Photoredox-Catalyst-Enabled para-Selective Trifluoromethylation of tert-Butyl Arylcarbamates

Article abstract of DOI:10.1002/anie.202105631

The direct incorporation of a trifluoromethyl group on an aromatic ring using a radical pathway has been extensively investigated. However, the direct highly para-selective C?H trifluoromethylation of a class of arenes has not been achieved. In this study, we report a light-promoted 4,5-dichlorofluorescein (DCFS)-enabled para-selective C?H trifluoromethylation of arylcarbamates using Langlois reagent. The preliminary mechanistic study revealed that the activated organic photocatalyst coordinated with the arylcarbamate led to para-selective C?H trifluoromethylation. Ten-gram scale reaction performs well highlighting the synthetic importance of this new protocol.

Full text of DOI:10.1002/anie.202105631

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How to cite:
International Edition: doi.org/10.1002/anie.202105631
German Edition: doi.org/10.1002/ange.202105631
Trifluoromethylation
Photoredox-Catalyst-Enabled para-Selective Trifluoromethylation of
tert-Butyl Arylcarbamates
Yaqiqi Jiang+, Bao Li+, Nana Ma, Sai Shu, Yujie Chen, Shan Yang, Zhibin Huang, Daqing Shi,*
and Yingsheng Zhao*
À
Abstract: The direct incorporation of a trifluoromethyl group
on an aromatic ring using a radical pathway has been
extensively investigated. However, the direct highly para-
to realize para-selective C H trifluoromethylation reactions.
The CF3 moiety is an important functional group in drug
candidates, as it imparts stability during oxidative metabo-
lism, and improves the solubility, lipophilicity, and anti-
oxidizability of bioactive compounds.[10] Hence, the develop-
ment of practical strategies for the preparation of trifluor-
omethylated compounds has always been an important topic
in synthetic chemistry. The MacMillan[11] group initially
demonstrated that a CF3 radical (generated using CF3SO2Cl
as the CF3 radical precursor) reacted directly with aromatic
compounds to yield trifluoromethylated products (Figure 1).
À
selective C H trifluoromethylation of a class of arenes has
not been achieved. In this study, we report a light-promoted
À
4,5-dichlorofluorescein (DCFS)-enabled para-selective C H
trifluoromethylation of arylcarbamates using Langlois reagent.
The preliminary mechanistic study revealed that the activated
organic photocatalyst coordinated with the arylcarbamate led
À
to para-selective C H trifluoromethylation. Ten-gram scale
reaction performs well highlighting the synthetic importance of
this new protocol.
À
T
he site-selective functionalization of a specific C H bond
poses significant challenges in synthetic chemistry. To this
À
point, various approaches to realize selective C H function-
alizations have been extensively explored. For example, the
directing group strategy provided an effective way to achieve
[2]
the ortho[1] or meta -selective C H functionalizations. The
À
application of noncovalent interactions served as another
À
pathway to perform meta or para-selective C H functional-
izations, which have been cleverly developed by the groups of
Nako,[3] Chattopadhyay,[4] Kuninobu,[5] Kanai,[6] Phipps,[7] and
Yu[8] groups. A recent report on a cyclometalated ruthenium
À
À
Figure 1. C H trifluoromethylation. a) Direct C H trifluoromethyla-
À
À
complex indicated uniquely promoted remote, selective C H
tion. b) This work: Organic photocatalyst-enabled para-selective C H
trifluoromethylation.
functionalizations, in which it acted as a strong bulk-
electronic-transient-metal functional group.[9] Although
these methods greatly improved routes to selectively install
a functional group on arenes, there is still no efficient method
Later, other reagents, such as Tf2O,[12] ArI(OCOCF3),[13] CF3-
containing sulfones,[14,15] CF3X,[16] (CF3CO)2O,[17] and Togni
reagents[18] were all used to introduce a CF3 group successfully
onto an aromatic ring via a free-radical mechanism. But the
lack of site selectivity of these methods has always posed
a problem and considerably affected the use of these routes in
synthetic chemistry. Herein, we report an organic photo-
catalyst 4,5-dichlorofluorescein (DCFS)-enabled para-selec-
tive trifluoromethylation of anilides through a novel radical/
radical cross-coupling pathway. Various arylcarbamates were
suitable for this reaction and led to the formation of para-
trifluoromethylated products in moderate to good yields.
Importantly, several bioactive compounds, such as chlorzox-
azone,[19] a vorinostat precursor, chlorpropham and a teriflu-
nomide precursor were also well suited. The ten-gram scale
reaction further highlights the importance of this new
synthetic method. A study of the reaction mechanism
revealed the activated organic photocatalyst coordinated
with the arylcarbamate to alter the spatial environment of
the ortho and meta positions on the phenyl ring and was the
key to achieve para-selectivity.
[*] Y. Jiang,[+] S. Shu, Y. Chen, S. Yang, Z. Huang, Prof. Dr. D. Shi,
Prof. Dr. Y. Zhao
Key Laboratory of Organic Synthesis of Jiangsu Province
College of Chemistry, Chemical Engineering and Materials Science
Soochow University, Suzhou 215123 (P. R. China)
and
School of Chemistry and Chemical Engineering
Henan Normal University, Xinxiang 453000 (P. R. China)
E-mail: dqshi@suda.edu.cn
yszhao@suda.edu.cn
B. Li,[+] N. Ma
Collaborative Innovation Center of Henan Province for Green
Manufacturing of Fine Chemicals, Key Laboratory of Green Chemical
Media and Reactions, Ministry of Education, School of Chemistry
and Chemical Engineering, Henan Normal University
Xinxiang 453000 (P. R. China)
[+] These authors contributed equally to this work.
Supporting information and the ORCID identification number(s) for
the author(s) of this article can be found under:
https://doi.org/10.1002/anie.202105631.
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Aniline is an important compound and a key skeletal
component in various drugs and natural products.[20] Among
could lead to a considerable improvement in yield and
selectivity (80%, para/ortho > 20/1). The other oxidants such
as (NH4)2S2O8, TBHP, and Na2S2O8 were further tested;
however, none can give better yields than that of K2S2O8 (see
the Supporting Information). Control experiments showed
that potassium persulfate and photoredox catalysts were both
indispensable for this transformation.
À
the reported direct C H trifluoromethylation reactions,
À
ortho-selective C H trifluoromethylation of anilides has
been well developed.[21] However, direct para-selective C H
trifluoromethylation has always posed
À
a
challenge.[22]
Recently, the site-selective introduction of a CF3 group onto
arenes was accomplished via the radical route reported by
Ritter et al.[23] However, only one example of a trifluoroace-
tyl-protected aniline was used as the substrate; the two-step
procedure and complex reaction conditions slightly limited
reaction feasibility. Recently, our group discovered the steric
hindrance of a ligand significantly affected site-selectivity
when the free radical reacted with aromatic rings;[24] there-
fore, a matched catalyst would coordinate with the protected
aniline, change the spatial environments of the ortho and meta
positions, and might lead to a para-selective trifluoromethy-
lation.
With the optimized reaction protocol, we next screened
protecting groups for photoredox catalyst-enabled light-
À
induced
para-selective
C H
trifluoromethylation
(Scheme 1). We found ethyl-, n-butyl-, and i-butyl-N-phenyl-
With these conditions in mind, Langlois reagent
(CF3SO2Na) was selected as the source of CF3 radicals
owing to its low toxicity and cost, and the commonly used tert-
butoxycarbonyl- protected aniline was shortlisted as the
standard substrate. First, tert-butyl carbanilate (1a) was
directly treated with CF3SO2Na (2) and potassium persulfate
(3 equiv) in the presence of the photoredox catalyst (2 mol%)
in acetonitrile at room temperature for 11 h (Table 1). The
photoredox catalysts fac-Ir(ppy)3 and Ru(Phen)3Cl2 provided
the trifluoromethylated product in low yields; meanwhile, the
ortho and para selectivity was rather poor. Several organic
photoredox catalysts, such as Eosin B, TPT (2,4,6-triphenyl-
pyrylium tetrafluoroborate), and Fluorescein were further
investigated. Interestingly, better selectivity and yield was
obtained when fluorescein was used as the catalyst. Several
fluorescein derivatives were further screened and we found
that 4,5-dichlorofluorescein (DCFS) could be used to gen-
erate the para-trifluoromethylated product 3a in 57% yield
with high site-selectivity. Next, we screened solvents including
DMSO, acetone, DCM, and DMF, and found that DMSO
Scheme 1. Comparison of different protecting groups.[a] [a] Reaction
conditions: 1 (0.2 mmol), 2 (2 equiv), DCFS (2 mol%), K2S2O8
(3 equiv), DMSO (2 mL) at room temperature (23–258C) using
irradiation with 40 W blue LEDs for 11 h, isolated yield.
carbamates to be good substrates, which led to the corre-
sponding product in good yields (3b–3e). The use of Cbz-
protected aniline resulted in a single para-trifluoromethylated
product 3e in 66% yield. Unfortunately, N-phenylbenzamide
and trifluoro-N-phenylmethanesulfonamide were completely
unreactive, along with starting material recovery. The sub-
strate 1 f, which is a key precursor of teriflunomide, could be
transformed into product 3 f with an acceptable yield. Further
study revealed that 2-benzoxazolinone was also an effective
substrate, affording a highly para-selective trifluoromethy-
lated product 3g in 57% yield.
Encouraged by these promising results, we next examined
if Boc-protected aniline derivatives could be tolerated in the
para-selective trifluoromethylation. Gratifyingly, both ortho
and meta-substituted aniline derivatives were well tolerated
and afforded the corresponding products in moderate to good
yields (Scheme 2). The functional groups, including OMe,
OEt, OBn, Me, Et, Ac, Cl, Br, and OCF3, were well tolerated
and led to the corresponding products in moderate to good
yields (5a–5k, 5m). It is noteworthy that the sensitive iodo
group on the meta-position was also a good substrate, which
led to the trifluoromethylated product 5l in 67% yields.
Unfortunately, the use of N-Boc-3-(trifluoromethyl)aniline
only afforded the trifluoromethylated product in 39% yield
(5p), along with recovery of the starting material. This is
likely due to the strong electron-withdrawing effect of the
trifluoromethyl group, which affected the reactivity of the
aromatic ring. Interestingly, when tert-butoxyacyl-protected
m-phenylenediamine 1n was used, a mixture of mono and di-
trifluoromethylated products were obtained in a total yield of
91% (m/d = 1.45). When the quantity of CF3SO2Na was
Table 1: Optimization of reaction conditions.[a]
(3a+3a’)
Yield [%]
3a/3a’
(p/o)
Entry
Photocatalyst
Oxidant
Solvent
1
2
3
4
5
6
7
8
9
fac-Ir(ppy)3
Ru(Phen)3Cl2
Eosin B
TPT
Fluorescein
DCFS
DCFS
DCFS
–
K2S2O8
K2S2O8
K2S2O8
K2S2O8
K2S2O8
K2S2O8
K2S2O8
–
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
DMSO
DMSO
DMSO
21
11
21
35
37
57
80
trace
trace
2:1
3:2
5:1
6:1
9:1
13:1
>20:1
K2S2O8
[a] Reaction conditions: 1a (0.2 mmol), 2 (2 equiv), DCFS (2 mol%),
K2S2O8 (3 equiv), DMSO (2 mL) at room temperature (23–258C) using
irradiation with 40 W blue LEDs for 11 h. Yields were based on GC with
tridecane as the internal standard.
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Scheme 3. Synthetic application. [a] Reaction conditions: substrate
(0.2 mmol), 2 (2 equiv), DCFS (2 mol%), K2S2O8 (3 equiv), DMSO
(2 mL) at room temperature (23–258C) using irradiation with 40 W
blue LEDs for 11 h, isolated yield. [b] Propham (8 mmol), 2 (2 equiv),
DCFS (2 mol%), K2S2O8 (3 equiv), DMSO (40 mL) at room temper-
ature (23–258C) using irradiation with 40 W blue LEDs for 11 h,
isolated yield. [c] Aripiprazole (0.2 mmol), 2 (2 equiv), DCFS (5 mol%),
(NH4)2S2O8 (3.5 equiv), DMSO (2 mL) at room temperature (23–
258C) using irradiation with 40 W blue LEDs for 15 h, isolated yield.
We further demonstrated that the reaction could be scaled up
to gram level for Propham, leading to trifluoromethylated
propham in 65% yield (1.28 g) (Scheme 3, 9). Impressively,
the ten-gram reaction is possible for this transformation,
highlighting the importance of this new protocol (Scheme 3,
b).
Several control experiments were performed to under-
stand the reaction route for this transformation. First, radical-
trapping experiments were performed, and the radical
scavenger TEMPO or BHT could both arrest this trans-
formation.[21] When 1,1-diphenylethylene was used as the
radical scavenger, compound 11 was formed in 41% yields
(Scheme 4a). We found that product 12 could be detected by
using HRMS[25] with the BHT as the radical scavenger
(Scheme 4b). These results suggested that a free-radical
pathway was the mechanism of this reaction wherein an
arene radical was formed through the single electron transfer
(SET) process.
When fac-Ir(ppy)3 and Ecosin Y were used instead of the
photoredox catalyst DCFS, a mixture of ortho and para-
trifluoromethylated products was obtained (Scheme 5a).
Based on the findings from our previous study, we speculated
that DCFS will interact with N-Boc-anilines. Based on this
Scheme 2. Substrate scope of the aniline derivatives.[a] [a] Reaction
conditions: 1a or 4 (0.2 mmol), 2 (2 equiv), DCFS (2 mol%), K2S2O8
(3 equiv), DMSO (2 mL) at room temperature (23–258C) using
irradiation with 40 W blue LEDs for 11 h, isolated yield. [b] 1.5 equiv
CF3SO2Na was used. [c] 4 (0.2 mmol), 2 (2 equiv), DCFS (5 mol%),
(NH4)2S2O8 (3.5 equiv), DMSO (2 mL) at room temperature (23–
258C) using irradiation with 40 W blue LEDs for 15 h, isolated yield.
reduced (1.5 equiv), the trifluoromethylated product 5n was
obtained in 88% yield with trace amounts of the double-
trifluoromethylated product. Next, a more challenging syn-
thetic route was undertaken and N-Boc-protected disubsti-
tuted anilines were subjected to standard conditions. Each of
these substrates afforded para-trifluoromethylated products
in good yields (5q–5z). Impressively, the 2,6-disubstituted
anilines were compatible, leading to the trifluoromethylated
product in good yields (5w, 5x). It is worth noting that
although various approaches have been reported to achieve
À
C H trifluoromethylation, none of these studies mention
para-trifluoromethylation data of the substituted aniline
derivatives.
Owing to the importance of incorporation of the CF3
group into arenes, it would be highly attractive to introduce
a trifluoromethyl group on bioactive compounds. We found
À
that this photoredox catalyst could promote para-selective C
H trifluoromethylation, and could, therefore, be used to
functionalize several well-known drugs and chemicals includ-
ing Propham, Chlorpropham, Chlorzoxazone, the key pre-
cursor of Vorinostat and Aripiprazole (Scheme 3, 6–8, 10).
Scheme 4. Free radical trapping experiments.
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In regard to these results, we may speculate that the steric
effect of the photoredox catalyst DCFS would alter the spatial
environment of the ortho and meta positions on the phenyl
À
ring, which would cause the highly para-selective C H
trifluoromethylation. Although the mode of the reaction is
not clear, an interaction of activated DCFS with N-Boc-
anilines via intermolecular hydrogen bonds is likely (see the
Supporting Information).
Based on our results and previously published studies,
a plausible reaction mechanism was proposed (Scheme 6). A
trifluoromethyl radical was produced using an established
process with 4,5-DCFS as an organic photocatalyst and
K2S2O8 as the oxidant. The DCFS·+ provided the key
intermediate I through the SET process, which further
Scheme 6. Plausible mechanism.
Scheme 5. Preliminary mechanistic studies.
tautomerized to yield intermediates II and III with the
activated DCFS. The steric effect of DCFS would increase the
steric hindrance of the ortho and meta positions on the phenyl
ring, thereby leading to the highly para-selective trifluoro-
methylation. However, it cannot be completely ruled out that
the free trifluoromethyl radical reacted with the DCFS-
activated phenyl ring.
hypothesis, experiments involving UV treatment were carried
out. We found that a new peak was generated when N-Boc-
anilines combined with DCFS (Scheme 5b). Fluorescence
quenching experiments[26] of fluorescence show the quenching
effect with 1a. The Stern–Volmer plot indicates that the
excited state of DCFS was quenched by 1a and the quenching
effect increased with the increase of the concentration of 1a
(see the Supporting Information for more details). These
results indicate that there is a weak interaction between
DCFS and the substrate during the catalytic cycle. However,
1H-NMR data do not reveal a clear interaction of the
substrate and catalyst (see the Supporting Information). It
may suggest the weak interaction between N-Boc-aniline and
the catalyst should be under the light. The substrate 13 can
also provide the tyrifluoromethylated product 14, and the
deuterium hydrogen completely retained. It may support our
hypothesis that intermediate A and B were formed during the
catalytic cycle, while intermediate C and D cannot be formed
(Scheme 5c). While tert-butyl methyl(phenyl)carbamate was
used, the starting material was completely recovered
(Scheme 5d, 1). Interestingly, the phenyl phenylcarbamate,
which has two electron-rich phenyl rings, afforded compound
18 in 62% yield, whereas compound 19 was not formed
(Scheme 5d, 2). These results indicated the importance of the
To summarize, we developed a photoirradiation reaction
À
and achieved DCFS-enabled para-selective C H trifluoro-
methylation of arylcarbamates using Langlois reagent. Sev-
eral arylcarbamates were found to be well-suited for this
reaction and led to the formation of para-trifluoromethylated
products in moderate to good yields. Importantly, several
bioactive compounds, such as chlorzoxazone, vorinostat
precursor, chlorpropham, and teriflunomide precursor, were
also found to be suitable. The preliminary mechanistic study
revealed that the activated organic photocatalyst coordinated
with the arylcarbamate to alter the spatial environments of
the ortho and meta positions on the phenyl ring and led to
para-selectivity.
Acknowledgements
This work was supported by Natural Science Foundation of
China (Nos. 21772139), the Major Basic Research Project of
the natural Science Foundation of Jiangsu Higher Education
Institutions (17KJA150006), the Jiangsu Province Natural
À
N H bond and further offer further evidence that the
photoredox catalyst DCFS had a weak interaction with the
substrate in the presence of light.
4
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Conflict of Interest
The authors declare no conflict of interest.
Keywords: photoirradiation · site selectivity · ten gram scale ·
trifluoromethylation
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Manuscript received: April 26, 2021
Revised manuscript received: June 22, 2021
Accepted manuscript online: June 23, 2021
Version of record online: && &&, &&&&
Angew. Chem. Int. Ed. 2021, 60, 1 – 6
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These are not the final page numbers!

Angewandte
Communications
Chemie
Communications
Trifluoromethylation
Y. Jiang, B. Li, N. Ma, S. Shu, Y. Chen,
S. Yang, Z. Huang, D. Shi,*
Y. Zhao*
&&&& — &&&&
Photoredox-Catalyst-Enabled para-
Selective Trifluoromethylation of tert-
Butyl Arylcarbamates
We report a light-promoted 4,5-dichloro-
fluorescein (DCFS)-enabled para-selec-
precursor, chlorpropham, and teri-
flunomide precursors, were suitable for
this reaction, leading to the formation of
the corresponding products in moderate
to good yields.
À
tive C H trifluoromethylation of arylcar-
bamates using the Langlois reagent.
Arylcarbamates, including the bioactive
compound chlorzoxazone, vorinostat
6
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ꢀ 2021 Wiley-VCH GmbH
Angew. Chem. Int. Ed. 2021, 60, 1 – 6
These are not the final page numbers!