Direct access to 2-difluoromethyl indoles via photoredox catalysis

Article abstract of DOI:10.1016/j.jfluchem.2019.05.009

A visible-light mediated approach to radical difluoromethylation of 3- and 3,5-substituted indoles was investigated using a readily synthesized difluoromethyl source, CF₂HPPh₃Br. Direct difluoromethylation of indoles in the two position is a rare feat in the literature. The reactions were conducted at room temperature, using Ir(ppy)₃ as photocatalyst in acetone, to afford the 2-difluoromethyl indoles in relatively low to moderate yields.

Full text of DOI:10.1016/j.jfluchem.2019.05.009

Accepted Manuscript
Title: Direct Access to 2-Difluoromethyl Indoles via
Photoredox Catalysis
Authors: Miles A. Rubinski, Simon E. Lopez, William R.
Dolbier Jr.
PII:
S0022-1139(19)30117-4
DOI:
Reference:
https://doi.org/10.1016/j.jfluchem.2019.05.009
FLUOR 9331
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Received date:
Revised date:
Accepted date:
3 April 2019
14 May 2019
15 May 2019
Please cite this article as: Rubinski MA, Lopez SE, Dolbier WR, Direct Access to
2-Difluoromethyl Indoles via Photoredox Catalysis, Journal of Fluorine Chemistry
(2019), https://doi.org/10.1016/j.jfluchem.2019.05.009
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Direct Access to 2-Difluoromethyl Indoles via Photoredox Catalysis
Miles A. Rubinski, Simon E. Lopez, and William R. Dolbier, Jr.*
Department of Chemistry, University of Florida, Gainesville, P.O. Box 117200, FL 32611-7200, Florida, USA.
*Corresponding author email: wrd@chem.ufl.edu
Graphical abstract
Highlights
CF2HPh3PBr is a very effective source of difluoromethyl radicals under photoredox catalysis.
Direct difluoromethylation of 3-substituted indoles at the 2-position has been accomplished for the first time.
fac-Ir(ppy)3 is the most effective photoredox catalyst for difluoromethylation of indoles using CF2HPh3PBr as
the radical precursor.
Abstract
A visible-light mediated approach to radical difluoromethylation of 3- and 3,5-substituted indoles was
investigated using
a
readily synthesized difluoromethyl source, CF2HPPh3Br. Direct

difluoromethylation of indoles in the two position is a rare feat in the literature. The reactions were
conducted at room temperature, using Ir(ppy)3 as photocatalyst in acetone, to afford the
2-difluoromethyl indoles in relatively low to moderate yields.
1. Introduction
Inspired by the enhancement of properties such as lipophilicity, bioavailability, and metabolic
stability, chemists have developed numerous methodologies to install fluoroalkyl moieties, especially
the trifluoromethyl and difluoromethyl groups [1]. These enhancements are being explored in fields
like pharmaceuticals, agrochemicals, and even novel materials. The expansion of possibilities for
realizing direct trifluoromethylation has increased significantly within the last two decades, especially
with respect to aromatic and hetero-aromatic substrates [2]. The CF2H group has also seen impressive
development, but the need for more general methods to access a similar breadth of compounds as seen
for trifluoromethylation is apparent. The CF2H group is especially popular as it has hydrogen bonding
capabilities, similar to an alcohol or amine, while still bestowing beneficial pharmacological properties
like other perfluoroalkyl groups [3]. The desire to install different fluoroalkyl groups into heterocyclic
structures has been the goal of many recent publications [4].
Indoles are a class of heterocycles that are widely present in bioactive natural products, as well
as pharmaceuticals (Figure 1), as a result of established activities like aiding with central nervous and
cardiovascular system diseases, antimitotic therapies, anti-inflammatory, antidepressant, as well as
being an effective option for the treatment of infections caused by various bacteria and viruses [5].
Additionally, indole derivatives containing fluorine atoms, trifluoromethyl groups, or other fluoroalkyl
groups have shown promise in their own right as potent pharmaceuticals. Direct and indirect access to
2- and 3-CF3 indole derivatives has been accomplished using a variety of copper-mediated, transition
Figure 1. Representative pharmaceutical indole derivatives. Adapted from Ref. 5.

metal catalyzed, and photoredox catalyzed approaches [6,7]. Installing a variety of fluoroalkyl groups
into the indole substructure has also been accomplished using a copper mediated approach [8].
However, reports for the generation of difluoromethyl indoles are significantly less prevalent in the
literature, especially on 3-substituted indoles bearing an unprotected nitrogen. One difficulty in
utilizing previously established fluoroalkylation strategies for analogous difluoromethylation reactions
is that the reactivity of the intermediates necessary to accomplish the desired products have different
properties [9]. Copper complexes that are suitable for generating relatively stable and isolatable
“CuCF3” intermediates are more challenging to generate for “CuCF2H”, with only three reports being
available [7d, 10]. Additionally, the CF2H radical is relatively nucleophilic as compared to other CF2R
radicals, like the CF3, CF2CO2Et, CF2CF2R, and CF2Cl (11). As a result, predicting the regiochemistry
by using the same method to generate each fluoroalkyl radical can be difficult. Excluding pathways
that involve direct fluorination of a carbonyl group to gain access to the –CF2R moiety, the options are
relatively limited (Figure 2).
In 2004, Konno and coworkers demonstrated the intermolecular annulation of 2-iodoanilines
with internal alkynes bearing CF3 and CF2H groups to furnish 2- and 3-fluoroalkyl indoles using

different Pd catalysts to control the regiochemistry (Figure 2, a) [12]. Next, in 2007 Wang et al. first
synthesized 2-benzyl bromide N-aryl difluoromethyl imidoyl chlorides in order to access the 2-CF2H
indoles via an intramolecular Grignard attack (Figure 2, b) [13]. Two separate reports of direct
ethoxycarbonyldifluoromethylation of alkenes and heterocycles were reported by Lin et al. in 2013,
and then by Jung in 2014, both using photoredox catalysis with bromodifluoroethylacetate
(Figure 2, c) [14, 15]. While neither group focused on indoles, there were several examples synthesized
by both groups, especially 3-Me indole. Further utilization of the bromodifluoroethylacetate as a
precursor to the difluoromethyl group was achieved by Guan et al. in 2015 via a Pd(PPh3)4 catalyzed
approach using XantPhos as a ligand for regioselective ethoxycarbonyl-difluoromethylation of several
electron-rich 3- and 5-substituted indoles (Figure 2, d) [16]. Copper catalyzed methods were then
developed by the Shi group, with the utilization of N-substituted indoles for regiocontrol being a novel
strategy (Figure 2, e) [17]. Based on our recent publications related to the pairing of photoredox
catalysis and fluoroalkylation, and the need for the development of direct difluoromethylation
strategies, we sought to take advantage of the mild reaction conditions provided by a photoredox
strategy with respect to synthesizing 2-CF2H indoles [18]. This work is, to the best of our knowledge,
the first report of direct regioselective difluoromethylation of indoles using photoredox catalysis.
Figure 2. Previous methodologies to synthesize –CF2R indoles.

This work:
Table 1. Optimization of reaction conditions. Reaction were done using a 0.2 mmol scale relative to
1a, with 2.0 equivalents of CF2H source, 2.0 mol% of catalyst, 2.0 equivalents of additive, and 2 mL

of solvent, unless otherwise noted, during 24 h. Yield were calculated using trifluorotoluene as internal
standard in the crude 19F-NMR spectrum.
Entry
CF2H Source
Catalyst
Solvent
Additive
Yield a (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
CF2HSO2Cl
CF2HSO2BOT
CF2HPPh3Br
CF2HPPh3Br
CF2HPPh3Br
CF2HPPh3Br
CF2HPPh3Br
CF2HPPh3Br
CF2HPPh3Br
CF2HPPh3Br
CF2HPPh3Br
CF2HPPh3Br
CF2HPPh3Br
CF2HPPh3Br
CF2HPPh3Br
CF2HPPh3Br
CF2HPPh3Br
CF2HPPh3Br
CF2HPPh3Br
CF2HPPh3Br
CF2HPPh3Br
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
DMF
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
Na2CO3
Na2HPO4
K2HPO4
KOAc
34
trace
39
32
6
trace
20
25
27
14
28
trace
44
39
33
28
23
37
53
3a
3a
3a
3b
3c
3d
3e
3f
3a
3a
3a
3a
3a
3a
3a
3a
3a
3a
3a
3a
3a
DMSO
Dioxane
DCE
Acetone
Acetone
Acetone
Acetone
Acetone
Acetone
Acetone
Acetone
Acetone
H2O
NaHCO3
CuBr2 (20%)
Et3N
trace
trace
a Isolated yield
2. Results and Discussion
Initially, we sought to determine which difluoromethyl radical source would be suitable for the
regioselective difluoromethylation of indoles using photoredox catalysis. To this end, we tested
three common -CF2H radical precursors, CF2HSO2Cl, difluoromethyl sulfonyl benzothiazole
(CF2HSO2BOT), and difluoromethyl triphenylphosphonium bromide (CF2HPPh3Br) [19]. To our

tentative satisfaction we detected the desired 2-CF2H indole using either CF2HSO2Cl or CF2HPPh3Br
in 34% and 39% yields, respectively, using 3-Me indole as the standard substrate with Ir(ppy)3 (3a),
Na2CO3 as an additive, and acetonitrile as solvent (Table 3, Entries 1 and 3). Next, we subjected the
discovery
Figure 3. Photocatalysts tested.
to an optimization protocol by varying the photocatalyst, solvent, and additive. The alternative
photocatalysts (3b-f, Figure 3) that were screened proved ineffective (Table 3, entries 4-8), providing
little to no reactivity in most cases. Ir(ppy)3 (3a) was determined to be the best option moving forward
(Entries 3, 13,14,18, 19). Then a variety of solvents like DCE, DMF, DMSO and acetone (Entries 9-

13) were evaluated, and only acetone showed an improvement in yield (entry 13, 44%). Having an
optimized photocatalyst and solvent combination, we then examined the effectiveness of different
additives on the course of the reaction (Entries 14-21). Using a weak base like NaHCO3 proved
beneficial to the reaction, giving our best yields yet at 53%, suggesting the phosphonium may be
sensitive to stronger bases. Using an organic base like Et3N, or a cocatalyst like Cu(OAC)2 did not
improve or help the reaction with trace product being formed in both cases (Entries 20-21). Satisfied
with our optimized conditions we then wanted to expand the substrate scope, starting with varying the
substituent in the 3-position (Figure 4). Our standard substrate 3-Me indole, 1a, gave the corresponding
2-CF2H indole, 2a, in 53% yield according to the crude 19F-NMR. Subsequent substrates were tested
with differing para-substituted phenyl groups in the 3-position, with only halogens, and methoxy
derivatives giving moderate to good yields (compounds 2b through 2e). Phenyl groups with strong
para-EWG were not well tolerated under these conditions and consequently were not extensively
screened, but 3-(4-nitrophenyl) indole (1f) was found to yield 17% of the desired product by NMR
analysis (2f). When the substituent was an electron-withdrawing group, like in the 3-carboxyaldehyde
indole case, the observed yield was appreciably lower at 35% (2g). Switching the substituent to a
heteroatom like in 3-(4-chlorophenyl)thio-indole, 1h, also did not improve the yield, giving only 28%
of the product (2h). Finally, with no modification to the indole structure we found 1i to react well with
high conversion at 53%, however this resulted in a mixture of products (ratio of 1.2:1; 3-CF2H:2-CF2H
respectively) with the desired compound being the minor product, making its isolation challenging
(compound 2i). Overall, the reaction works best with electron-rich substituents in the 3-position, and
tolerates a variety of substituents, albeit in relatively low yields.
Figure 4. Substrate scope 3-substituted indoles.

Crude yields were calculated by 19F-NMR, using trifluorotoluene as an internal standard. Isolated yields
in parentheses.

Next, we explored the impact of varying the substituent on the phenyl portion of the indole
structure, with an emphasis on position 5 (Figure 5). Interestingly, the yield of 3-phenyl-5-methoxy
indole (1j) have a lower yield than anticipated (37%, compound 2j). This could possibly be due to the
increased basicity of the indole thus interfering with the generation of the CF2H radical by reacting
counterproductively with the phosphonium. Substrates 1k and 1l gave the corresponding 2-CF2H indole
in moderate yields of 49% (2k) and 43% (2l) respectively. Finally, substrate 1m bearing 4,6-dichloro-
3-phenyl indole, also worked well with a similar yield observed as other halogen containing substrates
(42%, 2m). Interestingly, the 5-nitro-3-phenyl indole, 1n, afforded much better conversion when
compared to the 3-para-nitrophenyl indole, 1g (17% vs. 50% conversion). However, 2n was produced
alongside a byproduct (not isolated), allowing for only 24% of 2n to be isolated. Overall, the
substituents on the benzene-portion of the indole work best when they are not strongly donating or
withdrawing electrons, with problems of regioselectivity arising from highly EWGs and reactivity with
EDGs. Protecting groups on the indole nitrogen were not extensively screened, however N-Ac-3-Me
indole, 1o, provided the desired compound (2o) in 56% yield, suggesting that other similarly
withdrawing protecting groups, like Tos, Boc, and Bz, could be tolerated if desired (Figure 6).
A comment on the generally mediocre yields obtained in this study is appropriate: Unreacted
stating material was observed, but not isolated in most cases (one example: 5-Fluoro-3-Ph indole could
be seen in the crude 1HNMR very clearly, and in a similar concentration as the major product, 2k). The
vast majority of the conversion for the reaction is into the desired compound, with trace amounts of other
regioisomers being present. There are some tarlike by-products produced can be observed stuck on the
column during purification.
2.1. Mechanism
A plausible reaction mechanism for photoredox mediated radical addition to indoles is well
established in the literature (Figure 7). First, the photocatalyst is excited by visible light irradiation (A)

whereby it reduces the difluoromethyl triphenylphosphonium via a single-electron transfer process
(SET) generating the CF2H radical, and triphenyl phosphine as a byproduct (B). The CF2H radical can
then add regioselectively (C) to the 2-position of the starting indole (1), forming a highly stabilized
radical (4). The photocatalyst can then be regenerated by SET transfer (D) from the intermediate tertiary
radical (4), thus oxidizing the indole to the corresponding cation (5). Finally, the cationic intermediate
can be deprotonated (E) to afford the 2-CF2H indole (2).
Figure 5. Substrates tested with differing substituents on the phenyl ring of the indole skeleton. Crude
yields calculated using 19F-NMR and trifluorotoluene as an internal standard. Isolated yields in
parentheses.

Figure 6. N-Ac-3-Me indole example. Crude yields calculated using 19F-NMR and
trifluorotoluene as an internal standard. Isolated yields in parentheses.
Figure 7. Plausible mechanism for the photoredox difluoromethylation of indoles.

Several experiments were conducted to increase our confidence in the proposed reaction mechanism
(Table 2). First, we conducted the reaction in complete darkness, resulting in no reaction occurring
(entry 1). Then, we added TEMPO, a radical scavenger, and the corresponding TEMPO-CF2H adduct
could be detected in the 19F-NMR crude material (54%), as well as small amounts of product 2a (entry
2). We also tested the reaction by irradiating the reagents without photocatalyst, which afforded no
product, however the difluoromethyl source mostly decomposed (entry 3). These results indicate that
the proposed mechanism is both reasonable, and highly likely given the need for photocatalyst, visible
light irradiation, and the formation of the TEMPO-CF2H product which is formed primarily by trapping
the CF2H radical.
Table 2. Mechanistic investigations. Yields were calculated using the crude 19F-NMR spectrum and
trifluorotoluene as an internal standard.
Entry
Ir(ppy)3
2.0 %
2.0%
conditions
no light, 48h
TEMPO (2.0 equiv.)
Blue LED, 24h
yield 2a (%)
1
2
0
21
54
3
0.0%
Blue LED, 24h
0
3. Conclusion
In conclusion, we have developed the first report of photoredox mediated regioselective direct
difluoromethylation of 3- and 3, 5- substituted indoles. This methodology is useful as it does not require
any protecting or directing groups on the indole nitrogen. Additionally, the reaction utilizes the easily
synthesized CF2HPPh3Br, does not require expensive additives, and uses benign solvents as well as

ambient temperature. This reaction also represents a late stage functionalization of easily synthesized
substrates to afford the corresponding 2-CF2H indoles, which is beneficial when compared to other
routes the 2-CF2H indoles that require multistep synthesis of substrates, high reaction temperatures,
high catalyst loading, and can require the formation of the difluoromethyl unit post-reaction. Moderate
yields, and lacking generality in terms of substrate electronics and substitution patterns are both
drawbacks, but the possibility of improving this protocol has been established.
4. Experimental
1
NMR spectra were obtained either in CDCl3 or DMSOd6 using TMS as the internal standard for H
13
19
(300 MHz or 500 MHz as indicated) and C NMR (75 MHz), and CFCl3 for F NMR (282 MHz).
Reagents were purchased at commercial quality (Oakwood) and were used without further purification.
CF2HPPh3Br [20] and 3-arylindoles [21] were prepared according to the literature. Blue LED was
bought from FEIT Electric (16 W, 120 VAC, 60 Hz, 130 mA). High resolution mass spectrometric
measurements were performed by the University of Florida Department of Chemistry Mass
Spectrometry Services, using an Agilent 6220 Time-of-Flight (TOF) instrument.
General procedure for the photoredox direct synthesis of 2-difluoromethyl indoles (2a - o):
To an oven-dried 17 × 60 mm (8 mL) borosilicate vial equipped with a magnetic stirrer were added
the corresponding indole (0.1 mmol), fac-Ir(ppy)3 (1.3 mg, 0.002 mmol, 0.02 equiv) and K2CO3
(27.6 mg, 0.2 mmol, 2.0 equiv). To this mixture were added 1 mL acetone, and CF2HPPh3Br (78
mg, 0.2 mmol, 2 equiv) under a blanket of nitrogen. The vial was sealed, and stirred under blue
LED light at room temperature for 24 h. After this time, the solvent was removed in vacuo, and the
residue purified by column chromatography on silica gel eluting with hexanes/ethyl acetate. The Rf
values of the products are between 0.15 and 0.25 using 1% EtOAc/ hexanes and evolving to about
10% EtOAc/ hexanes.

4.1. 2-Difluoromethyl)-3-methyl-1H-indole (2a). 1H NMR (500 MHz, CDCl3) δ 8.2 (bs, 1H), 7.61 (d,
J = 8 Hz, 1H), 7.38 (d, J = 8.5 Hz, 1H), 7.29 (t, J = 8 Hz, 1H), 7.16 (t, J = 8 Hz, 1H), 6.94 (t, J = 51.2
Hz, 1H), 2.39 (s, 3H). 13C NMR (126 MHz, CDCl3) δ 135.7, 133.6, 128.7, 128.1, 124.2, 119.9, 119.7,
19
109.9 (t, JC-F = 234.6 Hz), 111.5, 8.2. F NMR (282 MHz, CDCl3) δ -110.7 (d, J = 54.4 Hz, 2F).
HRMS (-ESI-TOF): m/z Calcd. for [C10H9F2N]: 181.0703. Found: 180.0627 [M-H]-.
4.2. 2-Difluoromethyl)-3-phenyl-1H-indole (2b). 1H NMR (500 MHz, CDCl3) δ 8.57 (bs, 1H), 7.76 (d,
J = 7.8 Hz, 1H), 7.55-7.41 (m, 6H), 7.48 (d, J = 7.5 Hz, 1H), 7.21 (t, J = 7.8 Hz, 1H), 6.79 (t, J = 54
Hz, 1H).13C NMR (126 MHz, CDCl3) δ 136.7, 132.5, 129.6, 128.9, 127.4, 126.4, 124.7, 120.9, 120.6,
111.8, 110.7 (t, JC-F = 233Hz),. 19F NMR (282 MHz, CDCl3) δ -108.3 (d, J = 53.6 Hz, 2F). (-ESI-TOF):
m/z Calcd. for [C15H11F2N]: 243.0860. Found: 242.0789 [M-H]-.
1
4.3. 2-Difluoromethyl)-3-(4-methoxyphenyl)-1H-indole (2c). H NMR (500 MHz, CDCl3) δ 8.56 (bs,
1H), 7.73 (d, J = 8.1 Hz, 1H), 7.46 (m, 3H), 7.35 (t, J = 8.1 Hz, 1H), 7.20 (t, J = 7.2 Hz, 1H) 7.06 (d, J
= 8.7 Hz, 2H), 6.78 (t, J = 54 Hz, 1H), 3.89 (s, 3H). 13C NMR (126 MHz, CDCl3) δ 159.1, 135.7, 130.7,
126.6, 125.4, 124.8, 124.6, 114.4, 111.7, 110.2 (t, JC-F = 233 Hz), 55.4 (s). 19F NMR (282 MHz, CDCl3)
δ -108.2 (d, J = 53.6 Hz, 2F). (-ESI-TOF): m/z Calcd. for [C16H13F2NO]: 273.0965. Found: 272.0896
[M-H]-.
1
4.4. 3-(4-Bromophenyl)-2-(difluoromethyl)-1H-indole (2d). H NMR (500 MHz, CDCl3) δ 8.63 (bs,
1H), 7.65 (m, 3H), 7.38 (m, 4H), 7.22 (t, J = 7.5 Hz, 1H), 6.75 (t, J = 54 Hz, 1H). 13C NMR (126 MHz,
CDCl3) δ 135.6, 132.1, 131.5, 131.2, 126.2, 124.9, 121.6, 121.2, 120.3, 111.9, 109.9 (t, JC-F = 234 Hz).
19F NMR (282 MHz, CDCl3) δ -108.3 (d, J = 53.6 Hz, 2F). (-ESI-TOF): m/z Calcd. for [C15H10BrF2N]:
320.9965. Found: 319.9893 [M-H]-.

1
4.5. 3-(4-Chlorophenyl)-2-(difluoromethyl)-1H-indole (2e). H NMR (500 MHz, CDCl3) δ 8.58 (bs,
1H), 7.70 (d, J = 7.8 Hz, 2H), 7.47 (m, 5H), 7.37 (t, J = 7.5 Hz, 1H), 7.22 (t, J = 7.8 Hz, 1H), 6.76 (t, J
= 54 Hz, 1H). 13C NMR (126 MHz, CDCl3) δ 136.6, 133.5, 131.1, 130.8, 129.1, 126.3, 124.9, 121.1,
120.3, 118.7, 111.9, 109.9 (t, JC-F = 234 Hz). 19F NMR (282 MHz, CDCl3) δ -108.3 (d, J = 53.6 Hz,
2F). (-ESI-TOF): m/z Calcd. for [C15H10ClF2N]: 277.0470. Found: 276.0407 [M-H]-.
4.7. 2-(Difluoromethyl)-3-(4-nitrophenyl)-1H-indole (2f). 1H NMR (500 MHz, CDCl3) δ 8.78 (bs, 1H),
8.37 (d, J = 9 Hz, 2H), 7.74-7.67 (m, 3H), 7.53 (d, J = 8.1 Hz, 1H), 7.40 (t, J = 8.1 Hz, 1H), 7.27 (dt, J
= 8.1, 1.2 Hz, 1H), 6.78 (t, J = 53.6 Hz, 1H). 13C NMR (126 MHz, CDCl3) δ 146.9, 135.6, 132.1, 130.0,
125.8, 125.2, 124.3, 121.8, 120.0, 111.4, 109.5 (t, JC-F = 235 Hz). 19F NMR (282 MHz, CDCl3)
δ -
108.5 (d, J = 53.6 Hz, 2F). (-ESI-TOF): m/z Calcd. for [C15H9F2N2O2]: 288.0710. Found: 287.0649
[M-H]-.
4.8. 2-(Difluoromethyl)-1H-indole-3-carbaldehyde (2g). 1H NMR (500 MHz, DMSO-d6) δ 12.94 (bs,
1H), 10.23 (s, 1H), 8.17 (d, J = 8.4 Hz, 1H), 7.74 (t, J = 53.6 Hz, 1H), 7.55 (d, J = 8.4 Hz, 1H), 7.39-
7.26 (m, 2H). 13C NMR (126 MHz, DMSO-d6) δ 185.3, 138.1, 136.2, 125.4, 124.9, 123.5, 121.8, 116.1,
113.4, 109.9 (t, JC-F = 236 Hz). 19F NMR (282 MHz, CDCl3) δ -113.1 (d, J = 53.9 Hz, 2F). (+ESI-TOF):
m/z Calcd. for [C10H7F2NO]: 195.0496. Found: 196.0595 [M+H]+.
4.9. 3-((4-Chlorophenyl)thio)-2-(difluoromethyl)-1H-indole (2h). 1H NMR (500 MHz, CDCl3) δ 8.82
(bs, 1H), 7.61 (d, J = 8.1 Hz, 1H), 7.49 (d, J = 8.4 Hz, 1H), 7.37 (t, J = 8.1 Hz, 1H), 7.24-7.13 (m, 3H),
13
7.1 (t, J = 53.7 Hz, 1H), 7.0-6.9 (m, 2H). C NMR (126 MHz, CDCl3) δ 135.9, 133.7, 131.4, 129.0,
128.6, 127.7, 125.3, 121.8, 120.3, 112.2, 111.1, 109.0 (t, JC-F = 283 Hz). 19F NMR (282 MHz, CDCl3)
δ -111.7 (d, J = 53.6, 2F). (-ESI-TOF): m/z Calcd. for [C15H10ClF2NS]: 309.0191. Found: 308.0130
[M-H]-.

4.10. 2-(Difluoromethyl)-1H-indole (2i). 1H NMR (300 MHz, CDCl3) δ 8.41 (bs, 1H), 7.67 (d, J = 7.8
Hz, 1H), 7.44 (d, J = 8.1 Hz, 1H), 7.29 (t, J = 8.1 Hz, 1H), 7.17 (t, J = 7.8 Hz, 1H), 6.84 (t, JH-F = 55.5
Hz, 1H), 6.76 (s, 1H). 13C NMR (126 MHz, CDCl3) δ 136.2, 130.0 (t, JC-C–F = 24.2 Hz, C-CF2H), 126.9,
124.1, 121.6, 120.6, 111.6, 110.5 (t, J
= 233.4 Hz, CF2H), 103.9 (t, J
= 6.9 Hz, CH=C-
C–F
CH=C-C–F
CF2H). 19F NMR (282 MHz, CDCl3) δ -110.5 (d, J = 55.3 Hz, 2F). (-ESI-TOF): m/z Calcd. for
[C9H7F2N]: 167.0547. Found: 166.0479 [M-H]-.
4.11. 2-(Difluoromethyl)-5-methoxy-3-phenyl-1H-indole (2j). 1H NMR (500 MHz, CDCl3) δ 8.59 (bs,
13
1H), 7.66-7.36 (m, 7H), 7.12 (d, J = 9 Hz, 1H), 6.86 (t, J = 53.7 Hz, 1H), 3.94 (s, 3H). C NMR (126
MHz, CDCl3) δ 155.0, 132.7, 130.8, 129.5, 128.9, 127.3, 126.8, 126.4 (t, JC-C–F = 22.4 Hz), 119.7,
115.5, 112.7, 110.0 (t, JC-F = 234 Hz), 101.5, 55.9. 19F NMR (282 MHz, CDCl3) δ -108.2 (d, J = 53.6
Hz, 2F). (-ESI-TOF): m/z Calcd. for [C16H13F2NO]: 273.0965. Found: 272.0888 [M-H]-.
4.12. 2-(Difluoromethyl)-5-fluoro-3-phenyl-1H-indole (2k).1H NMR (500 MHz, CDCl3) δ 8.61 (bs,
1H), 7.55-7.47 (m, 4H), 7.45-7.35 (m, 3H), 7.12 (dt, J = 8.7, 1.8 Hz, 1H), 6.78 (t, J = 53.7 Hz, 1H). 13C
NMR (126 MHz, CDCl3) δ 182.7, 162.2, 130.3, 129.4, 129.0, 128.3, 127.6, 117.0 (d, J = 27.7 Hz),
113.4 (d, J = 8.8 Hz), 109.0 (t, JC-F = 230 Hz, CF2H), 106.5 (d, J = 24 Hz), 105.3. 19F NMR (282 MHz,
CDCl3) δ -108.6 (d, J = 53.6 Hz, 2F), -122.6 (td, 9, 4.5 Hz, 1F). (-ESI-TOF): m/z Calcd. for
[C15H10F3N]: 261.0765. Found: 260.0699 [M-H]-.
1
4.13. 5-Bromo-2-(difluoromethyl)-3-phenyl-1H-indole (2l). H NMR (500 MHz, CDCl3) δ 8.67 (bs,
1H), 7.85 (s, 1H), 7.54-7.34 (m, 7H), 6.76 (t, J = 53.4 Hz, 1H). 13C NMR (126 MHz, CDCl3) δ 182.6,
163.9, 162.7, 130.4, 129.6, 129.0, 128.4, 127.8, 123.2, 117.3, 113.9, 113.3, 109.7 (t, JC-F = 230 Hz).
19F NMR (282 MHz, CDCl3) δ -108.7 (d, J = 53.6, 2F). (-ESI-TOF): m/z Calcd. for [C15H10BrF2N]:
320.9965. Found: 319.9895 [M-H]-.

1
4.14. 4,6-Dichloro-2-(difluoromethyl)-3-phenyl-1H-indole (2m). H NMR (500 MHz, CDCl3) δ 8.66
13
(bs, 1H), 7.46-7.29 (m, 6H), 7.14 (d, J = 3 Hz, 1H), 6.49 (t, J = 53.7 Hz, 1H). C NMR (126 MHz,
CDCl3) δ 136.6, 131.5, 131.3, 130.9, 130.1, 127.9, 127.7, 127.5, 127.0, 125.6, 122.4, 121.9, 110.5,
109.4 (t, JC-F = 234.6 Hz). 19F NMR (282 MHz, CDCl3) δ -109.8 (d, J = 53.6 Hz, 2F). (-ESI-TOF): m/z
Calcd. for [C15H9 Cl2F2N]: 311.0080. Found: 310.0005 [M-H]-.
1
4.15. 2-(Difluoromethyl)-5-nitro-3-phenyl-1H-indole (2n). H NMR (500 MHz, CDCl3) δ 9.07 (bs,
13
1H), 8.69 (s, 1H), 8.26 (d, J = 9 Hz, 1H), 7.59. C NMR (126 MHz, CDCl3) δ 165.7, 144.4, 129.6,
19
129.3, 128.4, 128.3, 126.0, 120.1, 118.2, 112.0, 109.3. F NMR (282 MHz, CDCl3) δ -109.4 (d, J =
53.3 Hz, 2F). (+ESI-TOF): m/z Calcd. for [C15H10F2N2O2]: 288.0710. Found: 289.0792 [M+H]+.
1
4.16. 1-(2-(Difluoromethyl)-3-methyl-1H-indol-1-yl)ethan-1-one (2o). H NMR (500 MHz, CDCl3) δ
7.76-7.31 (m, 5H), 2.82 (s, 3H), 2.47 (t, 3H). 13C NMR (126 MHz, CDCl3) δ 169.6, 135.3, 130.6, 128.5,
126.4, 123.3, 122.4, 120.4, 114.4, 111.4 (t, JC-F = 239 Hz), 27.2, 9.28. 19F NMR (282 MHz, CDCl3) δ -
110.7 (d, J = 53.9 Hz, 2F). (+ESI-TOF): m/z Calcd. for [C12H11F2NO]: 223.0809. Found: 246.0710
[M+Na]+.
Acknowledgment:
We acknowledge funding from NIH S10 0D021758-01A1 (given to the UF mass spectrometry research
and education center).
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