Catalyst-Free and Redox-Neutral Innate Trifluoromethylation and Alkylation of Aromatics Enabled by Light

Article abstract of DOI:10.1021/jacs.7b08685

The Minisci alkylation is useful to functionalize aromatics via alkyl radical addition. Current approaches to prepare alkyl radicals follow either oxidative or reductive pathways from various functional groups. Developing new strategy beyond these traditional methods remains elusive yet highly significant. In this article, we present a redox-neutral and catalyst-free protocol to engender alkyl radicals in the context of trifluoromethylation and general alkylation of arenes. This protocol, via the Norrish type I concept to produce alkyl radicals, accommodates various functional groups and delivers the product in good yields. This method identified a series of compounds as the trifluoromethylation and alkylation reagents assisted by light. It is expected that these compounds can find potential applications in other radical-involved reactions.

Full text of DOI:10.1021/jacs.7b08685

Article
pubs.acs.org/JACS
Catalyst-Free and Redox-Neutral Innate Trifluoromethylation and
Alkylation of Aromatics Enabled by Light
Peng Liu,†,‡,§ Wenbo Liu,†,§ and Chao-Jun Li*,†
†Department of Chemistry and FQRNT Centre for Green Chemistry and Catalysis, McGill University, 801 Sherbrooke St. W.,
Montreal, Quebec H3A 0B8, Canada
‡Ministry of Education Key laboratory of Combinatorial Biosynthesis and Drug Discovery, Hubei Provincial Engineering and
Technology Research Center for Fluorinated Pharmaceuticals, School of Pharmaceutical Sciences, Wuhan University, Wuhan
430071, China
S
* Supporting Information
ABSTRACT: The Minisci alkylation is useful to functionalize
aromatics via alkyl radical addition. Current approaches to prepare
alkyl radicals follow either oxidative or reductive pathways from various
functional groups. Developing new strategy beyond these traditional
methods remains elusive yet highly significant. In this article, we
present a redox-neutral and catalyst-free protocol to engender alkyl
radicals in the context of trifluoromethylation and general alkylation of
arenes. This protocol, via the Norrish type I concept to produce alkyl radicals, accommodates various functional groups and
delivers the product in good yields. This method identified a series of compounds as the trifluoromethylation and alkylation
reagents assisted by light. It is expected that these compounds can find potential applications in other radical-involved reactions.
1. INTRODUCTION
The Minisci alkylation is a powerful tool to functionalize
aromatics via alkyl radical addition.1−4 Complementary to the
Friedel−Crafts alkylation, it is particularly effective to function-
alize electron-deficient aromatics. The original Minisci protocol
employs aliphatic carboxylic acids to generate alkyl radicals
through the oxidative decarboxylation.4 Numerous other
methods to prepare alkyl radicals have since been invented in
the context of Minisci alkylation. Current approaches to access
alkyl radicals consist of two general strategies: (a) the oxidative
and (b) the reductive approaches. Besides Minisci’s seminal
oxidative decarboxylation protocol using silver catalyst and
persulfate, other decarboxylative protocols were also estab-
lished, such as Barton’s decarboxylation,5−8 photoredox,9−18
and hypervalent iodine-based protocols.19,20 Besides aliphatic
carboxylic acids, other functional groups, including sulfi-
nates,21−27 boronates,28−36 and even carbon−hydrogen
Figure 1. Different approaches to access alkyl radicals for the Minisci
bonds37−48 among others,49 can also serve as the radical
alkylation.
precursors for the oxidative strategy.50,51 On the other hand,
the reductive strategy also found wide applications based on
various functional groups, including alkyl halides,52−59 sulfonyl
superstoichiometric amount (> 3 equiv), not only impair the
halides,60−63 and olefins.64−67 In addition, another useful
substrate scope and evoke chemoselectivity issues but also
generate obnoxious byproducts especially for large scale
synthesis. Therefore, redox-neutral protocols obviating these
external oxidizing and reducing reagents are desirable.73 In the
past few years, the photoredox catalysis is very successful along
this line.74−77 Nevertheless, various photocatalysts are
mandated to initiate the single electron transfer process, and
strategy involving alkyl halides to generate alkyl radicals is via
the homolytic radical substitution (SH2); for example, alkyl
iodides can be converted into alkyl radicals in the presence of
more reactive methyl or phenyl radicals to alkylate protonated
heteroaromatics in synthetically useful yields68−71 (Figure 1).
In terms of the redox-economy toward more sustainable
synthesis,72 the above-mentioned methods to access alkyl
radicals are not satisfying because of the involvement of harsh
oxidants and reductants. These redox reagents, often used in
Received: August 20, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/jacs.7b08685
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the generation of alkyl radicals in these protocols still follows
either reductive or oxidative mechanism. Accessing alkyl
radicals in a redox-neutral manner without external redox
reagents or photocatalysts remains unexplored yet highly
significant. In this article, we wish to report such an approach
enabled by a series of α-methyl-α-sulfone phenyl methyl
ketones as the alkylation regents assisted by light irradiation
(Figure 1).
2. RESULTS AND DISCUSSION
2.1. Research Design. It is well-established that alkyl
halides can undergo homolytic cleavage under light irradiation
to generate alkyl radicals in a redox-neutral manner.78−81 This
light-promoted approach is not applicable to the Minisci
alkylation82 due to two reasons: (1) insufficient concentration
of alkyl radical due to its reversible combination with halogen
radical generated simultaneously; (2) the more reactive halogen
radical would compete with the less reactive alkyl radical, which
makes the side reactions predominate.83 Therefore, to utilize
light to homolytically generate alkyl radical in a synthetically
useful way without the assistance of halogen radical trapper,84
the following criteria should be met: (1) the undesired twin
radical is less reactive than the target alkyl radical; (2) the
reversible reaction of homolytic cleavage should be inferior to
the desired Minisci alkylation. We hypothesized that these
requirements can be met when the undesired radical is also a
carbon radical: (1) since they are both carbon radicals, the
target alkyl radical would at least bear a comparable reactivity
with the undesired carbon radical; (2) the reactivity of the
undesired carbon radical could be further diminished through
modulating its electronics and sterics thanks to the wealth of
knowledge of carbon radical.66,85−89
Figure 2. Norrish type I reactions toward the Minisci alkylation.
The Norrish type I reaction refers to the homolytic α-
cleavage of carbonyls.90 This reaction engenders a pair of
carbon radicals, one of which is an acyl radical (Figure 2a). The
acyl radical further undergoes decarbonylation to produce
another alkyl radical. Such a reaction is valuable to construct
carbon−carbon bonds via intramolecular decarbonylation as
only one potential product can be formed (Figure 2b).91,92 In
contrast, its intermolecular counterpart is typically not
synthetically useful due to the presence of multiple radicals
(Figure 2c). Inspired by Garcia-Garibay’s elegant work on
engineering Norrish I reaction93−99 and the so-called
“captodative effect”,100,101 we considered that using a stabilized
dummy substituent R1 might solve the regioselectivity issue:
(1) the α-cleavage would prefer the pathway to produce the
more stable dummy radical R1, which generates the desired
radical in a more selective way; (2) the more stable dummy
radical R1 is less reactive, which could not compete with the
target radical to react with the aromatics and the desired
Minisci product would prevail (Figure 2d). Therefore, a
hypothesis to alkylate aromatics based on the Norrish I
concept can be proposed (Figure 2e). With these in mind, we
embarked on identifying a proper dummy substituent R.1
2.2. Library Screening for Trifluoromethylation. In
surveying the context of Minisci alkylation, we recognized that
trifluoromethylation is a good starting point. Trifluoromethy-
lation of aromatics is highly important in the pharmaceutical
industry and material chemistry.102−109 Various trifluorome-
thylation protocols have been developed via using electrophilic,
nucleophilic, and radical trifluoromethyl reagents. Considering
the mild conditions, broad functional group compatibility and
avoidance of prefunctionalization and directing groups, innate
trifluoromethylation of aromatics via radical addition is superior
to other metal-involved approaches.106,110−112 In this regard,
the state-of-the-art methods are represented by exploiting metal
trifluoromethylsulfinates under oxidative conditions21,113 and
photoredox catalysis via CF3SO2Cl and others under reductive
conditions.60,114−116 Despite there being some early reports
about homolytically generating CF3 radical via using
CF3I,117−121 bis(trifluoromethyl)peroxide,122 or CF3SO2Cl123
under thermal or light conditions, the reactions are extremely
sluggish perhaps due to the interference of untamed halogen
radicals. Moreover, the gaseous CF3I, bis(trifluoromethyl)-
peroxide, and volatile CF3SO2Cl are not convenient to store
and handle, especially in the pharmaceutical industry. There-
fore, developing a readily synthesized and stable CF3 radical
source, which can be used in a redox-neutral reaction, is both
conceptually important and synthetically practical.
Following the hypothesis demonstrated in Figure 2d, a
library comprising a wide array of trifluoromethyl compounds
was constructed. Given the ease of structural analysis, 1,3,5-
trimethoxybenzene was selected as the substrate to evaluate the
feasibility of different trifluoromethylation reagents (Table 1).
Under light irradiation, regular ketones, esters, and oxime124
with CF3 group did not produce any product (1−6) and α-
diketone 7 only delivered the product in 9% yield. Considering
the lower carbon−sulfur bond strength than carbon−carbon
bond and more rapid kinetics of desulfonylation than
decarbonylation,125,126 we turned our attention to trifluor-
omethyl sulfones.127−129 Although sulfone 8 failed to give any
product, a 10% yield could be detected with 9 as the CF3
B
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a
Table 1. Evaluations of Different Trifluoromethyl
Table 2. Scope of the Arenes for the Trifluoromethylation
Compounds
a
All the reactions were conducted with 1,3,5-trimethoxybenzene (0.05
mmol) and CF3 source (0.075 mmol) in 0.25 mL of CH3CN under
argon for 12 h at rt (ca. 25 °C), and the reaction yields were quantified
1
by H NMR via mesitylene as the internal standard except 14.
source. Introducing a second methyl group did not increase the
yield (10). Fortunately, when the dummy groups were aryl
methyl ketones (11−13), the yields were significantly enhanced
(20%−72%).130 Further adding one methyl group to the
methylene carbon of 11 raised the isolated yield of the desired
trifluoromethyl product to 96% (14). The high reactivity of 14
is attributed to the stabilizing effect of both carbonyl and
methyl groups (the so-called “captodative effect”),100,101 as well
as the steric bulkiness. The stabilizing effect induces the ease to
undergo the homolytic cleavage, and the bulky environment
induces its lower capacity to react with the aromatic than with
trifluoromethyl radical.
After identifying the appropriate compound (14), we further
evaluated the scope of this trifluoromethylation reagent toward
both aromatics and heteroaromatics (Table 2). To our delight,
they were both compatible with our protocol. With respect to
the aromatics, we observed good to excellent yields with many
functional groups such as methoxy (15, 19), benzylic methyl
(16), ester (17), ketone (18), and phenol (21). Not only the
electron-rich aromatics but also regular aromatics without
electron donating groups can deliver the trifluoromethylation
products smoothly (20, 22). Regarding the heteroaromatics,
pyrrole (23), unprotected indoles (24, 25, and 26), caffeine
(27), imidazoles (28, 29), flavonoid (30), nucleosides (31, 32),
and even amino acid (33) and peptide (34) were applicable.
The broad functional group compatibility suggests the
usefulness of this reagent in the context of trifluoromethylation.
Moreover, UV−vis spectrum indicates that this trifluorome-
thylation reagent 14 has light absorption around 380 nm (UVA
region) (Figure 3), which overlaps with the emission spectrum
of a household compact fluorescence lamp (CFL).131 To
further demonstrate the flexibility and robustness of this
reagent, we found that a simple household CFL could be
employed as the light source to promote the reactions (Table
a
All the reactions were conducted with arene (0.1 mmol), CH3CN
(0.5 mL), and 300 W xenon lamp under argon with specified amount
of CF3 source 14 at rt (ca. 25 °C), and the yields are isolated ones.
b
c
d
e
1.5 equiv of 14. 3.0 equiv of 14. 2.0 equiv of 14. Yields were
f
quantified by GC-MS due to volatility of products. H2O, 0.1 mL, was
added into 0.5 mL of CH3CN.
3). The lower yields driven by CFL than those by regular xenon
lamp can be attributed to the lower conversion of the starting
material. Prolonging the reaction time can enhance the
conversion rate and consequently the reaction yields.
2.3. Application to the Alkylation. After successfully
applying 14 to trifluoromethylate aromatics, we decided to
further extend this concept into a more general strategy for the
C
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Table 4. Optimization for the Isopropylation of 2-
Phenylquinoline
a
b
entry
solvent
TFA (equiv)
T (°C)
yield (%)
1
CH3CN
acetone
acetone
acetone
acetone
CH3CN
DCM
1
1
rt
rt
7
13
22
51
68
19
12
3
2
3
1
50
50
50
50
50
50
50
50
50
80
80
4
3
5
10
10
10
10
10
10
10
10
20
Figure 3. UV−vis of 14.
6
7
Table 3. Household CFL as light source to promote the
8
DMF
a
trifluoromethylation
9
DMSO
EtOAc
MeOH
acetone
acetone
10
19
15
75
81
10
11
12
13
a
All the reactions were conducted with 0.1 mmol of 35 and 0.15 mmol
of 36 in 0.5 mL solvent with a 300 W mercury lamp under argon for
b
10 h. The yield was determined by GC/MS.
examined (Table 5). Different substituents such as phenyl
(37), methyl (38), methoxy (39, 40), ester (41), −CN (42),
and −Cl (45) can all be tolerated. Both the 2 and 4 positions of
the quinoline can be alkylated in good yields (44−49). Besides
the quinoline, a wide range of heteroarenes such as pyridine
(50), benzothiazole (51), acridine (52), phenanthridine (53),
caffeine (54), and purine (55) can also be tolerated.
Unfortunately, the regular electron-deficient arenes such as
ethyl benzoate and benzonitrile are not applicable to this
protocol. Regarding the substrates with more than one reactive
site, different regioisomers could be detected (56, 57) (Table
5).
Subsequently, other alkyl substituents were also evaluated
(Table 6). It was found that primary (58−60, 68), secondary
(61, 65−67), and tertiary alkyl groups (62) can all alkylate the
heteroarenes in good yields (32−72%) even with only 1.5 equiv
of alkylation reagents. Interestingly, benzyl (63) and methyl
groups (64) are not applicable in this alkylation reaction. The
failure to produce 63 is perhaps due to the relative high stability
of benzyl radical, which would undergo other side reactions
faster than the desired radical addition. The fact that methyl
radical is not suitable in this reaction (64) is perhaps due to its
high energy, which makes its generation via this approach
difficult.134
a
All the reactions were conducted with arene (0.1 mmol), 14 (0.15
mmol), CH3CN (0.5 mL), and 45 W CFL under argon for 48 h, and
the yields are isolated ones, which are followed by the conversion in
the parentheses. The conversion was calibrated by H NMR. The
conversion was calibrated by GC/MS. This yield was determined by
GC/MS due to its volatility.
b
c
1
d
alkylation.32,132 Different from the electrophilic CF3 radical, the
nucleophilic alkyl radical tends to react with the electron-
deficient heteroaromatics in acidic conditions. Therefore, the
reaction between 2-phenyl quinoline 35 and isopropyl radical
source 36 was selected as the model considering the
significance of the quinoline scaffold in oncology drug
discovery133 (Table 4). Initially, the same solvent, CH3CN,
for the trifluoromethylation was employed with 1 equiv of TFA
at rt. To our delight, the desired alkylation product could be
detected in 7% yield (entry 1). When the solvent was switched
to acetone, the product was obtained in 13% yield (entry 2).
Further increasing the temperature to 50 °C raised the yield to
22% (entry 3). Moreover, increasing the amount of TFA would
boost the yield to 68% (entries 4 and 5). In addition, solvent
screening indicated that acetone was the best solvent (entries
6−11). A higher temperature of 80 °C would enhance the yield
to 75% (entry 12). Finally, it was found that more TFA would
result in the product in the yield of 81% (entry 13).
3. CONCLUSION
Although the Norrish type I reaction has been uncovered for
more than 80 years, synthetic examples to apply this reaction,
especially in an intermolecular version, are rare. Herein, we
demonstrated such a synthetic application via the Norrish type
I concept. The benefit via the Norrish type I process is to
generate alkyl radical without redox process, implying that the
SET initiators and external redox reagents can be avoided.
Consequently, a general approach to trifluoromethylate and
alkylate (hetero)aromatics in a redox-neutral manner without
any catalyst was developed. Notably, the trifluoromethylation
can be conducted at room temperature via a household CFL as
After the optimized reaction conditions of isopropylation
were established, the scope of the heteroaromatics was
D
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a
a
Table 5. Scope of the Heteroarenes for the Alkylation
Table 6. Scope of the Alkyl Groups for the Alkylation
a
All the reactions were conducted with 0.1 mmol of heteroarene and
0.15 mmol of alkylation reagents in 0.5 mL of acetone with a 300 W
mercury lamp under argon for 10 h, and the yields are isolated ones.
generation of UV light requires relatively special equipment
compared to the photoredox chemistry. Reagents that are active
under the visible light region are more ideal. Nonetheless, it is
hoped that these compounds would find potential applications
in other radical-involved reactions with the benefit to avoid the
catalysts and external oxidants or reductants.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/jacs.7b08685.
■
S
Experimental procedures, characterization data, NMR
spectra, photographs of lamp used in the study, UV-vis
absorption spectrum of compount 36, and optimization
of trifluoromethylation with CFL light source (PDF)
AUTHOR INFORMATION
Corresponding Author
*cj.li@mcgill.ca
ORCID
■
a
All the reactions were conducted with 0.1 mmol heteroarene, 0.12
mmol of 36 in 0.5 mL of acetone with a 300 W mercury lamp under
argon for 10 h. isolated yield and the ratio of different isomers for 56
and 57 was determined by GC/MS.
b
Chao-Jun Li: 0000-0002-3859-8824
Author Contributions
the light source. The success of this approach hinges upon the
identification of a series of sulfone compounds, which can be
homolytically cleaved under light irradiation. These trifluor-
omethylation and alkylation reagents are stable to air and water,
are soluble in all common organic solvents, and can be readily
synthesized from cheap starting materials.130,135−139 Despite
these advantages, some limitations are still associated with this
protocol, one of which is the involvement of UV light. The
§P. Liu and W. Liu contributed equally to this work.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
We are grateful to the Canada Research Chair Foundation (to
C.-J.L.), the CFI, FQRNT Center for Green Chemistry and
■
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(32) Matsui, J. K.; Primer, D. N.; Molander, G. A. Chem. Sci. 2017, 8,
3512−3522.
Catalysis, NSERC, and McGill University for support of our
research. P.L. is grateful to China Scholarship Council, and
W.L. is grateful to McGill Chemistry Department for fellowship
support.
́ ́
(33) Castro, S.; Fernandez, J. J.; Fananas, F. J.; Vicente, R.;
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