Direct introduction of ethoxycarbonyldifluoromethyl-group to heteroarenes with ethyl bromodifluoroacetate via visible-light photocatalysis

Article abstract of DOI:10.1002/cjoc.201300411

A mild and versatile approach for the direct introduction of ethoxycarbonyldifluoromethyl-group to heteroarenes via visible-light photocatalysis has been developed. The new photoredox protocol has enabled the difluoromethylenation of heteroarenes containing a wide range of common functional groups under mild conditions. Copyright

Full text of DOI:10.1002/cjoc.201300411

FULL PAPER
DOI: 10.1002/cjoc.201300411
Direct Introduction of Ethoxycarbonyldifluoromethyl-Group
to Heteroarenes with Ethyl Bromodifluoroacetate via
Visible-Light Photocatalysis
Qingyu Lin,a Lingling Chu,a and Feng-Ling Qing*,a,b
a Key Laboratory of Organofluorine Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy
of Sciences, 345 Lingling Lu, Shanghai 200032, China
b College of Chemistry, Chemical Engineering and Biotechnology, Donghua University, 2999 North Renmin Lu,
Shanghai 201620, China
A mild and versatile approach for the direct introduction of ethoxycarbonyldifluoromethyl-group to hetero-
arenes via visible-light photocatalysis has been developed. The new photoredox protocol has enabled the difluoro-
methylenation of heteroarenes containing a wide range of common functional groups under mild conditions.
Keywords difluoromethylenation, heteroarenes, visible-light photocatalysis
Introduction
tion by C－H substitution. However, only a few radical
difluoromethylenation reactions of arenes have been
reported,[6] and most current approaches exhibit low
efficiency and limited substrate scope. In some cases,
hazardous reagents (PhSeCF2CO2Et) and high-energy
UV irradiation are required.[6b] Thus, the development
of a radical difluoromethylenation protocol with broader
generality under mild conditions is still highly desirable.
During the last decade, visible-light photocatalysis
has turned out to be a powerful and reliable tool in or-
ganic chemistry.[7] Recently, visible-light photocata-
lyzed direct trifluoromethylation of arenes and hetero-
arenes have been successively reported by the groups of
MacMillan and Cho.[8] Later, Sanford developed a mild
method for the trifluoromethylation of arylboronic acids
by merging visible-light photocatalysis and transition-
metal catalysis.[9] Furthermore, the hydrotrifluorometh-
ylation[10a] and aminotrifluoromethylation[10b] of alkenes
As a result of the special properties of the difluoro-
methylene (CF2) groups, difluoromethylenated arenes
are important structural units found in many pharma-
ceuticals, agrochemicals and advanced materials.[1]
Consequently, extensive efforts have been devoted to-
ward the development of mild and versatile methods for
incorporating the difluoromethylene groups onto aro-
matic rings. Over the past several years, transition-
metal-mediated or -catalyzed difluoromethylenation
reaction has proved to be an efficient strategy to incor-
porate the difluormethylene units into aromatic com-
pounds.[2,3] In the presence of a palladium[2] or copper
catalyst,[3] aryl halides or boronic acids could be regio-
specially transformed into the corresponding CF2 ana-
logues with high efficiency, providing an attractive al-
ternative to the traditional DAST-mediated difluorina-
tion process.[4] However, these methods require the use
of prefunctionalized aromatic substrates and cause re-
dundant synthetic efforts. In contrast, transition-metal-
catalyzed direct difluoromethylenation of aryl C－H
bonds remains a big challenge, presumably because of
the difficulty in finding a catalytic system that could not
only activate C－H bonds, but also promote Ar/CF2
reductive elimination. Until very recently, a single ex-
ample of Rh-catalyzed intramolecular C－H difluoro-
methylenation reaction has been described by Gong and
coworkers.[5] On the other hand, a free radical pathway
could preclude the need for prefunctionalization, offer-
ing an attractive access to the direct difluoromethylena-
＋
catalyzed by [Ru(bpy)3]2 under visible light irradiation
have been explored. In contrast to these impressive pro-
gresses, methods for related visible-light photocatalyzed
difluoromethylenation of arenes have not been devel-
oped. On the other hand, recent studies by Stephenson
demonstrated the transformation of BrCF2CO2Et into
the •CF2CO2Et radical via visible-light photocatalysis.[11]
On the basis of this work, we envisioned that a mild and
operationally simple process for the direct difluoro-
methylenation of heteroarenes could be achieved by
utilizing visible light-mediated photoredox catalysis
(Scheme 1).
*
E-mail: flq@mail.sioc.ac.cn
Received May 18, 2013; accepted July 12, 2013; published online July 19, 2013.
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/cjoc.201300411 or from the author.
Chin. J. Chem. 2013, 31, 885—891
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Scheme 1 Direct difluoromethylenation of heteroarenes via
visible-light photocatalysis
J＝30.1 Hz), 120.1 , 119.8 , 113.8 (t, J＝3.7 Hz), 111.6
(t, J＝252.4 Hz), 63.6, 13.9, 8.5; 19F NMR (282 MHz,
CDCl3) δ: –101.8 (s, 2F); IR (thin film) ν: 3405, 3061,
2985, 1763, 1302 cm−1; MS (EI) m/z: 253 (M＋, 21.0),
180 (100); HRMS calcd for C13H13NO2F2: 253.0914;
found 253.0918.
2+*
Ru(phen)3
1 e-
visible light
2+
+
Ethyl 2-(3-(2-bromoethyl)-1H-indol-2-yl)-2,2-di-
fluoroacetate (2b) Flash chromatography (silica gel,
petroleum ether∶EtOAc＝10∶1) afforded 2b (257 mg,
74%); pale yellow liquid. 1H NMR (300 MHz, CDCl3) δ:
8.56 (s, 1H), 7.66 (d, J＝8.1 Hz, 1H), 7.39 (d, J＝8.4
Hz, 1H), 7.31 (t, J＝6.9 Hz, 1H), 7.19 (t, J＝7.5 Hz,
1H), 4.34 (q, J＝7.2 Hz, 2H), 3.57 (t, J＝7.2 Hz, 2H),
3.46 (t, J＝7.2 Hz, 2H), 1.34 (t, J＝7.2 Hz, 3H); 13C
NMR (100 MHz, CDCl3) δ: 163.4 (t, J＝35.8 Hz),
135.7, 127.5, 124.7, 124.2 (t, J＝29.7 Hz), 120.7, 119.7,
115.3 (t, J＝3.1 Hz), 111.9, 111.3 (t, J＝249.7 Hz), 63.9,
31.7, 28.0, 13.9; 19F NMR (282 MHz, CDCl3) δ: –101.8
(s, 2F); IR (thin film) ν: 3403, 2982, 1762, 1303, 1119
cm−1; MS (EI) m/z (%): 345 (M＋, 36.4), 252 (100);
HRMS calcd for C14H14NO2F2Br: 345.0176; found
345.0179.
Ru(phen)3
Ru(phen)3
BrCF2CO2Et
CF2CO2Et
R
R
CF2CO2Et
this work
X
X
Experimental
1H NMR (TMS as the internal standard) and 19F
NMR spectra (CFCl3 as the outside standard and low
field is positive) were recorded on a 300 or 400 MHz
spectrometer. 13C NMR was recorded on 400 MHz
spectrometer. The following abbreviations were used to
explain the multiplicities: s＝singlet, d＝doublet, t＝
triplet, q＝quartet, m＝multiplet. Substrates 1a－1c, 1f,
1k－1m, 1o－1w, 1y were purchased from commercial
sources and used as received. Substrates 1d,[12a] 1e,[12b]
1g,[12b] 1h,[12c] 1i,[12c] 1j,[12b], 1n[12c] and 1x[12d] were
prepared according to literature procedures.
Ethyl 2,2-difluoro-2-(3-(2-hydroxyethyl)-1H-in-
dol-2-yl)acetate (2c) Flash chromatography (silica gel,
petroleum ether∶EtOAc＝3∶1) afforded 2c (274 mg,
1
60%); yellow liquid. H NMR (400 MHz, CDCl3) δ:
8.99 (s, 1H) 7.69 (d, J＝8.0 Hz, 1H), 7.37 (d, J＝8.0 Hz,
1H), 7.29 (t, J＝6.8 Hz, 1H), 7.17 (t, J＝7.6 Hz, 1H),
4.32 (q, J＝6.8 Hz, 2H), 3.92 (t, J＝6.8 Hz, 2H), 3.21 (t,
J＝6.8 Hz, 2H), 2.18 (s, 1H), 1.32 (t, J＝7.2 Hz, 1H);
13C NMR (100 MHz, CDCl3) δ: 163.6 (t, J＝36.1 Hz),
135.8, 128.0, 124.4 (t, J＝29.8 Hz), 124.3, 120.4, 119.9,
114.2 (t, J＝2.6 Hz), 111.8, 111.5 (t, J＝250.7 Hz), 63.8,
63.2, 27.5, 13.8; 19F NMR (282 MHz, CDCl3) δ: –100.9
(s, 2F); IR (thin film) ν: 3551, 3396, 3062, 2983, 1759,
1303 cm−1; MS (EI) m/z (%): 283 (M＋, 39.3), 252 (100);
HRMS calcd for C14H15NO3F2: 283.1020; found
283.1015.
General procedure for the direct difluoromethylena-
tion of heteroarenes with BrCF2CO2Et via visible-
light photocatalysis
A 25 mL Schlenk flask equipped with a rubber sep-
tum and a magnetic stir bar was charged with
Ru(phen)3Cl2•xH2O (0.016 mmol, 1.0 mol%), DMSO
(16 mL), heteroarene 1a (1.6 mmol), BrCF2CO2Et (3.2
mmol), and N,N-dimethyl-4-toluidine (1.6 mmol) under
nitrogen atomsphere. The mixture was degassed three
times by the freeze-pump-thaw procedure. Then the vial
was placed at a distance of ca. 2 cm from the blue LEDs.
The mixture was stirred under nitrogen atmosphere and
irradiated by blue LEDs for 2 h. After the reaction was
complete, the reaction mixture was diluted with water.
The resulting mixture was extracted with diethyl ether,
and the combined organic phase was washed with brine
then dried with magnesium sulfate. The solvent was
removed under vacuum and the crude product was puri-
fied by flash column chromatography to give the desired
product 2a.
Ethyl 2-(3-(2-(2-bromo-2,2-difluoroacetamido)-
ethyl)-1H-indol-2-yl)-2,2-difluoroacetate (2d) Flash
chromatography (silica gel, petroleum ether∶EtOAc＝
10∶1) afforded 2d (334 mg, 47%); white solid; m.p.
1
117−119 ℃; H NMR (400 MHz, CDCl3) δ: 8.66 (s,
1H), 7.68 (d, J＝7.6 Hz, 1H), 7.41 (d, J＝8.4 Hz, 1H),
7.32 (t, J＝7.6 Hz, 1H), 7.19 (t, J＝7.6 Hz, 1H), 4.34 (q,
J＝6.8 Hz, 2H), 3.68 (q, J＝6.0 Hz, 2H), 3.20 (t, J＝6.8
Hz, 2H), 1.34 (t, J＝7.2 Hz, 3H); 13C NMR (100 MHz,
CDCl3) δ: 163.4 (t, J＝34.4 Hz), 160.1 (t, J＝27.4 Hz),
135.7, 127.6, 124.8, 124.3 (t, J＝19.8 Hz), 120.9, 119.7,
113.9 (t, J＝3.8 Hz), 111.9, 111.8 (t, J＝315.5 Hz),
111.2 (t, J＝250.6 Hz), 63.9, 40.8, 23.3, 13.9; 19F NMR
(282 MHz, CDCl3) δ: –60.5 (s, 2F), –100.6 (s, 2F); IR
(thin film) ν: 3352, 3325, 3065, 2925, 1762, 1707, 1133
cm−1; MS (EI) m/z (%): 438 (M＋, 5.39), 117 (100);
HRMS calcd for C16H15N2O3F4Br: 438.0202; found
438.0201.
Ethyl 2,2-difluoro-2-(3-methyl-1H-indol-2-yl)-ace-
tate (2a) Flash chromatography (silica gel, petroleum
ether∶EtOAc＝30∶1) afforded 2a (187 mg, 74%);
1
yellow liquid. H NMR (300 MHz, CDCl3) δ: 8.61 (s,
1H), 7.70 (d, J＝7.8 Hz, 1H), 7.42－7.34 (m, 2H), 7.26
(t, J＝6.9 Hz, 1H), 4.41 (q, J＝7.2 Hz, 2H), 2.52 (s, 3H),
1.39 (t, J＝6.9 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ:
163.7 (t, J＝35.8 Hz), 135.7 , 128.6 , 124.3 , 123.4 (t,
2-(2-(2-Ethoxy-1,1-difluoro-2-oxoethyl)-1H-indol-
3-yl)acetic acid (2e) Flash chromatography (silica gel,
886
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Chin. J. Chem. 2013, 31, 885—891

Direct Introduction of Ethoxycarbonyldifluoromethyl-Group to Heteroarenes
petroleum ether∶EtOAc＝2∶1) afforded 2e (198 mg,
67%); yellow solid; m.p. 103−105 ℃; 1H NMR (400
MHz, CDCl3) δ: 11.11 (s, 1H), 8.83 (s, 1H), 7.63 (d, J＝
8.0 Hz, 1H), 7.37 (d, J＝8.4 Hz, 1H), 7.30 (t, J＝6.8 Hz,
1H), 7.20 (t, J＝6.8 Hz, 1H), 4.30 (q, J＝6.8 Hz, 2H),
4.02 (s, 2H), 1.28 (t, J＝6.8 Hz, 3H); 13C NMR (100
MHz, CDCl3) δ: 177.4, 163.3 (t, J＝35.4 Hz), 135.5,
127.7, 125.0 (t, J＝29.9 Hz), 124.6, 120.8, 119.7, 111.8,
111.1 (t, J＝250.6 Hz), 109.4 (t, J＝3.0 Hz), 63.9, 29.5,
13.7; 19F NMR (282 MHz, CDCl3) δ: –101.8 (s, 2F); IR
(thin film) ν: 3393, 2986, 1762, 1711, 1306, 1096 cm−1;
MS (EI) m/z (%): 297 (M＋, 100); HRMS calcd for
C14H13NO4F2: 297.0813; found 297.0815.
271 (M＋, 19.2), 198 (100); HRMS calcd for C13H12N-
O2F3: 271.0820; found 271.0824.
Ethyl 2-(5-bromo-3-methyl-1H-indol-2-yl)-2,2-
difluoroacetate (2i) Flash chromatography (silica gel,
petroleum ether∶EtOAc＝10∶1) afforded 2i (225 mg,
68%); white solid; m.p. 94−98 ℃; 1H NMR (300 MHz,
CDCl3) δ: 8.55 (s, 1H), 7.73 (s, 1H), 7.34 (d, J＝9.3 Hz,
1H), 7.22 (d, J＝9.0 Hz, 1H), 4.36 (q, J＝7.2 Hz, 2H),
2.38 (s, 3H), 1.34 (t, J＝6.9 Hz, 3H); 13C NMR (100
MHz, CDCl3) δ: 163.4 (t, J＝35.8 Hz), 134.2, 130.3,
127.2, 124.6 (t, J＝29.2 Hz), 122.4, 113.4 (t, J＝2.4 Hz),
113.3, 113.1, 111.1 (t, J＝250.0 Hz), 63.7, 13.9, 8.4; 19F
NMR (282 MHz, CDCl3) δ: –102.2 (s, 2F); IR (thin film)
ν: 3358, 2916, 1752, 1306, 1101 cm−1; MS (EI) m/z (%):
331 (M＋, 34.5), 258 (100); HRMS calcd for C13H12N-
O2F2Br: 331.0019; found 331.0021.
2-(2-Ethoxy-1,1-difluoro-2-oxoethyl)-3-methyl-
1H-indole-6-carboxylic acid (2j) Flash chromatog-
raphy (silica gel, petroleum ether∶EtOAc＝2∶1 then
1∶1) afforded 2j (213 mg, 72%); white solid; m.p.
173−176 ℃; 1H NMR (300 MHz, CDCl3) δ: 9.95 (s,
1H), 8.16 (s, 1H), 7.79 (dd, J＝8.4, 1.2 Hz, 1H), 7.69 (d,
J＝8.4 Hz, 1H), 4.36 (q, J＝7.2 Hz, 2H), 2.40 (t, J＝2.1
Hz, 3H), 1.29 (t, J＝7.2 Hz, 3H); 13C NMR (100 MHz,
CDCl3) δ: 168.5, 162.8 (t, J＝36.3 Hz), 135.4, 131.2,
127.0 (t, J＝28.9 Hz), 126.3, 120.5, 119.6, 114.6, 112.2
(t, J＝3.8 Hz), 111.8 (t, J＝248.9 Hz), 64.1, 14.0, 8.5;
19F NMR (282 MHz, CDCl3) δ: –101.9 (s, 2F); IR (thin
film) ν: 3393, 1760, 1682, 1306, 1090 cm−1; MS (EI)
m/z (%): 297 (M＋, 19.9), 224 (100); HRMS calcd for
C14H13NO4F2: 297.0813; found 297.0811.
Ethyl 2,2-difluoro-2-(3-methyl-1H-pyrrolo[2,3-
b]pyridin-2-yl)acetate (2k) Flash chromatography
(silica gel, petroleum ether∶EtOAc＝2∶1) afforded
2k (284 mg, 70%); white solid; m.p. 112−114 ℃. 1H
NMR (300 MHz, CDCl3) δ: 13.83 (s, 1H), 8.56 (d, J＝
4.5 Hz, 1H), 7.97 (d, J＝4.8 Hz, 1H), 7.17－7.13 (m,
1H), 4.32 (q, J＝6.9 Hz, 2H), 2.46 (s, 3H), 1.26 (t, J＝
7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ: 163.4 (t,
J＝35.3 Hz), 148.3, 144.5, 128.9, 125.2 (t, J＝29.2 Hz),
121.6, 115.7, 111.8 (t, J＝250.0 Hz), 111.2 (t, J＝4.3
Hz), 63.4, 13.8, 8.4; 19F NMR (282 MHz, CDCl3) δ:
–102.2 (s, 2F); IR (thin film) ν: 3033, 2962, 1762, 1296,
1096 cm−1; MS (EI) m/z (%): 254 (M＋, 17.9), 181 (100);
HRMS calcd for C12H12N2O2F2: 254.0867; found
254.0869.
Ethyl 2,2-difluoro-2-(5-methoxy-3-phenyl-1H-
indol-2-yl)acetate (2l) Flash chromatography (silica
gel, petroleum ether∶EtOAc＝8∶1) afforded 2l (191
mg, 65%); yellow liquid. 1H NMR (400 MHz, CDCl3) δ:
8.74 (s, 1H), 7.48－7.33 (m, 6H), 7.02－7.00 (m, 2H),
4.00 (q, J＝7.2 Hz, 2H), 3.79 (s, 3H), 1.10 (t, J＝7.2 Hz,
3H); 13C NMR (100 MHz, CDCl3) δ: 162.8 (t, J＝33.9
Hz), 155.0, 132.7, 130.5, 130.3, 128.4, 128.0, 127.5,
124.4 (t, J＝27.8 Hz), 119.3 (t, J＝5.3 Hz), 115.8, 112.8,
110.9 (t, J＝248.0 Hz), 101.3, 63.5, 55.9, 13.6; 19F
NMR (282 MHz, CDCl3) δ: –95.3 (s, 2F); IR (thin film)
ν: 3398, 2991, 1761, 1298, 1161 cm−1; MS (EI) m/z (%):
Ethyl 2-(3-(2-amino-2-oxoethyl)-1H-indol-2-yl)-
2,2-difluoroacetate (2f) Flash chromatography (silica
gel, petroleum ether∶EtOAc＝1∶1) afforded 2f (310
1
mg, 65%); white solid; m.p. 166−167 ℃; H NMR
(400 MHz, DMSO-d6) δ: 11.68 (s, 1H) 7.56 (d, J＝8.4
Hz, 1H), 7.41 (d, J＝8.4 Hz, 1H), 7.30 (s, 1H), 7.20 (t,
J＝8.0 Hz, 1H), 7.05 (t, J＝8.0 Hz, 1H), 6.91 (s, 2H),
4.26 (q, J＝7.0 Hz, 2H), 3.61 (s, 2H), 1.21 (t, J＝6.8 Hz,
3H); 13C NMR (100 MHz, DMSO-d6) δ: 172.1, 163.0 (t,
J＝35.9 Hz) 136.1, 128.1, 125.1 (t, J＝29.8 Hz), 123.9,
120.2, 120.0, 112.5, 112.0 (t, J＝249.0 Hz), 111.0 (t,
J＝4.0 Hz), 64.0, 30.7, 14.0; 19F NMR (400 MHz,
CDCl3) δ: –99.2 (s, 2F); IR (thin film) ν: 3448, 3426,
3185, 2292, 1764, 1751, 1296 cm−1; MS (EI) m/z (%):
＋
296 (M , 10.6), 117 (100); HRMS calcd for
C14H14N2O3F2: 296.0972; found 296.0974.
Ethyl 2-(3-cyano-1H-indol-2-yl)-2,2-difluoroace-
tate (2g) Flash chromatography (silica gel, petroleum
ether∶EtOAc＝4∶1) afforded 2g (68 mg, 26%); pale
yellow solid; m.p. 119−120 ℃; 1H NMR (400 MHz,
CDCl3) δ: 9.72 (s, 1H), 7.79 (d, J＝8.4 Hz, 1H), 7.54 (d,
J＝8.4 Hz, 1H), 7.42 (t, J＝8.0 Hz, 1H), 7.35 (t, J＝7.2
Hz, 1H), 4.43 (q, J＝7.2 Hz, 2H), 1.39 (t, J＝7.2 Hz,
3H); 13C NMR (100 MHz, CDCl3) δ: 162.1 (t, J＝33.3
Hz), 134.8, 133.7 (t, J＝31.1 Hz), 130.2, 127.3, 126.2,
123.3, 120.2, 113.3, 112.7, 109.1 (t, J＝251.8 Hz),
87.85, 64.6, 13.8; 19F NMR (282 MHz, CDCl3) δ:
–101.2 (s, 2F); IR (thin film) ν: 3224, 2237, 1769, 1288,
1093 cm−1; MS (EI) m/z (%): 264 (M＋, 19.0), 191 (100);
HRMS calcd for C13H10N2O2F2: 264.0710; found
264.0713.
Ethyl 2,2-difluoro-2-(5-fluoro-3-methyl-1H-indol-
2-yl)acetate (2h) Flash chromatography (silica gel,
petroleum ether∶CH2Cl2＝2∶1) afforded 2h (197 mg,
73%); white solid; m.p. 97－99 ℃. 1H NMR (300 MHz,
CDCl3) δ: 8.48 (s, 1H), 7.28－7.20 (m, 2H), 7.01 (td,
J＝9.0, 2.1 Hz, 1H), 4.34 (q, J＝6.9 Hz, 2H), 2.36 (t,
J＝2.1 Hz, 3H), 1.32 (t, J＝7.2 Hz, 3H); 13C NMR (100
MHz, CDCl3) δ: 163.5 (t, J＝35.4 Hz), 159.2, 156.8,
132.1, 129.0, 128.9, 125.1 (t, J＝29.3 Hz), 113.8 (t, J＝
4.4 Hz), 113.0 (d, J＝25.5 Hz), 112.5 (t, J＝9.0 Hz),
111.3 (t, J＝250.8 Hz), 104.5 (t, J＝22.4 Hz), 63.7, 13.9,
8.5; 19F NMR (282 MHz, CDCl3) δ: –101.7 (d,
J＝2.8 Hz, 2F), 123.4 (td, J＝12.8, 6.0 Hz, 1F); IR (thin
film) ν: 3381, 1746, 1302, 1096 cm−1; MS (EI) m/z (%):
Chin. J. Chem. 2013, 31, 885—891
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887

Lin, Chu & Qing
FULL PAPER
345 (M＋, 53.7), 272 (56.2), 83 (100); HRMS calcd for
C14H13NO4F2: 345.1177; found 345.1174.
(282 MHz, CDCl3) δ: –104.0 (s, 2F); IR (thin film) ν:
2986, 1771, 1292, 1105 cm−1; MS (EI) m/z (%): 240
(M＋, 18.6), 167 (100); HRMS calcd for C12H10O3F2:
240.0598; found 240.0599.
Ethyl 2,2-difluoro-2-(1-methyl-3-phenyl-1H-
indo-l-2-yl)acetate (2m) Flash chromatography (sil-
ica gel, petroleum ether∶EtOAc＝1∶1) afforded 2m
Ethyl 2,2-difluoro-2-(3-methylbenzo[b]thiophen-
2-yl)acetate (2q) Flash chromatography (silica gel,
petroleum ether∶CH2Cl2＝10∶1) afforded 2q (180
mg, 42%); corlorless liquid. 1H NMR (400 MHz, CDCl3)
δ: 7.86－7.83 (m, 1H), 7.78－7.76 (m, 1H), 7.45－7.43
(m, 2H), 4.36 (q, J＝7.6 Hz, 2H), 2.55 (t, J＝1.6 Hz,
3H), 1.34 (t, J＝7.2 Hz, 3H); 13C NMR (100 MHz,
CDCl3) δ: 163.2 (t, J＝35.4 Hz), 140.1, 138.9 (t, J＝4.0
Hz), 128.1 (t, J＝27.8 Hz), 126.1, 124.6, 122.7, 122.5,
112.7 (t, J＝250.7 Hz), 63.5, 13.9, 12.0; 19F NMR (282
MHz, CDCl3) δ: –94.3 (s, 2F); IR (thin film) ν: 2979,
1765, 1294, 1102 cm−1; MS (EI) m/z (%): 270 (M＋,
23.7), 197 (100); HRMS calcd for C13H12O2F2S:
270.0526; found 270.0528.
1
(392 mg, 77%); white solid; m.p. 49－50 ℃; H NMR
(400 MHz, CDCl3) δ: 7.50－7.38 (m, 8H), 7.17 (t, J＝
6.4 Hz, 1H), 3.99 (s, 3H), 3.84 (q, J＝7.8 Hz, 2H), 1.18
(t, J＝7.6 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ:
162.8 (t, J＝32.6 Hz), 137.8, 133.1, 131.0, 128.1, 127.5,
127.3, 124.8 (t, J＝26.4 Hz), 121.0, 120.7, 111.9 (t, J＝
246.2 Hz), 109.7, 63.4, 31.8 (t, J＝4.5 Hz), 13.7; 19F
NMR (282 MHz, CDCl3) δ: −92.9 (s, 2F); IR (thin film)
ν: 3056, 2983, 1770, 1107 cm−1; MS (EI) m/z (%): 329
(M＋, 48.9), 84 (100); HRMS calcd for C19H17NO2F2:
329.1227; found 329.1231.
Ethyl 2-(1-acetyl-3-methyl-1H-indol-2-yl)-2,2-di-
fluoroacetate (2n) Flash chromatography (silica gel,
petroleum ether∶EtOAc＝10∶1) afforded 2n (307 mg,
Ethyl 2,2-difluoro-2-(1-methyl-1H-pyrrol-2-
yl)acetate (2s) Vacuum distillation afforded the de-
1
65%); yellow solid; m.p. 97－99 ℃; H NMR (400
1
MHz, CDCl3) δ: 7.61 (t, J＝7.2 Hz, 2H), 7.40 (t, J＝7.2
Hz, 1H), 7.31 (t, J＝7.2 Hz, 1H), 4.36 (q, J＝7.2 Hz,
2H), 2.74 (s, 3H), 2.46 (t, J＝4.0 Hz, 3H), 1.34 (t, J＝
7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ: 168.9,
162.9 (t, J＝33.0 Hz), 135.0, 131.1 (t, J＝1.6 Hz), 126.6,
126.5 (t, J＝29.2 Hz), 124.1 (t, J＝3.1 Hz), 123.4, 120.6,
113.9, 112.9 (t, J＝246.1 Hz), 62.7, 26.6, 14.0, 9.7 (t,
J＝6.1 Hz); 19F NMR (282 MHz, CDCl3) δ: –96.0 (s,
2F); IR (thin film) ν: 3055, 2984, 1777, 1704, 1312
cm−1; MS (EI) m/z (%): 295 (M＋, 4.8), 180 (100);
HRMS calcd for C15H15NO3F2: 295.1020; found
295.1024.
sired product 2s (1.30 g, 40%); colorless liquid. H
NMR (300 MHz, CDCl3) δ: 6.67 (s, 1H), 6.38－6.36 (m,
1H), 6.06 (t, J＝3.0 Hz, 1H), 4.36 (q, J＝7.2 Hz, 2H),
3.74 (s, J＝7.2 Hz, 3H), 1.35 (t, J＝7.2 Hz, 3H); 13C
NMR (100 MHz, CDCl3) δ: 163.4 (t, J＝34.2 Hz),
127.1, 122.6 (t, J＝29.5 Hz), 112.3, 111.3 (t, J＝245.2
Hz), 107.3 (t, J＝10.9 Hz), 63.2, 35.3, 13.9; 19F NMR
(282 MHz, CDCl3) δ: –96.2 (s, 2F); IR (thin film) ν:
2985, 1765, 1297, 1100 cm−1; MS (EI) m/z (%): 203
(M＋, 21.8), 130 (100); HRMS calcd for C9H11NO2F2:
203.0758; found 203.0760.
Ethyl 2,2-difluoro-2-(furan-2-yl)acetate (2t)
Flash chromatography (silica gel, petroleum ether∶
CH2Cl2＝5∶1) afforded 2t (102 mg, 33%); corlorless
liquid. 1H NMR (400 MHz, CDCl3) δ: 7.50 (s, 1H), 6.74
(d, J＝1.6 Hz, 1H), 6.44 (d, J＝1.2 Hz, 1H), 4.36 (q,
J＝6.8 Hz, 2H), 1.34 (t, J＝6.8 Hz, 3H); 13C NMR (100
MHz, CDCl3) δ: 162.4 (t, J＝34.0 Hz), 144.9 (t, J＝2.9
Hz), 144.5 (t, J＝33.5 Hz), 111.6 (t, J＝3.4 Hz), 110.7,
108.7 (t, J＝246.1 Hz), 63.5, 13.8; 19F NMR (282 MHz,
CDCl3) δ: –102.6 (s, 2F); IR (thin film) ν: 2923, 1770,
1277, 1109 cm−1; MS (EI) m/z (%): 190 (M＋, 12.8), 117
(100); HRMS calcd for C8H8O3F2: 190.0442; found
190.0444.
Ethyl 2,2-difluoro-2-(thiophen-2-yl)acetate (2u)
Flash chromatography (silica gel, petroleum ether∶
CH2Cl2＝10∶1) afforded 2u (85 mg, 26%); corlorless
liquid. 1H NMR (300 MHz, CDCl3) δ: 7.48 (dd, J＝5.1,
1.2 Hz, 1H), 7.40 (m, 1H), 7.08－7.05 (m, 1H), 4.36 (q,
J＝7.2 Hz, 2H), 1.35 (t, J＝6.9 Hz, 3H); 13C NMR (100
MHz, CDCl3) δ: 163.3 (t, J＝34.9 Hz), 134.0 (t, J＝29.6
Hz), 129.0, 128.5 (t, J＝5.6 Hz), 111.7 (t, J＝248.2 Hz),
63.4, 13.8; 19F NMR (282 MHz, CDCl3) δ: –92.8 (s, 2F);
IR (thin film) ν: 3110, 2986, 1768, 1304, 1247, 1098
cm−1; MS (EI) m/z (%): 206 (M＋, 21.0), 133 (100);
HRMS calcd for C8H8O2F2S: 206.0213; found
206.0212.
tert-Butyl 2-(2-ethoxy-1,1-difluoro-2-oxoethyl)-
1H-indole-1-carboxylate (2o) Flash chromatography
(silica gel, petroleum ether∶CH2Cl2＝2∶1) afforded
1
2o (173 mg, 32%); corlorless liquid. H NMR (400
MHz, CDCl3) δ: 8.03 (d, J＝8.8 Hz, 1H), 7.63 (d, J＝
7.2 Hz, 1H), 7.40 (t, J＝6.8 Hz, 1H), 7.29 (t, J＝6.8 Hz,
1H), 7.17 (s, 1H), 4.35 (q, J＝7.2 Hz, 2H), 1.69 (s, 9H),
1.32 (t, J＝7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ:
162.7 (t, J＝33.7 Hz), 149.8, 136.4, 131.1 (t, J＝32.2
Hz), 127.9, 126.1, 123.4, 122.0, 115.8, 112.0 (t, J＝8.2
Hz), 110.5 (t, J＝244.6 Hz), 62.8, 28.1, 13.9; 19F NMR
(282 MHz, CDCl3) δ: –97.7 (s, 2F); IR (thin film) ν:
2979, 1780, 11735, 1331, 1159 cm−1; MS (EI) m/z (%):
339 (M＋, 1.19), 117 (100); HRMS calcd for C17H19N-
O4F2: 339.1282; found 339.1280.
Ethyl 2-(benzofuran-2-yl)-2,2-difluoroacetate (2p)
Flash chromatography (silica gel, petroleum ether∶
CH2Cl21＝10∶1) afforded 2p (120 mg, 32%); corlorless
liquid. H NMR (400 MHz, CDCl3) δ: 7.63 (d, J＝10.0
Hz, 1H), 7.53 (d, J＝11.2 Hz, 1H), 7.38 (t, J＝10.0 Hz,
1H), 7.28 (t, J＝10.0 Hz, 1H), 7.14 (s, 1H), 4.39 (q, J＝
9.6 Hz, 2H), 1.35 (t, J＝9.6 Hz, 3H); 13C NMR (100
MHz, CDCl3) δ: 162.1 (t, J＝33.7 Hz), 155.4, 146.4 (t,
J＝33.3 Hz), 126.4, 123.8, 122.3, 112.0, 109.0 (t, J＝
248.2 Hz), 108.1 (t, J＝3.7 Hz), 63.7, 13.8; 19F NMR
888
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© 2013 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Chin. J. Chem. 2013, 31, 885—891

Direct Introduction of Ethoxycarbonyldifluoromethyl-Group to Heteroarenes
Results and Discussion
Table 1 Optimization of the reaction conditionsa
Ru(Phen)3Cl2 xH2O
(1.0 mol %)
Our initial investigation focused on the reaction of
3-methyl indole 1a with BrCF2CO2Et using
Ru(phen)3Cl2•xH2O as the photocatalyst and blue LEDs
as the source of visible light (Table 1). Unfortunately,
only a trace amount of the desired difluoromethylenated
product 2a were detected by 19F NMR spectroscopy and
GC-MS at room temperature with 1.0 mol% Ru(phen)3-
Cl2 in DMSO (Table 1, Entry 1). The yield was im-
+
BrCF2CO2Et
Blue LEDs
solvent, amine, r.t.
N
H
1a
CF2CO2Et
N
H
2a
Entry Amine
Solvent
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMF
Yield of 2a/%
proved to 16% by using triethylamine as a sacrificial
reductant to quench the Ru(II)* species (Entry 2). En-
couraged by this result, we next examined various
amines such as N,N-diisopropylethylamine (i-Pr2NEt),
tetramethylethylenediamine (TMEDA), triphenylamine
(Ph3N), N,N-dimethylaniline (PhNMe2), and 4,N,N-tri-
methylaniline (p-Me-C6H4-NMe2) (Entries 3－7). Al-
1
－
8
16
41
25
14
83c
75d
80
70
71
0
2
Et3N
3
iPr2NEt
TMEDA
Ph3N
4
5
i
6
p-Me-C6H4-NMe2
PhNMe2
though Pr2NEt, TMEDA and Ph3N all proved to be ef-
7
ficient stoichiometric electron donors used in photore-
dox catalysis,[7] they failed to improve the reaction yield
as expected and afforded the desired products in rela-
tively low yields (Entries 3－5). By contrast, the use of
4,N,N-trimethylaniline as the reductant significantly
accelerated this transformation, furnishing the desired
product 2a in 83% yield (Entry 6). N,N-Dimethylaniline,
a simple analogue of 4,N,N-trimethylaniline, was found
to be slightly less effective than 4,N,N-trimethylaniline
in the current reaction (Entry 7). Further screening of
different solvents disclosed that DMSO is the most effi-
cient solvent. Although a comparative yield was also
obtained when the reaction was conducted in DMF, the
reaction in DMSO gave more reproducible results (En-
try 8). Other solvents, such as N-methyl pyrrolidone
(NMP) and CH3OH, gave the desired product in slightly
lower yields, while toluene completely shut down the
desired reaction (Entries 9－11). Finally, control ex-
periments indicated that both photocatalyst and light are
required for this transfomation, and no trace amounts of
the desired products were observed in the absence of
any of them (Entries 12, 13). The desired difluoro-
methylenation reaction could also be induced by the use
of a 100W household light bulb as a light source, albeit
with moderate efficiency (Entry 14).
With the optimized reaction conditions in hand, we
next examined the substrate scope of the visible-light
photocatalyzed direct difluoromethylenation of het-
eroarenes, and found that this new protocol could allow
the direct and efficient incorporation of the －CF2CO2-
Et group into a wide range of heteroarenes, including
indoles, azaindoles, benzofurans, benzothiazoles, pyr-
roles, furans and thiazoles (Scheme 2). For these sub-
strates containing more than one reactive site, a mixture
of regioisomers were obtained with modest to excellent
regioselectivities (2o－2p, 2r) and the 2-substituted
isomers were preferentially formed due to the formation
of more stable benzylic radical as an intermediate.
Many important and potentially reactive functional
groups, such as alkyl and aromatic bromides, unpro-
8
p-Me-C6H4-NMe2
p-Me-C6H4-NMe2
p-Me-C6H4-NMe2
p-Me-C6H4-NMe2
p-Me-C6H4-NMe2
p-Me-C6H4-NMe2
p-Me-C6H4-NMe2
9
NMP
10
11
12e
13f
14g
MeOH
PhMe
DMSO
DMSO
DMSO
0
0
46
a Reaction conditions: 1a (0.2 mmol), BrCF2CO2Et (0.4 mmol),
Ru(phen)3Cl2•xH2O (1 mol%), amine (1.0 equiv.), solvent (2 mL),
r.t., 2 h, blue LEDs. b 19F NMR yield with fluorobenzene as an
c
internal standard. 15% yield of di-difluoromethylenated product
was also observed. d 14% yield of di-difluoromethylenated prod-
uct was also observed. No photocatalyst. f No light. g With a 100
e
W household light bulb.
tected alcohols, carboxylic acids, amides, and nitriles
were well tolerated under the mild reaction conditions
(2b, 2c, 2e－2p). Whereas unprotected alkyl amine did
undergo aminolysis to give the di-functionalized prod-
uct 2d in moderate yield. Indoles bearing electron-
withdrawing group, either on the benzene ring or the
pyrrole ring, proved to be viable substrates for this
transformation, whereas indole bearing electron-with-
drawing group on the pyrrole afforded the corre-
sponding product in comparatively lower yield (2g－2j).
Furthermore, 5-nitroindole did not react under the opti-
mized conditions, probably due to the presence of the
nitro group. This result provides additional evidence for
the single electron transfer (SET) mechanism proposed
in Scheme 1. Notably, the reaction has proven to be eas-
ily scaled up, and product 2s could be isolated in 40%
yield on a gram-scale.
Conclusions
In conclusion, a mild and efficient approach for the
direct incorporation of the －CF2CO2Et group into a
wide range of heteroarenes via visible-light photocata-
Chin. J. Chem. 2013, 31, 885—891
© 2013 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.cjc.wiley-vch.de
889

Lin, Chu & Qing
Scheme 2 Direct difluoromethylenation of heteroarenes with BrCF2CO2Et via visible light photocatalysisa
FULL PAPER
R1
R1
Ru(Phen)3Cl2 xH2O
(1.0 mol%)
R2
R2
BrCF2CO2Et
CF2CO2Et
p-methyl-C6H4-NMe2
DMSO, r.t.
X
X
X = N, O, S
2a - 2u
blue LEDs
1a - 1v
OH
CF2CO2Et
Br
CF2CO2Et
CF2CO2Et
N
H
N
N
H
H
2c 60%
2a 74%
2b 74%
COOH
CH2CONH2
NHCOCF2Br
CF2CO2Et
CF2CO2Et
CF2CO2Et
N
H
N
H
N
H
2d 47%b
2e 67%
2f 65%
CN
Br
F
CF2CO2Et
CF2CO2Et
CF2CO2Et
N
H
N
H
N
H
2i 68%c
2h 73%c
2g 26%c
Ph
MeO
CF2CO2Et
CF2CO2Et
CF2CO2Et
N
H
HO2C
N
N
N
H
H
2j 72%c
2l 65%c
2k 70%
Ph
3
CF2CO2Et
CF2CO2Et
2
CF2CO2Et
N
N
N
Boc
2o 32%
C2:C3 5:1
Ac
2n 65%
2m 77%
3
3
CF2CO2Et
CF2CO2Et
2r 92%d
2
CF2CO2Et
2q 42%
2
N
O
H
S
2p 32%
C2:C3 20:1
C2:C3 2.3:1
CF2CO2Et
2u 26%
CF2CO2Et
2t 33%
CF2CO2Et
S
O
N
2s 40%
[gram scale]
a
b
Reaction was conducted on a 1.6 mmol scale under the optimal conditions of Entry 6 in Table 1. Isolated yield. 3 equiv. of
BrCF2CO2Et. c Reaction was conducted on a 1.0 mmol scale. d 19F NMR yield.
Tozer, M. J.; Herpin, T. F. Tetrahedron 1996, 52, 8619; (e) Hu, J.;
Zhang, W.; Wang, F. Chem. Commun. 2009, 7465; (f) Lv, C.; Shen,
Q.; Liu, D. Chin. J. Org. Chem. 2012, 32, 1380; (g) Qing, F.-L. Chin.
J. Org. Chem. 2012, 32, 815
lysis has been developed. Ongoing efforts will focus on
the extension of the substrate scope of this transforma-
tion.
[2] (a) Guo, Y.; Shreeve, J. M. Chem. Commun. 2007, 3583; (b) Guo, C.;
Wang, R.-W.; Qing, F.-L. J. Fluorine Chem. 2012, 143, 135.
Acknowledgement
[3] (a) Kobayashi, Y.; Kumadaki, I. Tetrahedron Lett. 1969, 10, 4095;
(b) Weiming, Q.; Burton, D. J. Tetrahedron Lett. 1996, 37, 2745; (c)
Yokomatsu, T.; Murano, T.; Suemune, K.; Shibuya, S. Tetrahedron
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The National Natural Science Foundation of China
(Nos. 21072028, 21272036) and the National Basic Re-
search Program of China (No. 2012CB21600) are
greatly acknowledged for funding this work.
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Chin. J. Chem. 2013, 31, 885—891
© 2013 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.cjc.wiley-vch.de
891