcd (ESI) m/z for C12
H10ClF
2
NNaO: [M+Na] 280.0311, found: 280.0300.
2-chloro-2,2-difluoro-1-(1H-indol-3-yl)ethan-1-one (3l): yellow solid (19.3mg, 42%, mp
1
6
150-152 °C); H NMR (DMSO-d , 400 MHz): δ 12.67 (s, 1 H), 8.48-7.46 (m, 1 H), 8.20-8.18 (m,
1
3
6
1 H), 7.60-7.58 (m, 1 H), 7.36-7.31 (m, 2 H); C NMR (DMSO-d , 100 MHz): δ 175.7 (t, JCF
=
28.2 Hz), 137.2 (t, JCF = 6.7 Hz), 136.5, 126.1, 124.2, 123.4, 121.1, 120.6 (t, JCF = 302.8 Hz),
19
6
113.0, 107.3; F NMR (DMSO-d , 376 MHz) δ -60.0 (s, 2 F). HRMS Calcd (ESI) m/z for
+
C
10
H
6
ClF
2
NNaO: [M+Na] 251.9998, found: 251.9995.
2-chloro-1-(1,5-dimethyl-1H-indol-3-yl)-2,2-difluoroethan-1-one (3m): yellow solid (40.7
1
mg, 79%, mp 118-120 °C); H NMR (CDCl
3
, 400 MHz): δ 8.20 (s, 1 H), 7.87 (s, 1 H), 7.24 (s, 1
13
H), 7.19 (d, J = 8.4 Hz, 1 H), 3.84 (s, 3 H), 2.49 (s, 3 H); C NMR (CDCl
3
, 100 MHz): δ 176.1 (t,
J
CF = 28.7 Hz), 138.0 (t, JCF = 6.9 Hz), 135.5, 133.7, 127.5, 125.9, 122.3, 120.9 (t, JCF = 303.2 Hz),
19
3
109.7, 107.4, 33.9, 21.5; F NMR (CDCl , 376 MHz) δ -60.4 (s, 2 F). HRMS Calcd (ESI) m/z for
+
C
12
H10ClF
2
NNaO: [M+Na] 280.0311, found: 280.0299.
2
-chloro-1-(1,6-dimethyl-1H-indol-3-yl)-2,2-difluoroethan-1-one (3n): off-white solid (44.8
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7
8
9
1
mg, 87%, mp 114-116 °C); H NMR (CDCl
.4 Hz, 1 H), 7.19 (d, J = 8.4 Hz, 1 H), 3.85 (s, 3 H), 2.49 (s, 3 H); C NMR (CDCl
δ 176.1 (t, JCF = 28.7 Hz), 138.0 (t, JCF = 6.8 Hz), 135.5, 133.7, 127.5, 125.9, 122.3, 120.9 (t, JCF
3
, 400 MHz): δ 8.20 (s, 1 H), 7.87 (s, 1 H), 7.25 (d, J =
1
3
8
3
, 100 MHz):
1
9
=
3
303.1 Hz), 109.7, 107.4, 33.9, 21.5; F NMR (CDCl , 376 MHz) δ -60.4 (s, 2 F). HRMS Calcd
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
+
(ESI) m/z for C12
H
10ClF
2
NNaO: [M+Na] 280.0311, found: 280.0307.
methyl 3-(2-chloro-2,2-difluoroacetyl)-1-methyl-1H-indole-6-carboxylate (3o): yellow solid
1
(22.9 mg, 38%, mp 159-160 °C); H NMR (CDCl
3
, 400 MHz): δ 8.41 (d, J = 8.4 Hz, 1 H), 8.14 (s,
, 100 MHz): δ 176.1 (t, JCF = 29.2 Hz),
167.2, 140.1 (t, JCF = 6.7 Hz), 136.8, 130.9, 126.3, 124.7, 122.3, 120.7 (t, JCF = 302.9 Hz), 112.2,
13
1 H), 8.06-8.03 (m, 2 H), 3.97 (s, 6 H); C NMR (CDCl
3
19
3
108.0, 52.3, 34.2; F NMR (CDCl , 376 MHz) δ -61.0 (s, 2 F). HRMS Calcd (ESI) m/z for
+
C
13
H10ClF
2
NNaO
3
: [M+Na] 324.0209, found: 324.0204.
2-chloro-1-(1-ethyl-1H-indol-3-yl)-2,2-difluoroethan-1-one (3p): off-white solid (42.1 mg,
1
82%, mp 76-77 °C); H NMR (CDCl
3
, 400 MHz): δ 8.44-8.41 (m, 1 H), 7.99 (s, 1 H), 7.45-7.37
13
(m, 3 H), 4.31-4.25 (m, 2 H), 1.60-1.56 (m, 3 H); C NMR (CDCl
3
, 100 MHz): δ 176.1 (t, JCF =
28.7 Hz), 136.5 (t, JCF = 6.9 Hz), 136.3, 127.5, 124.3, 123.8, 122.7, 120.9 (t, JCF = 303.1 Hz),
1
9
3
110.2, 107.9, 42.3, 15.0; F NMR (CDCl , 376 MHz) δ -60.4 (s, 2 F). HRMS Calcd (ESI) m/z for
+
C
12
H10ClF
2
NNaO: [M+Na] 280.0311, found: 280.0301.
1-(1-allyl-1H-indol-3-yl)-2-chloro-2,2-difluoroethan-1-one (3q): yellow oil (43.0 mg, 80%);
H NMR (CDCl , 400 MHz): δ 8.42-8.41 (m, 1 H), 7.97 (s, 1 H), 7.39-7.35 (m, 3 H), 6.07-5.97 (m,
1
3
1
3
1 H), 5.35 (d, J = 10.4 Hz, 1 H), 5.22 (d, J = 17.2 Hz, 1 H), 4.81 (d, J = 5.6 Hz, 2 H); C NMR
(CDCl , 100 MHz): δ 176.3 (t, JCF = 29.0 Hz), 137.1 (t, JCF = 6.8 Hz), 136.6, 131.2, 127.4, 124.4,
3
1
9
3
123.9, 122.6, 120.8 (t, JCF = 303.0 Hz), 119.4, 110.5, 108.2, 49.8; F NMR (CDCl , 376 MHz) δ
+
-60.5 (s, 2 F). HRMS Calcd (ESI) m/z for C13
292.0300.
H10ClF
2
NNaO: [M+Na] 292.0311, found:
2-chloro-2,2-difluoro-1-(1-(prop-2-yn-1-yl)-1H-indol-3-yl)ethan-1-one (3r): white solid (34.5
1
mg, 65%, mp 69-70 °C); H NMR (CDCl
3
, 400 MHz): δ 8.43-8.40 (m, 1 H), 8.13 (t, J = 1.6 Hz, 1
13
H), 7.48-7.45 (m, 1 H), 7.46-7.38 (m, 2 H), 4.95 (d, J = 2.8 Hz, 2 H), 2.59 (t, J = 2.8 Hz, 1 H); C
NMR (CDCl , 100 MHz): δ 176.4 (t, JCF = 29.0 Hz), 136.4 (t, JCF = 7.0 Hz), 136.1, 127.5, 124.7,
3
19
3
124.2, 122.8, 120.8 (t, JCF = 303.0 Hz), 110.1, 108.5, 76.1, 75.3, 37.0; F NMR (CDCl , 376 MHz)
+
δ -60.7 (s, 2 F). HRMS Calcd (ESI) m/z for C13
H
8
ClF
2
NNaO: [M+Na] 290.0155, found:
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1
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1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
2
90.0157.
1
-(1-benzyl-1H-indol-3-yl)-2-chloro-2,2-difluoroethan-1-one (3s): yellow solid (42.6 mg,
1
6
7
7%, mp 86-88 °C); H NMR (CDCl
3
, 400 MHz): δ 8.42 (d, J = 8.0 Hz, 1 H), 8.00 (s, 1 H),
1
3
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
3
.35-7.30 (m, 6 H), 7.16 (d, J = 6.0 Hz, 2 H), 5.37 (s, 2 H); C NMR (CDCl , 100 MHz): δ 176.4
(t, JCF = 29.0 Hz), 137.5 (t, JCF = 6.8 Hz), 136.7, 134.8, 129.1, 128.4, 127.5, 126.9, 124.6, 123.9,
19
3
122.7, 120.8 (t, JCF = 303.1 Hz), 110.7, 108.3, 51.3; F NMR (CDCl , 376 MHz) δ -60.5 (s, 2 F).
+
HRMS Calcd (ESI) m/z for C17
H12ClF
2
NNaO: [M+Na] 342.0468, found: 342.0456.
Typical Procedure for Synthesis of Bromodifluoromethyl Indol-3-yl Ketones 4.
o
Indoles (0.2 mmol) and bromodifluoroacetic acid (3 equiv) were reflux at 100 C oil bath in 2
mL of DCE under an air atmosphere, and progress of the reaction was monitored by TLC. After
completion of the reaction, as determined by TLC, the reaction was cooled to room temperature.
The saturated sodium bicarbonate solution (5 mL) and water (5 mL) was added, and the product
was extracted with ethyl acetate (20 mL), the organic layers were washed with saturated brine and
it was removed in a rotary evaporator. The product was purified by silica gel chromatography
(petroleum ether/EtOAc = 20:1-15:1) to afford corresponding products 4.
2-bromo-1-(1,2-dimethyl-1H-indol-3-yl)-2,2-difluoroethan-1-one (4a): off-white solid (51.2
1
mg, 85%, mp 114-115 °C); H NMR (CDCl
3
, 400 MHz): δ 8.08-8.06 (m, 1 H), 7.32-7.27 (m, 3 H),
1
3
3.69 (s, 3 H), 2.74 (s, 3 H); C NMR (CDCl
3
, 100 MHz): δ 177.7 (t, JCF = 27.1 Hz), 150.8, 136.8,
19
124.6, 123.0, 122.9, 122.2 (t, JCF = 5.7 Hz), 115.0 (t, JCF = 315.6 Hz), 109.7, 106.5, 30.0, 13.6; F
+
NMR (CDCl
323.9806, found: 323.9804.
2-bromo-2,2-difluoro-1-(2-methyl-1H-indol-3-yl)ethan-1-one (4e): yellow solid (44.1 mg,
3 2
, 376 MHz) δ -58.6 (s, 2 F). HRMS Calcd (ESI) m/z for C12H10BrF NNaO: [M+Na]
1
6
77%, mp 163-165 °C); H NMR (DMSO-d , 400 MHz): δ 12.64 (s, 1 H), 7.95-7.93 (m, 1 H), 7.48
13
6
(d, J = 8.8 Hz, 1 H), 7.28-7.24 (m, 2 H), 2.72 (s, 3 H); C NMR (DMSO-d , 100 MHz): δ 176.7 (t,
J
CF = 26.7 Hz), 151.0, 135.2, 125.2, 122.9, 122.4, 121.2 (t, JCF = 4.7 Hz), 114.5 (t, JCF = 313.3 Hz),
1
9
6
112.0, 105.1, 16.0; F NMR (DMSO-d , 376 MHz) δ -60.0 (s, 2 F). HRMS Calcd (ESI) m/z for
+
C
11
H
8
BrF
2
NNaO: [M+Na] 309.9650, found: 309.9650.
2-bromo-2,2-difluoro-1-(1-methyl-2-phenyl-1H-indol-3-yl)ethan-1-one (4f): white solid (59.1
1
mg, 81%, mp 92-93 °C); H NMR (CDCl
3
, 400 MHz): δ 8.27-8.25 (m, 1 H), 7.51 (d, J = 5.6 Hz, 3
13
3
H), 7.40-7.37 (m, 5 H), 3.52 (s, 3 H); C NMR (CDCl , 100 MHz): δ 178.0 (t, JCF = 27.5 Hz),
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49.9, 137.0, 131.0, 130.0, 129.6, 128.4, 125.9, 123.8, 123.4, 122.5 (t, JCF = 3.5 Hz), 114.9 (t, JCF
1
9
=
3
316.6 Hz), 110.3, 107.4, 31.2; F NMR (CDCl , 376 MHz) δ -57.2 (s, 2 F). HRMS Calcd (ESI)
+
m/z for C17
H12BrF
2
NNaO: [M+Na] 385.9963, found: 385.9961.
2
-bromo-2,2-difluoro-1-(1-methyl-1H-indol-3-yl)ethan-1-one (4g): red solid (43.2 mg, 75%,
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1
mp 118-120 °C); H NMR (CDCl
3
, 400 MHz): δ 8.41-8.38 (m, 1 H), 7.95 (s, 1 H), 7.38-7.36 (m, 3
, 100 MHz): δ 176.8 (t, JCF = 26.0 Hz), 138.1 (t, JCF = 6.9 Hz),
1
3
H), 3.89 (s, 3 H); C NMR (CDCl
3
19
3
137.1, 127.3, 124.4, 123.8, 122.6, 114.4 (t, JCF = 316.6 Hz), 110.1, 107.2, 34.0; F NMR (CDCl ,
+
376 MHz) δ -56.8 (s, 2 F). HRMS Calcd (ESI) m/z for C11
H
8
BrF
2
NNaO: [M+Na] 309.9650,
found: 309.9647.
2-bromo-2,2-difluoro-1-(5-methoxy-1-methyl-1H-indol-3-yl)ethan-1-one (4h): white solid
1
(55.5 mg, 88%, mp 116-118 °C); H NMR (CDCl
3
, 400 MHz): δ 7.89-7.88 (m, 2 H), 7.27-7.25 (m,
13
1 H), 6.99 (dd, J = 2.4, 2.4 Hz, 1 H), 3.90 (s, 3 H) , 3.86 (s, 3 H); C NMR (CDCl
3
, 100 MHz): δ
176.8 (t, JCF = 25.9 Hz), 157.3, 137.8 (t, JCF = 8.0 Hz), 132.0, 128.4, 114.7, 114.6 (t, JCF = 316.7
1
9
3
Hz), 111.0, 106.9, 103.8, 55.7, 34.1; F NMR (CDCl , 376 MHz) δ -56.7 (s, 2 F). HRMS Calcd
+
(ESI) m/z for C12
H
10BrF
2
NNaO
2
: [M+Na] 339.9755, found: 339.9751.
2-bromo-1-(1,4-dimethyl-1H-indol-3-yl)-2,2-difluoroethan-1-one (4i): white solid (38.9 mg,
1
65%, mp 125-126 °C); H NMR (CDCl
3
, 400 MHz): δ 8.00 (s, 1 H), 7.26 (t, J = 7.6 Hz, 1 H), 7.19
1
3
(d, J = 8.0 Hz, 1 H), 7.11 (d, J = 7.2 Hz, 1 H), 3.85 (s, 3 H), 2.84 (s, 3 H); C NMR (CDCl
3
, 100
MHz): δ 176.1 (t, JCF = 24.9 Hz), 139.0 (t, JCF = 7.6 Hz), 138.0, 133.8, 125.9, 125.8, 124.6, 115.1
19
3
(t, JCF = 318.2 Hz), 108.4, 107.6, 34.1, 22.9; F NMR (CDCl , 376 MHz) δ -54.7 (s, 2 F). HRMS
+
Calcd (ESI) m/z for C12
H10BrF
2
NNaO: [M+Na] 323.9806, found: 323.9801.
2-bromo-2,2-difluoro-1-(1H-indol-3-yl)ethan-1-one (4l): yellow solid (25.4 mg, 46%, mp
1
6
163-165 °C); H NMR (DMSO-d , 400 MHz): δ 12.64 (s, 1 H), 8.47-8.45 (m, 1 H), 8.20-8.18 (m,
1
3
6
1 H), 7.60-7.58 (m, 1 H), 7.35-7.29 (m, 2 H); C NMR (DMSO-d , 100 MHz): δ 176.8 (t, JCF
=
25.5 Hz), 137.1 (t, JCF = 6.9 Hz), 136.5, 126.2, 124.2, 123.3, 121.2, 114.2 (t, JCF = 315.3 Hz),
19
6
113.0, 106.8; F NMR (DMSO-d , 376 MHz) δ -57.4 (s, 2 F). HRMS Calcd (ESI) m/z for
+
C
10
H
6
BrF
2
NNaO: [M+Na] 295.9493, found: 295.9496.
2-bromo-1-(1,5-dimethyl-1H-indol-3-yl)-2,2-difluoroethan-1-one (4m): yellow solid (43.8
1
mg, 73%, mp 99-101 °C); H NMR (CDCl
3
, 400 MHz): δ 8.20 (s, 1 H), 7.89 (s, 1 H), 7.25 (d, J =
1
3
8
3
.4 Hz, 1 H), 7.18 (d, J = 8.4 Hz, 1 H), 3.84 (s, 3 H), 2.49 (s, 3 H); C NMR (CDCl , 100 MHz):
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2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
δ 176.7 (t, JCF = 26.0 Hz), 138.0 (t, JCF = 7.3 Hz), 135.5, 133.7, 127.6, 125.9, 122.3, 114.5 (t, JCF
1
9
=
3
316.8 Hz), 109.7, 106.8, 34.0, 21.5; F NMR (CDCl , 376 MHz) δ -56.6 (s, 2 F). HRMS Calcd
+
(ESI) m/z for C12
H10BrF
2
NNaO: [M+Na] 323.9806, found: 323.9804.
2
-bromo-1-(1,6-dimethyl-1H-indol-3-yl)-2,2-difluoroethan-1-one (4n): yellow solid (43.5 mg,
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
72%, mp 106-108 °C); H NMR (CDCl
3
, 400 MHz): δ 8.20 (s, 1 H), 7.89 (s, 1 H), 7.26 (d, J = 8.4
1
3
Hz, 1 H), 7.19 (d, J = 8.4 Hz, 1 H), 3.85 (s, 3 H), 2.49 (s, 3 H); C NMR (CDCl
3
, 100 MHz): δ
176.7 (t, JCF = 25.7 Hz), 138.0 (t, JCF = 7.2 Hz), 135.5, 133.7, 127.6, 125.9, 122.4, 114.5 (t, JCF
=
19
316.9 Hz), 109.7, 106.8, 34.0, 21.5; F NMR (CDCl
3
, 376 MHz) δ -56.6 (s, 2 F). HRMS Calcd
+
(ESI) m/z for C12
H10BrF
2
NNaO: [M+Na] 323.9806, found: 323.9806.
methyl 3-(2-bromo-2,2-difluoroacetyl)-1-methyl-1H-indole-6-carboxylate (4o): yellow solid
1
(28.6 mg, 41%, mp 157-159 °C); H NMR (CDCl
3
, 400 MHz): δ 8.41 (dd, J = 3.2, 3.2 Hz, 1 H),
13
8.13 (s, 1 H), 8.07-8.03 (m, 2 H), 3.97 (s, 6 H); C NMR (CDCl
3
, 100 MHz): δ 176.7 (t, JCF
=
26.3 Hz), 167.1, 140.0 (t, JCF = 6.8 Hz), 136.7, 130.9, 126.2, 124.7, 122.3, 114.2 (t, JCF = 316.5
19
3
Hz), 112.2, 107.4, 52.3, 34.2; F NMR (CDCl , 376 MHz) δ -57.3 (s, 2 F). HRMS Calcd (ESI)
+
m/z for C13
H10BrF
2
NNaO
3
: [M+Na] 367.9704, found: 367.9700.
2-bromo-1-(1-ethyl-1H-indol-3-yl)-2,2-difluoroethan-1-one (4p): off-white solid (49.2 mg,
1
82%, mp 69-71 °C); H NMR (CDCl
3
, 400 MHz): δ 8.42-8.40 (m, 1 H), 8.01 (s, 1 H), 7.43-7.40
1
3
(m, 1 H), 7.39-7.35 (m, 2 H), 4.28-4.23 (m, 2 H), 1.56 (t, J = 7.6 Hz, 3 H); C NMR (CDCl
3
, 100
MHz): δ 176.7 (t, JCF = 25.9 Hz), 136.5 (t, JCF = 7.2 Hz), 136.3, 127.6, 124.3, 123.8, 122.7, 114.5
19
3
(t, JCF = 316.7 Hz), 110.2, 107.3, 42.3, 15.0; F NMR (CDCl , 376 MHz) δ -56.7 (s, 2 F). HRMS
+
Calcd (ESI) m/z for C12
H10BrF
2
NNaO: [M+Na] 323.9806, found: 323.9806.
1-(1-allyl-1H-indol-3-yl)-2-bromo-2,2-difluoroethan-1-one (4q): brown oil (43.6 mg, 70%);
H NMR (CDCl , 400 MHz): δ 8.42-8.40 (m, 1 H), 7.99 (s, 1 H), 7.40-7.33 (m, 3 H), 6.07-5.97 (m,
1 H), 5.35 (d, J = 10.4 Hz, 1 H), 5.22 (d, J = 17.2 Hz, 1 H), 4.81 (d, J = 5.6 Hz, 2 H); C NMR
(CDCl , 100 MHz): δ 176.9 (t, JCF = 26.1 Hz), 137.1 (t, JCF = 7.1 Hz), 136.6, 131.2, 127.5, 124.4,
1
3
1
3
3
19
3
123.8, 122.7, 119.4, 114.4 (t, JCF = 316.7 Hz), 110.5, 107.6, 49.8; F NMR (CDCl , 376 MHz) δ
+
-56.8 (s, 2 F). HRMS Calcd (ESI) m/z for C13
335.9805.
H10BrF
2
NNaO: [M+Na] 335.9806, found:
2-bromo-1-(1-butyl-1H-indol-3-yl)-2,2-difluoroethan-1-one (4t): yellow oil (53.0 mg, 81%);
1
H NMR (CDCl
3
, 400 MHz): δ 8.43-8.40 (m, 1 H), 7.98 (s, 1 H), 7.42-7.35 (m, 3 H), 4.19 (t, J =
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8
9
1
3
7
.2 Hz, 2 H), 1.92-1.85 (m, 2 H), 1.39-1.34 (m, 2 H), 0.99-0.95 (m, 3 H); C NMR (CDCl
3
, 100
MHz): δ 176.8 (t, JCF = 25.9 Hz), 137.2 (t, JCF = 7.1 Hz), 136.5, 127.5, 124.3, 123.7, 122.7, 114.5
19
(
3
t, JCF = 316.9 Hz), 110.3, 107.2, 47.4, 31.7, 20.0, 13.5; F NMR (CDCl , 376 MHz) δ -56.7 (s, 2
+
F). HRMS Calcd (ESI) m/z for C14
H14BrF
2
NNaO: [M+Na] 352.0119, found: 352.0116.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
2-bromo-2,2-difluoro-1-(1-pentyl-1H-indol-3-yl)ethan-1-one (4u): brown oil (54.8 mg, 80%);
H NMR (CDCl , 400 MHz): δ 8.35-8.32 (m, 1 H), 7.89 (s, 1 H), 7.33-7.26 (m, 3 H), 4.10 (t, J =
7.2 Hz, 2 H), 1.85-1.78 (m, 2 H), 1.27-1.22 (m, 4 H), 0.81 (t, J = 6.8 Hz, 3 H); C NMR (CDCl
100 MHz): δ 176.8 (t, JCF = 25.8 Hz), 137.2 (t, JCF = 7.1 Hz), 136.5, 127.5, 124.3, 123.7, 122.7,
1
3
13
3
,
19
3
114.5 (t, JCF = 316.9 Hz), 110.3, 107.2, 47.6, 29.3, 28.8, 22.1, 13.8; F NMR (CDCl , 376 MHz) δ
+
-56.6 (s, 2 F). HRMS Calcd (ESI) m/z for C15
366.0273.
H16BrF
2
NNaO: [M+Na] 366.0276, found:
Typical Procedure for Synthesis of Difluoromethyl Indol-3-yl Ketones 5.
o
Indoles (0.2 mmol) and difluoroacetic acid (3 equiv) were reflux at 100 C oil bath in 2 mL of
DCE under an air atmosphere, and progress of the reaction was monitored by TLC. After
completion of the reaction, as determined by TLC, the reaction was cooled to room temperature.
Water (2×5 mL) was added, and the product was extracted with ethyl acetate (20 mL), the organic
layers were washed with saturated brine and it was removed in a rotary evaporator. The product
was purified by silica gel chromatography (petroleum ether/EtOAc = 20:1-15:1) to afford
corresponding products 5.
1-(1,2-dimethyl-1H-indol-3-yl)-2,2-difluoroethan-1-one (5a): white solid (33.9 mg, 76%, mp
1
82-84 °C); H NMR (CDCl
3
, 400 MHz): δ 7.96-7.93 (m, 1 H), 7.33-7.28 (m, 3 H), 6.38 (t, JHF
=
1
3
54.0 Hz, 1 H), 3.71 (s, 3 H), 2.77 (s, 3 H); C NMR (CDCl
3
, 100 MHz): δ 182.6 (t, JCF = 24.4 Hz),
148.9, 136.7, 125.2, 122.9, 122.9, 120.6 (t, JCF = 3.0 Hz), 110.2 (t, JCF = 248.6 Hz), 109.8, 109.4,
1
9
3
29.7, 12.9; F NMR (CDCl , 376 MHz) δ -125. 6 (d, JHF = 54.1 Hz, 2 F). HRMS Calcd (ESI) m/z
+
for C12
H
11
F
2
NNaO: [M+Na] 246.0701, found: 246.0690.
1-(1-ethyl-2-methyl-1H-indol-3-yl)-2,2-difluoroethan-1-one (5b): yellow oil (35.6 mg, 73%);
H NMR (CDCl , 400 MHz): δ 7.94 (d, J = 4.8 Hz, 1 H), 7.35-7.34 (m, 1 H), 7.29-7.27 (m, 2 H),
6.39 (t, JHF = 54.0 Hz, 1 H), 4.22-4.16 (m, 2 H), 2.77 (s, 3 H), 1.38 (t, J = 7.2 Hz, 3 H); C NMR
1
3
1
3
(CDCl
3
, 100 MHz): δ 182.7 (t, JCF = 24.7 Hz), 148.0, 135.7, 125.5, 122.9, 122.8, 120.8 (t, JCF
=
19
3
.4 Hz), 110.5 (t, JCF = 249.1 Hz), 109.8, 109.7, 38.1, 14.5, 12.7; F NMR (CDCl
3
, 376 MHz) δ
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5
5
5
5
5
5
6
+
-
125.6 (d, JHF = 54.1 Hz, 2 F). HRMS Calcd (ESI) m/z for C13
found: 260.0847.
-(1-allyl-2-methyl-1H-indol-3-yl)-2,2-difluoroethan-1-one (5c): yellow oil (29.7 mg, 60%);
H NMR (CDCl , 400 MHz): δ 7.95 (d, J = 8.0 Hz, 1 H), 7.30-7.24 (m, 3 H), 6.39 (t, JHF = 54.0
Hz, 1 H), 5.91-5.86 (m, 1 H), 5.18 (d, J = 10.4 Hz, 1 H), 4.84 (d, J = 17.2 Hz, 1 H), 4.72-4.71 (m,
13 2
H F NNaO: [M+Na] 260.0857,
1
1
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
3
1
3
2 H), 2.71 (s, 3 H); C NMR (CDCl
3
, 100 MHz): δ 182.9 (t, JCF = 24.6 Hz), 148.5, 136.2, 130.9,
19
125.3, 123.0, 120.8 (t, JCF = 3.1 Hz), 117.4, 110.4 (t, JCF = 248.9 Hz), 110.1, 109.8, 45.3, 12.7; F
NMR (CDCl
3
, 376 MHz) δ -125.5 (d, JHF = 54.1 Hz, 2 F). HRMS Calcd (ESI) m/z for
+
C
14
H
13
F
2
NNaO: [M+Na] 272.0857, found: 272.0850.
1-(1-benzyl-2-methyl-1H-indol-3-yl)-2,2-difluoroethan-1-one (5d): orange solid (36.6 mg,
1
61%, mp 93-95 °C); H NMR (CDCl
3
, 400 MHz): δ 8.00 (d, J = 7.6 Hz, 1 H), 7.30-7.22 (m, 6 H),
13
6.99-6.97 (m, 1 H), 6.41 (t, JHF = 54.0 Hz, 1 H), 5.35 (s, 2 H), 2.73 (s, 3 H); C NMR (CDCl
3
,
100 MHz): δ 183.0 (t, JCF = 24.8 Hz), 148.6, 136.6, 135.2, 129.0, 127.9, 125.8, 125.4, 123.2,
19
3
123.1, 120.9 (t, JCF = 3.3 Hz), 110.5 (t, JCF = 249.2 Hz), 110.3, 110.1, 46.6, 13.0; F NMR (CDCl ,
+
15 2
376 MHz) δ -125.5 (d, JHF = 53.8 Hz, 2 F). HRMS Calcd (ESI) m/z for C18H F NNaO: [M+Na]
322.1014, found: 322.1010.
2,2-difluoro-1-(5-methoxy-1-methyl-1H-indol-3-yl)ethan-1-one (5h): white solid (29.8 mg,
1
62%, mp 124-126 °C); H NMR (CDCl
3
, 400 MHz): δ 7.94 (s, 1 H), 7.89 (s, 1 H), 7.26 (d, J = 3.2
Hz, 1 H), 6.99 (dd, J = 2.8, 2.4 Hz, 1 H), 6.10 (t, JHF = 54.4 Hz, 1 H), 3.90 (s, 3 H), 3.85 (s, 3 H);
1
3
C NMR (CDCl
3
, 100 MHz): δ 182.6 (t, JCF = 24.9 Hz), 157.1, 137.7 (t, JCF = 7.0 Hz), 132.0,
1
9
127.8, 114.4, 112.0 (t, JCF = 252.2 Hz), 110.7, 110.0, 103.7, 55.7, 33.9; F NMR (CDCl
3
, 376
+
11 2 2
MHz) δ -120.1 (d, JHF = 54.1 Hz, 2 F). HRMS Calcd (ESI) m/z for C12H F NNaO : [M+Na]
262.0650, found: 262.0640.
2,2-difluoro-1-(1H-indol-3-yl)ethan-1-one (5l): off-white solid (10.0 mg, 26%, mp
1
6
130-132 °C); H NMR (DMSO-d , 400 MHz): δ 12.42 (s, 1 H), 8.48 (d, J = 2.4 Hz, 1 H), 8.18 (dd,
J = 2.4, 1.6 Hz, 1 H), 7.55 (dd, J = 1.6, 2.0 Hz, 1 H), 7.31-7.25 (m, 2 H), 6.84 (t, JHF = 53.6 Hz, 1
1
3
6
H); C NMR (DMSO-d , 100 MHz): δ 181.8 (t, JCF = 23.4 Hz), 136.5, 136.5 (t, JCF = 3.7 Hz),
1
9
6
125.5, 123.9, 122.8, 121.1, 112.7, 111.6, 109.4 (t, JCF = 244.9 Hz); F NMR (DMSO-d , 376
+
MHz) δ -123.8 (d, JHF = 53.8 Hz, 2 F). HRMS Calcd (ESI) m/z for C10
18.0388, found: 218.0383.
7 2
H F NNaO: [M+Na]
2
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,2,2-Trifluoro-1-(1-methyl-1H-indol-3-yl)ethan-1-ol (6).
A
10
mL
round
bottom
flask
was
charged
with
2
0
,2,2-trifluoro-1-(1-methyl-1H-indol-3-yl)ethan-1-one (2g) (45.4 mg, 0.2 mmol), NaBH (15.1 mg,
4
.4 mmol), methanol (3 mL), and a magnetic stirring bar. The reaction mixture was stirred at room
10
11
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59
60
temperature. The progress of the reaction was monitored by TLC. After completion of the reaction,
as determined by TLC, the reaction was extracted with ethyl acetate (20 mL) and water (10 mL),
the organic layers were washed with saturated brine and it was removed in a rotary evaporator.
The product was purified by silica gel chromatography (petroleum ether/EtOAc = 15:1) to afford
1
6a 1
corresponding product 6 (38.9 mg, 85%) as a yellow oil:
3
H NMR (CDCl , 400 MHz): δ 7.68 (d,
J = 8.0 Hz, 1 H), 7.32 (d, J = 8.0 Hz, 1 H), 7.27 (t, J = 7.2 Hz, 1 H), 7.22-7.16 (m, 2 H), 5.27 (s, 1
13
3
H); 3.74 (s, 3 H); C NMR (CDCl , 100 MHz): δ 136.8, 128.2, 126.2, 124.8 (q, JCF = 280.3 Hz),
19
3
122.4, 120.1, 119.2, 109.6, 107.8, 67.3 (q, JCF = 33.3 Hz), 32.9; F NMR (CDCl , 376 MHz) δ
+
-77.8 (s, 3 F); HRMS Calcd (ESI) m/z for C11
1-Methyl-1H-indole-3-carboxylic acid (7).
10 mL round bottom
H
10
F
3
NNaO: [M+Na] 252.0607, found: 252.0614.
A
flask
was
charged
with
2,2,2-trifluoro-1-(1-methyl-1H-indol-3-yl)ethan-1-one (2g) (45.4 mg, 0.2 mmol), NaOH (5 M, 1.2
mL), ethanol (0.4 mL), and a magnetic stirring bar. The reaction mixture was refluxed for 4 h and
2
then cooled to room temperature, and H O (10 mL) was added. The layers were separated, and the
organic layer was extracted with 1 M aq. NaOH (10 mL). The combined aqueous phases were
acidified to pH 1 with 12 M aq. HCl, extracted with ethyl acetate (2 × 10 mL), and the solvent was
evaporated. The product was purified by silica gel chromatography (petroleum ether/EtOAc = 5:1)
20 1
to afford corresponding product 7 (28.4 mg, 80%) as a white solid (mp 182-184 °C): H NMR
6
(DMSO-d , 400 MHz): δ 8.04-8.03 (m, 2 H), 7.51 (d, J = 8.0 Hz, 1 H), 7.27-7.19 (m, 2 H), 3.85 (s,
13
6
3 H); C NMR (DMSO-d , 100 MHz): δ 165.7, 137.0, 136.1, 126.4, 122.2, 121.3, 120.7, 110.6,
+
106.2, 33.0. HRMS Calcd (ESI) m/z for C10
H
9
NNaO
2
: [M+Na] 198.0525, found: 198.0528.
Acknowledgement. This work was supported by generous grants from the National Natural
Science Foundation of China (NSFC-21472147, 21272183).
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Supporting Information. Copies of H, C, and F NMR spectra for products. This
material is available free of charge via the Internet at http://pubs.acs.org.
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References
(
1) (a) Gillis, E. P.; Eastman, K. J.; Hill, M. D.; Donnelly, D. J.; Meanwell, N. A. J. Med.
Chem. 2015, 58, 8315. (b) Wang, J.; Sánchez-Roselló, M.; Aceña, J. L.; del Pozo, C.; Sorochinsky,
A. E.; Fustero, S.; Soloshonok, V. A.; Liu, H. Chem. Rev. 2014, 114, 2432. (c) O’Hagan, D. Chem.
Soc. Rev. 2008, 37, 308. (d) Hagmann, W. K. J. Med. Chem. 2008, 51, 4359.
(
2) For selected recent reviews, see: (a) Champagne, P. A.; Desroches, J.; Hamel, J.-D.;
Vandamme, M.; Paquin, J.-F. Chem. Rev. 2015, 115, 9073. (b) Alonso, C.; Martínez de Marigorta,
E.; Rubiales, G.; Palacios, F. Chem. Rev. 2015, 115, 1847. (c) Yang, X.; Wu, T.; Phipps, R. J.;
Toste, F. D. Chem. Rev. 2015, 115, 826. (d) Ni, C.; Hu, M.; Hu, J. Chem. Rev. 2015, 115, 765. (e)
Fan, X.; Zhu, H.; Zhu, C. Acta Chim. Sinica 2015, 73, 979. (f) Charpentier, J.; Früh, N.; Togni, A.
Chem. Rev. 2015, 115, 650. (g) Ni, C.; Zhu, L.; Hu, J. Acta Chim. Sinica 2015, 73, 90. (h) Merino,
E.; Nevado, C. Chem. Soc. Rev. 2014, 43, 6598.
(
3) (a) Zhang, Z.; Yu, W.; Wu, C.; Wang, C.; Zhang, Y.; Wang, J. Angew. Chem., Int. Ed. 2016,
5
5, 273. (b) Luo, H.; Wu, G.; Zhang, Y.; Wang, J. Angew. Chem., Int. Ed. 2015, 54, 14503. (c) He,
Y.-T.; Wang, Q.; Zhao, J.; Liu, X.-Y.; Xu, P.-F.; Liang, Y.-M. Chem. Commun. 2015, 51, 13209. (d)
Zhang, K.; Xu, X.-H.; Qing, F.-L. J. Org. Chem. 2015, 80, 7658. (e) Pitre, S. P.; McTiernan, C. D.;
Ismaili, H.; Scaiano, J. C. ACS Catal. 2014, 4, 2530. (f) Li, Z.; Zhang, C.; Zhu, L.; Liu, C.; Li, C.
Org. Chem. Front. 2014, 1, 100.
(
4) (a) Thomas, J. B.; Giddings, A. M.; Wiethe, R. W.; Olepu, S.; Warner, K. R,; Sarret, P.;
Gendron, L.; Longpre, J.-M.; Zhang, Y.; Runyon, S. P.; Gilmour, B. P. J. Med. Chem. 2014, 57,
472. (b) Gao, Y.; Osman, S.; Koide, K. ACS Med. Chem. Lett. 2014, 5, 863.
5) (a) Ma, C.-H.; Kang, T.-R.; He, L.; Liu, Q.-Z. Eur. J. Org. Chem. 2014, 3981. (b)
7
(
Kawanami, T.; Karns, A. S.; Adams, C. M.; Serrano-Wu, M. Tetrahetron Lett. 2013, 54, 7202. (c)
Rowan, A. S.; Moody, T. S.; Howard, R. M.; Underwood, T. J.; Miskelly, I. R.; He, Y.; Wang, B.
Tetrahedron: Asymmetry 2013, 24, 1369.
(
6) Wynne, J. H.; Lloyd, C. T.; Jensen, S. D.; Boson, S.; Stalick, W. M. Synthesis 2004, 2277.
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7
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(
7) Mitchell, L.; Williamson, P.; Ehrlichová, B.; Anderson, A. E.; Seymour, V. R.; Ashbrook,
S. E.; Acerbi, N.; Daniels, L. M.; Walton, R. I.; Clarke, M. L.; Wright, P. A. Chem. Eur. J. 2014,
0, 17185.
8) (a) Vitaku, E.; Smith, D. T.; Njardarson, J. T. Angew. Chem., Int. Ed. 2016, 55, 2243. (b)
2
(
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Schmitt, E.; Rugeri, B.; Panossian, A.; Vors, J.-P.; Pazenok, S.; Leroux, F. R. Org. Lett. 2015, 17,
4510.
(9) Williams, T. J.; Greaney, M. F. Org. Lett. 2014, 16, 4024.
(10) Miao, T.; Li, P.; Zhang, Y.; Wang, L. Org. Lett. 2015, 17, 832.
(11) (a) Vaghoo, H.; Prakash, G. K. S.; Narayanan, A.; Choudhary, R.; Paknia, F.; Mathew, T.;
Olah, G. A. Org. Lett. 2015, 17, 6170. (b) Naeimi, H.; Amini, A.; Moradian, M. Org. Chem. Front.
2014, 1, 415. (c) Wilkinson, M. C. Org. Lett. 2011, 13, 2232.
(12) There is a small amount of trifluoromethyl-substituted trisindolylalkane 2g’ determined
by NMR spectroscopy and ESI-MS.
(13) (a) Hine, J.; Duffey, D. C. J. Am. Chem. Soc. 1959, 81, 1131. (b) Salomon, P.; Zard, S. Z.
Org. Lett. 2014, 16, 2926.
(14) For review: (a) Belhomme, M.-C.; Besset, T.; Poisson, T.; Pannecoucke, X. Chem. Eur. J.
2015, 21, 12836. For selected recent examples, see: (b) Feng, Z.; Min, Q.-Q.; Zhang, X. Org. Lett.
2016, 18, 44. (c) Prieto, A.; Melot, R.; Bouyssi, D.; Monteiro, N. ACS Catal. 2016, 6, 1093. (d)
Qu, C.; Xu, P.; Ma, W.; Cheng, Y.; Zhu, C. Chem. Commun. 2015, 51, 13508. (e) Shao, C.; Shi, G.;
Zhang, Y.; Pan, S.; Guan, X. Org. Lett. 2015, 17, 2652. (f) Belhomme, M.-C.; Poisson, T.;
Pannecoucke, X. J. Org. Chem. 2014, 79, 7205.
(15) (a) Ge, S.; Chaladaj, W.; Hartwing, J. F. J. Am. Chem. Soc. 2014, 136, 4149. (b) Han, C.;
Salyer, A. E.; Kim, E. H.; Jiang, X.; Jarrard, R. E.; Powers, M. S.; Kirchhoff, A. M.; Salvador, T.
K.; Chester, J. A.; Hockerman, G. H.; Colby, D. A. J. Med. Chem. 2013, 56, 2456. (c) Guo, C.;
Wang, R.-W.; Qing, F.-L. J. Fluorine Chem. 2012, 143, 135.
(16) (a) Ayano, S.; Yuta, N. PCT Int. Appl. WO 1521978 (CAN 161: 456552), 2014. (b)
Dong, J.; Pan, L.; Xu, X.; Liu, Q. Chem. Commun. 2014, 50, 14797.
(17) (a) Ratni, H.; Rogers-Evans, M.; Bissantz, C.; Grundschober, C.; Moreau, J.-L.; Schuler,
F.; Fischer, H.; Sanchez, R. A.; Schnider, P. J. Med. Chem. 2015, 58, 2275. (b) Banister, S. D.;
Moir, M.; Stuart, J.; Kevin, R. C.; Wood, K. E.; Longworth, M.; Wilkinson, S. M.; Beinat, C.;
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Buchanan, A. S.; Glass, M.; Connor, M.; McGregor, I. S.; Kassiou, M. ACS Chem. Neurosci. 2015,
6
, 1546. (c) Lian, X.-L.; Ren, Z.-H.; Wang, Y.-Y.; Guan, Z.-H. Org. Lett. 2014, 16, 3360. (d)
Ueyama, T.; Mochida, S.; Fukutani, T.; Hirano, K.; Satoh, T.; Miura, M. Org. Lett. 2011, 13, 706.
18) (a) Yokoyama, Y. Chem. Rev. 2000, 100, 1717. (b) Islamova, N. I.; Chen, X.; Fan, C.-J.;
(
0
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0
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2
3
4
5
6
7
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9
0
Andino, R. S.; Lees, W. J. Polym. Degrad. Stab. 2013, 98, 1662. (c) Thomas, C. J.; Wolak, M. A.;
Birge, R. R.; Lees, W. J. J. Org. Chem. 2001, 66, 1914.
(19) (a) Zhao, M.-N.; Ran, L.; Chen, M.; Ren, Z. H.; Wang, Y.-Y.; Guan, Z.-H. ACS Catal.
2015, 5, 1210. (b) Yu, L.; Li, P.; Wang, L. Chem. Commum. 2013, 49, 2368. (c) Xu, S.; Huang, X.;
Hong, X.; Xu, B. Org. Lett. 2012, 14, 4614. (d) Xu, X.-H.; Liu, G.-K.; Azuma, A.; Tokunaga, E.;
Shibata, N. Org. Lett. 2011, 13, 4854.
(20) Nemoto, K.; Tanaka, S.; Konno, M.; Onozawa, S.; Chiba, M.; Tanaka, Y.; Sasaki, Y.;
Okubo, R.; Hattori, T. Tetrahetron 2016, 72, 734.
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