Visible-light-induced direct C(sp3)-H difluromethylation of tetrahydroisoquinolines with the in situ generated difluoroenolates

Article abstract of DOI:10.1039/c4cc02768j

An effective approach to C1-difluoromethylated tetrahydroisoquinoline derivatives has been developed through C-H functionalization of tertiary amines by visible-light photoredox catalysis. This method uses stable, easily obtained α,α-difluorinated gem-dio

Full text of DOI:10.1039/c4cc02768j

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Visible-light-induced direct C(sp3)–H
difluromethylation of tetrahydroisoquinolines
with the in situ generated difluoroenolates†
Cite this: Chem. Commun., 2014,
50, 7521
Received 15th April 2014,
Accepted 21st May 2014
Weipeng Li,a Xuebin Zhu,a Haibin Mao,a Zhongkai Tang,a Yixiang Chenga and
Chengjian Zhu*ab
DOI: 10.1039/c4cc02768j
www.rsc.org/chemcomm
An effective approach to C1-difluoromethylated tetrahydroisoquino-
line derivatives has been developed through C–H functionalization
of tertiary amines by visible-light photoredox catalysis. This method
uses stable, easily obtained a,a-difluorinated gem-diol as the CF2
source. The corresponding products were obtained in moderate to
high yields at ambient temperature.
Fluorinated organic compounds have attracted considerable
attention from the pharmaceutical, chemical, and agrochemical
industries due to their beneficial effects on the physiochemical
properties and pharmacological profiles of drugs.1 Over the past
decades, great efforts have been dedicated to developing efficient
methods to introduce trifluoromethyl and monofluoromethyl
Scheme 1 Difluoromethylation of tertiary amines.
We began our study by coupling N-aryl substituted tetra-
groups into molecules.2 However, the development of available hydroisoquinoline 1a with a,a-difluorinated gem-diol 2a in the
and practical difluoromethylation methods remains largely elusive presence of
a catalytic amount of commercially available
and represents a challenge.3 Recently, it was found that generation Ru(bpy)3Cl2. Unfortunately only a trace amount of desired product
of nucleophilic a,a-difluoroenolates using a,a-difluorinated was detected accompanied by the difluorinated compound due to
gem-diols is an efficient strategy to install the CF2 group into the mismatch between reaction rates of the C–C bond cleavage and
useful scaffolds.4 For the past few years, visible light photoredox the formation of imine (see details in ESI†). We envisioned that
catalysis has emerged as a powerful method to functionalize adding the a,a-difluorinated gem-diol to the reaction system after
a large number of organic compounds.5 With our continual full conversion of the iminiums7q,r should be helpful to prevent the
interest in photoredox catalysis,6 we focus our attention on direct undesired side reaction.
C–H difluoromethylation of tertiary amines by means of visible-
Next, we investigated the reaction using Ru(bpy)3Cl2 as a
light photoredox catalysis, since the tertiary amines could produce catalyst and CCl4 as an oxidant, and 58% yield was obtained
the highly active iminium ions by irradiation with visible-light.7 In (Table 1, entry 1). Encouraged by this result, the reaction conditions
2009, Qing and co-workers reported copper-catalyzed oxidative were screened in detail. Firstly, different oxidants were tested and it
difluoromethylation of tertiary amines by using TBHP as an was found that the oxidant played an important role in the reaction
oxidant.8 Thus, our protocol to use gem-diols for visible light because the yields decreased sharply when either CBrCl3 or CBr4 was
photoredox difluoronation of tertiary amines could be a new and used (Table 1, entries 2 and 3). It was found that CH3CN was the best
efficient protocol to introduce difluoromethylene into nitrogen- solvent after screening various organic solvents (Table 1, entries 4–7).
containing compounds (Scheme 1).
Notably, the yield could be improved to 77% by increasing the NEt3
loading to 4 equiv. (entry 9). In addition, other bases could not
efficiently improve the yields (Table 1, entries 10–13).
With the established optimal reaction conditions in hand, we
next engaged in expanding substrate scope. First, various tetra-
hydroisoquinolines were tested and the desired products could be
obtained in good to excellent yields (60–95%, Table 2, entries 1–15).
It was found that N-aryl substituted tetrahydroisoquinolines
a State Key Laboratory of Coordination Chemistry, School of Chemistry and
Chemical Engineering, Nanjing University, Nanjing 210093, P. R. China.
E-mail: cjzhu@nju.edu.cn
b Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences,
Shanghai 200032, China
† Electronic supplementary information (ESI) available. See DOI: 10.1039/
c4cc02768j
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Table 1 Optimization of reaction conditionsa
Entry
Oxidant
Solvent
Base
Yieldb (%)
1
2
3
4
5
6
7
8
CCl4
CBrCl3
CBr4
CCl4
CCl4
CCl4
CCl4
CCl4
CCl4
CCl4
CCl4
CCl4
CCl4
CH3CN
CH3CN
CH3CN
CH2Cl2
THF
NEt3 (2 equiv.)
NEt3 (2 equiv.)
NEt3 (2 equiv.)
NEt3 (2 equiv.)
NEt3 (2 equiv.)
NEt3 (2 equiv.)
NEt3 (2 equiv.)
NEt3 (3 equiv.)
NEt3 (4 equiv.)
DABCO (4 equiv.)
K2CO3 (4 equiv.)
K3PO4 (4 equiv.)
Mg(OtBu)2 (4 equiv.)
58
22
28
54
NR
36
25
69
77
56
55
44
25
DMF
DMSO
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
9
10
11
12
13
a
The reactions were carried out with 1a (0.2 mmol), an oxidant
(0.8 mmol,), and Ru(bpy)3Cl2 (1 mol%) in CH3CN (2 mL) at room
temperature and 5 W blue LED for 24 hours. Then light was turned off,
2a (0.4 mmol) and base (0.8 mmol) were added, and the reaction was
b
carried for another 30 minutes at room temperature. Isolated yield.
bearing electron-donating groups could furnish higher yields than
those bearing electron-withdrawing groups. For example, N-3,4-
dimethylphenyl substituted tetrahydroisoquinoline afforded
the desired product 3h in 95% yield, but the substrate bearing
a strong electron-withdrawing CF3 on the phenyl ring could
only produce the product 3i in 36% yield, even when the
oxidation reaction time was increased to 60 hours. The position
of substituents on the N-aryl groups also significantly influenced
Scheme 2 The reactions were carried out with 1a (0.2 mmol), CCl4
(0.8 mmol) and Ru(bpy)3Cl2 (1 mol%) in CH3CN (2 mL) at room tempera-
ture and 5 W blue LED for 24 hours. Then 2 (0.4 mmol) and NEt3 (0.8 mmol)
were added, and the reaction was carried out for another 30 minutes at
room temperature. Isolated yields.
Table 2 The reaction scopea
the reaction results. para-Substituted analogues generally provided
higher yields compared to meta-substituted (3b vs. 3j, 3d vs. 3k)
and ortho-substituted (3b vs. 3j) substrates. N-Benzyl substituted
substrate 1o was also found to be effective for the reaction, and
61% yield was obtained. When N,N-dimethylaniline was tested,
no desired product was detected (Table 2, entry 16). Next, we
examined the reaction scope with various substituted gem-diol
derivatives (Scheme 2). The experimental results suggested that
a,a-difluorinated gem-diols with a variety of substituted groups
could give the desired products in moderate to good yields. Electro-
nic properties of substituted groups had little influence on reaction
yields (4b–4m). In consideration of the prevalence of heteroarenes in
drug molecules, heteroaromatic substrates (4k, 4l) were tested, and
good yields were obtained. It is worth mentioning that the deloca-
lized conjugated substrate (4m) was also a viable participant which
further expanded the substrate scope.
Entry
R1
1
3
Yieldb (%)
1
2
3
4
5
6
7
8
C6H5
4-F-C6H4
1a
1b
1c
1d
1e
1f
1g
1h
1i
1j
1k
1l
1m
1n
1o
3a
3b
3c
3d
3e
3f
3g
3h
3i
3j
3k
3l
3m
3n
3o
77
72
63
55
77
63
89
95
36
60
52
62
87
76
61
NR
4-Cl-C6H4
4-Br-C6H4
4-OMe-C6H4
4-Me-C6H4
4-t-Bu-C6H4
3,4-Me-C6H3
4-CF3-C6H4
3-F-C6H4
3-Br-C6H4
2-F-C6H4
2-OMe-C6H4
C6H5
9c
10
11
12
13
14d
15
16
Bn
N,N-Dimethylaniline
a
The reactions were carried out with 1 (0.2 mmol), CCl4 (0.8 mmol,),
and Ru(bpy)3Cl2 (1 mol%) in CH3CN (2 mL) at room temperature and
5 W blue LED for 24 hours. Then light was turned off, 2a (0.4 mmol) and
NEt3 (0.8 mmol) were added, and the reaction was carried out for
The possible mechanism is shown in Scheme 3. At first,
irradiation of Ru(bpy)3(II) by visible light generates the excited-
state *Ru(bpy)3(II) which could be reductively quenched by
N-phenyl-tetrahydroisoquinoline accompanied by the formation
b
c
another 30 minutes at room temperature. Isolated yield. Reaction
time for the oxidation step lengthened to 60 hours. 6,7-Dimethoxy-
1,2,3,4-tetrahydroisoquinoline was used. NR = no reaction.
d
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Scheme 3 Possible mechanism.
of radical cation 4 and Ru(bpy)3(I).7q The resulting Ru(bpy)3(I)
reduces CCl4 to the chlorine anion and the trichloromethyl
radical. The trichloromethyl radical abstracts the H-atom from
radical cation 4 generating iminium 5. Under basic conditions,
a,a-difluorinated gem-diol 2 undergoes trifluoroacetate-release
through C–C bond fragmentation which could in situ generate
difluoroenolate 6. This active intermediate could be rapidly
trapped by iminium 5 to generate product 3.
In summary, we have developed an effective method to
synthesize C1-difluoromethylated N-aryltetrahydroisoquinolines by
means of visible-light photoredox catalysis using a,a-difluorinated
gem-diol as a difluoromethylene reagent under mild conditions.
This protocol was fairly feasible and easy-to-handle, and inexpensive
reagent CCl4 was used here as the sacrificial oxidant.
We gratefully acknowledge the Nature National Science Founda-
tion of China (21172106, 21074054, 21372114), the National Basic
Research Program of China (2010CB923303) and the Research
Fund for the Doctoral Program of Higher Education of China
(20120091110010) for their financial support.
Notes and references
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This journal is ©The Royal Society of Chemistry 2014
Chem. Commun., 2014, 50, 7521--7523 | 7523