Visible-light photoredox catalyzed cyclization of aryl alkynoates for the synthesis of trifluoromethylated coumarins

Article abstract of DOI:10.1016/j.catcom.2018.06.009

A strategy for the synthesis of coumarin derivatives via visible-light photoredox catalysis has been developed using fac-Ir(ppy)₃ as the photocatalyst under mild conditions. Trifluoromethanesulfonyl chloride is utilized as the trifluoromethylat

Full text of DOI:10.1016/j.catcom.2018.06.009

Accepted Manuscript
Visible-light photoredox catalyzed cyclization of aryl alkynoates
for the synthesis of trifluoromethylated coumarins
Mei-jie Bu, Guo-ping Lu, Chun Cai
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doi:10.1016/j.catcom.2018.06.009
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11 June 2018
Please cite this article as: Mei-jie Bu, Guo-ping Lu, Chun Cai , Visible-light photoredox
catalyzed cyclization of aryl alkynoates for the synthesis of trifluoromethylated coumarins.
Catcom (2017), doi:10.1016/j.catcom.2018.06.009
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ACCEPTED MANUSCRIPT
Visible-Light Photoredox Catalyzed Cyclization of Aryl Alkynoates for the Synthesis
of Trifluoromethylated Coumarins
Mei-jie Bua, Guo-ping Lua, Chun Caia,b,
a Chemical Engineering College, Nanjing University of Science & Technology, 200 Xiaolingwei, Nanjing 210094, PR China
b Key Laboratory of Organofluorine Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 345 Linglin g Road, Shanghai 200032, PR China

Correspondingauthor.
E-mail address: c.cai@njust.edu.cn

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ABSTRACT
A strategy for the synthesis of coumarin derivatives via visible-light photoredox catalysis has been developed using fac-Ir(ppy)3 as the photocatalyst
under mild conditions. Trifluoromethanesulfonyl chloride is utilized as the trifluoromethylation reagent, which is cheap and readily available. Aryl
alkynoates are trifluoromethylated, then undergo a radical cyclization and a cascade ester migration to generate target products.
Keywords:
Photoredoxcatalysis
Trifluoromethanesulfonyl chloride
Coumarin
Cyclization
Trifluoromethylation

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1. Introduction
Coumarin derivatives are significant structures in natural products and pharmaceuticals due to their unique properties like anticancer,
anti-HIV, anticoagulant, anti-inflammatory, enzyme inhibition, antimicrobial and antioxidant activities [1,2]. They could also be applied
in material science as fluorescent dyes [3]. The introduction of trifluoromethyl group into the coumarin scaffold may improve the
pharmacological or chemical evaluation of its derivatives, thus, great efforts have be spent exploring their synthesis. Since the synthesis
of 4-trifluoromethylated coumarins has been well established [4,5], more and more attentions are paid on the preparation of 3-
trifluoromethylated coumarins. Direct trifluoromethylation of coumarins serves as an efficient approach to this structure (Scheme 1a).
The first example was reported as early as 1991 by refluxing coumarin with bis(trifluoroacetyl) peroxide [6]. Bi’s group [7] tamed
Togni reagent in the C−H 3-trifluoromethylation of hymecromone. Sodium trifluoromethanesulfinate (Langlois reagent) has also been
harnessed for the direct trifluoromethylation, in which Mn(OAc)3 [8], CuCl/TBHP [9], or a hypervalent iodine(III) reagent [10] was
employed for the generation of trifluoromethyl radical. Construction of coumarin skeleton from aryl alkynoates via radical process
which has been discussed in several recent reports [11-20], provides an alternative to 3-trifluoromethylated coumarins (Scheme 1b).
Based on this strategy, a copper-catalyzed trifluoromethylation with Togni reagent was disclosed by Lu and Ding [11]. Other reported
methods include trifluoromethylation of ortho-hydroxycinnamic esters [21],Perkin condensation with 3,3,3-
Scheme 1. Methods for the synthesis of 3-trifluoromethylated coumarins: (a) direct trifluoromethylation of coumarins; (b) trifluoromethylation of aryl
alkynoates; (c) trifluoromethylationof ortho-hydroxycinnamicesters; (d) Perkincondensation; (e)fluorinationof coumarin-3-carboxylicacids.
trifluoropropionic acid [22], and treatment of coumarin-3-carboxylic acids with sulfur tetrafluoride [23]. Nonetheless, the existed
methods suffer from their respective drawbacks like high temperature, excess oxidants or inaccessible starting materials, in addition,
toxic orexpensive trifluoromethylationreagentsare required in some cases.
Visible-light photoredoxcatalysis has gained extensive attention over the past decade as an access for new transformations [24,25]. A
great amount of methods have been developed for the photoredox catalyzed trifluoromethylation [26-28], by using reagents like
CF3SO2Cl [29,30], CF3SO2Na [31], CF3I [32,33], Togni reagent [34], Umemoto reagent [35], etc. Among these reagents, CF3SO2Cl is
cheap, commercially available, and easy to operate with. The single-electron reduction of CF3SO2Cl by the excited state of a
commonly-used photocatalyst (e.g., fac-Ir(ppy)3, Ru(bpy)3Cl2, or Eosin Y) could produce CF3 radical, which is highly reactive for
trifluoromethylation. We hypothesized that the CF3 radical obtained in this manner would reacted with aryl alkynoates under room
temperature to form3-trifluoromethylated coumarins.
2. Experimental
2.1. General
Unless otherwise noted, all commercially available reagents were used without further purification. Photoreactions were carried out
under an atmosphere of argon in an oven-dried Schlenk tube and irradiated with a 5 W blue LED lamp. The LED lamp (QB-4038) is
produced by Weelte lighting factory of Longgang, Shenzhen, and was purchased from Fantesen Household Light at taobao.com. The
products were purified by column chromatography oversilica gel. Analytical thin-layer chromatography was performed on glass plates
1
precoated with silica gel, and compounds were detected by visualization under an ultraviolet lamp (254 nm). H, 13C and 19F NMR
spectra were recorded on an AVANCE III 500 Bruker spectrometer operating at 500 MHz, 125 MHz and 470 MHz, respectively.
Chemical shifts were reported in ppm. Coupling constants (J values) are reported in Hz. GC analyses were recorded on an Agilent
7890A instrument.Low-resolution massspectra (EI) were obtained at 70eV on a 5975C Mass SelectiveDetector.
2.2. Typical procedurefor the synthesis ofaryl alkynoate ester
To a solution of the relative phenol (3.0 mmol, 1.0 equiv) in DCM (30 mL) was added arylpropiolic acid (3.3 mmol, 1.1 equiv) at 0
oC, then a mixture of DCC (929 mg, 4.5 mmol, 1.5 equiv) and DMAP (37 mg, 0.3 mmol, 0.1 equiv) in CH2Cl2 (15 mL) was added
dropwise. The mixture was stirred at room temperature for 12 h. Then, the crude mixture was filtered and washed with DCM and
concentrated.Purification was achievedby column chromatographyon silica gelusing hexane and ethylacetate aseluents.

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2.3. Typical procedurefor the cyclizationofaryl alkynoates withtrifluoromethanesulfonylchloride
A 10-mL Schlenk tube with a magnetic stirring bar was equipped with aryl alkynoate ester (0.2 mmol), K2CO3 (56 mg, 0.4 mmol, 2
equiv.), and Ir(ppy)3 (2 mg, 1 mol%). The tube was evacuated and backfilled with dry argon (this operation was repeated three times).
Dry acetonitrile (1 mL) was added by syringe, followed by the addition of CF3SO2Cl (43 L, 0.4 mmol, 2 equiv.). The resulting mixture
was irradiated with a 5 W blue LED lamp and stirred at room temperature for 24 h. After completion of the reaction, the solvent was
removed under reduced pressure. Purification was achieved by column chromatography on silica gel using hexane and ethyl acetate as
eluents.
Table 1
Optimization of the reaction conditions.a
Entry Photocatalyst
Solvent
CH3CN
CH3CN
CH3CN
CH3CN
DMF
Base
K2HPO4
K2HPO4
K2HPO4
K2HPO4
K2HPO4
K2HPO4
K2HPO4
K2HPO4
K2HPO4
K3PO4
Yield (%)b
48
1
Ru(bpy)3Cl2
Ir(ppy)3
Eosin Y
-
2
72
3c
4
trace
NR
18
5
Ir(ppy)3
Ir(ppy)3
Ir(ppy)3
Ir(ppy)3
Ir(ppy)3
Ir(ppy)3
Ir(ppy)3
Ir(ppy)3
Ir(ppy)3
Ir(ppy)3
Ir(ppy)3
Ir(ppy)3
Ir(ppy)3
Ir(ppy)3
Ir(ppy)3
Ir(ppy)3
6
DMSO
DCM
trace
55
7
8
DCE
44
9
HOAc
48
10
11
12
13
14
15
16
17
18d
19e
20f
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
56
K2CO3
Cs2CO3
NaOAc
KOAc
79
49
54
52
DIPEA
2,6-lutidine
-
77
75
trace
NR
79
K2CO3
K2CO3
K2CO3
17
a
Unless otherwise noted, the reaction conditions are as follows: 1a (0.2 mmol), CF3SO2Cl (0.4 mmol), photocatalyst (1 mol%), base (0.4 mmol), solvent (1 mL),
irradiationwith a 5 W blue LED lamp under argon at rt for24 h.
b Isolatedyieldof pure product basedon 1a.
c 5 mol% eosin Y was used, andthe reaction was irradiatedwith a 5 W green LED lamp.
d The experiment was performedin thedark.
e The experiment was irradiatedwith a 23 W household white CFL.
f The experiment was irradiatedwith ambient light.
3. Results anddiscussion
Evaluation of the proposed strategy was first examined with the reaction between phenyl 3-phenylpropiolate (1a) and
trifluoromathanesulfonyl chloride, using K2HPO4 as the base and Ru(bpy)3Cl2 as the photocatalyst. To our delight, the desired product
2a was obtained in moderate yield after a reaction time of 24 h (Table 1, entry 1). The yield went up to 72% when Ir(ppy)3 was
employed as the photocatalyst (cf. entry 2). Altering the photocatalyst to Eosin Y, an organic dye which was reported to be efficient for
the generation of trifluoromethyl radical [30], gave only trace product in this case (entry 3). No reaction was detected when no
photocatalyst was added (entry 4). The influence of solvent selection was examined (entries 5-9), and acetonitrile remained to be the
optimal medium for the tandem radical trifluoromethylation/cyclization. Several inorganic and organic bases were then screened
(entries 10-16). The best result was obtained by potassium carbonate, and Hünig’s base also gave a similar yield. Control experiments
indicated that base and light are both essential to this photocatalytic protocol (entries 17, 18). A 23 W household white CFL was
compared with the 5W blue LED, and the same yield was provided (entry 19). The 5 W LED lamp should be better fromthe viewpoint
of energy-saving. Only 17% yield was obtained irradiated with ambient light (entry 20).
With optimized conditions available, the substrate scope and limitations were then explored regarding the substitution pattern on aryl
alkynoate (1). It is interest to find that the reactions didn’t proceed through 6-endo cyclization [11], instead, 5-exo cyclization and 1,2-
migration of the ester group [15-20] might occur. As shown in Table 2, moderate to good yields of trifluoromethylated coumarin
derivatives (2) were gained by the photocatalytic cyclization of aryl alkynoates with a few exceptions. It is obvious that the substituent

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R1 has a great effect on this visible-light-mediated reaction. Substrates bearing electron-neutral alkyl group at para-position of the
phenylworks well, with the corresponding 7-substituted-3-trifluoromethylated
Table 2
Substrate scope of the cyclization of aryl alkynoates with CF3SO2Cl.a
a
Unless otherwise noted, the reaction conditions are as follows: 1a (0.2 mmol), CF3SO2Cl (0.4 mmol), Ir(ppy)3 (1 mol%), K2CO3 (0.4 mmol), CH3CN (1 mL),
irradiationwith a blue LED lamp (5 W) under argon at rt for24 h.Isolatedyield.
b K2CO3 was replacedby Hünig’s base (0.4 mmol).
Scheme 2. Scale-up experiment. Reaction conditions: 1m (1 g, 3.9 mmol), CF3SO2Cl (7.8 mmol), Ir(ppy)3 (1 mol%), K2CO3 (3.9 mmol), CH3CN (19.5 mL),
irradiationwith three 5 W blue LED lamps under argonat rt for 36h.

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Scheme 3. Radical capturingexperiment withTEMPO.
Fig. 1. Timeprofileof the trifluoromethylation/cyclization withandwithout light.
coumarins obtained in good yields (2b, c). Halogen moieties are conserved through the reaction, leaving easy handles for further
functionalization via transition-metal catalysis (2d-g). Reactions of aryl alkynoates 2e-g obtained better yields when trimethylamine
was used as the base. Substrate 1h (R1 = p-CF3) could also serve as a substrate for this transformation, and the exact structure of the
product 2h was confirmed by X-ray single crystal diffraction (Table 2). However, the reactions resulted in complexmixtures when R1 is
methoxy or cyano at para-position, because unexpected radicals or radical anions might be formed and strong electron-withdrawing
group at para-position are not favorable in this kind of reactions [16,19]. When the meta-positions were replaced by two methyl groups,
a yield of 61% was provided (2i). Only trace product was detected when only one ortho hydrogen atom was available, owing to the
effect ofsteric hindrance (2j). Substrates with different substituent groups R2 were then subjected to the optimal reaction conditions.In
this
Scheme 4. Proposedmechanismforphotocatalytic trifluoromethylation/cyclization.

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case, aryl groups with electron-donating, -neutral, or -withdrawing substituents at para-position were all tolerated (2k-o). However, the
present method seems to be incompatible when an alkyl group was employed as R2. The cyclization of phenyl 3-cyclopropylpropiolate
only led to trace product (2p).
The photoreaction of the substrate 1m was conducted on a gram scale, and it proceeded smoothly with the formation of the desired
product 2min 72% yield aftera reaction time of36 h, thus demonstrating the preparative utility ofthis chemistry (Scheme 2).
4. Mechanistic study
Experiments were carried out in order to gain insight into the mechanism of the photocatalytic cyclization (see supporting
information for details). When the reaction of 1m was performed in presence of 2 equivalents of TEMPO, the reaction became sluggish
and the substrate was recovered almost quantitatively, suggesting a mechanism of radical pathway (Scheme 3). The reaction was
monitored by 19F NMR, and there is no obvious peak for TEMPO-CF3. This is because Ir(IV) could not be reduced to Ir(III). The
catalytic cycle ceased, therefore no more CF3 radical would be formed. A light on/off experiment was then conducted under the
standard reaction conditions (Fig. 1). The trifluoromethylation of 1m ceased in the dark, which indicates the necessity of continuous
irradiation and that a chain propagation is not themain mechanistic processforthis visible-light-induced transformation.
Based on the above experiments and previous reports [15-20,29,30], a plausible catalytic cycle for the photocatalytic cyclization with
CF3SO2Cl was suggested in Scheme 4. The photocatalyst Ir(ppy)3 is activated by visible light to the excited state, and is oxidatively
quenched by CF3SO2Cl. Trifluoromethyl radical is formed upon the release of Cl− and SO2. The addition of CF3 radical to aryl
alkynoate 1 gives the alkenyl radical 3, which undergoes an intramolecular radical spirocyclization to formthe cyclic intermediate 4. A
single-electron oxidation of the radical 4 by Ir(IV) leads to cation 5. Ir(IV) was reduced to Ir(III), and that thereby completes the
photocatalytic cycle. Intermediate 6 was produced by 1,2-migration of the ester group, and deprotonation of 6 finally provides the
coumarin derivative 2.
5. Conclusions
In this work, a mild methodology for the visible-light-mediated trifluoromethylation-cyclization-migration of aryl alkynoates has
been developed. Various 3-trifluoromethylated coumarin derivatives could be afforded by this transformation under room temperature.
In this chemistry, visible light is utilized as a clean source of energy, while trifluoromethanesulfonyl chloride serves as a cheap and
readily available trifluoromethylation reagent.
Acknowledgments
We gratefully acknowledge the Chinese Postdoctoral Science Foundation (2016T90465, 2015M571761) for financial support. We
thankLan Yi at Test CenterNanjing University ofScience &Technology forthe help in obtaining the NMRdata.
Appendix A. Supplementary data
Supplementary data associatedwith this article can be found in the online version.

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Highlights
 A photoredox catalyzed synthesis of 3-trifluoromethylated coumarins is reported.
 An efficient and commercially available trifluoromethylation reagent is employed.
 Visible light serves as a green source of energy for this transformation.
 The reaction undergoes a tandem trifluoromethylation-cyclization-migration process.