The copper(ii)-catalyzed and oxidant-promoted regioselective C-2 difluoromethylation of indoles and pyrroles

Article abstract of DOI:10.1039/d0cc03345f

A novel and efficient approach for the highly selective C-2 difluoromethylation of indole derivatives was developed by using sodium difluoromethylsulfinate (HCF2SO2Na) as the source of difluoromethyl groups and a Cu(ii) complex as the catalyst. Various substrates were well tolerated in this transformation and the desired products were obtained in moderate to good yields. Moreover, the late-stage C-2 difluoromethylation of bioactive molecules containing an indole ring was achieved in good yields. Generally, this reaction features excellent functional group compatibility, broad substrate scope and excellent C-2 selectivity. This journal is

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DOI: 10.1039/D0CC03345F
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Copper (II)-catalyzed and Oxidant promoted regioselective C-2
difluoromethylation of indoles and pyrroles
Received 00th January 20xx,
Accepted 00th January 20xx
a
a
a
a
a
a
a
Dong Zhang, Zheng Fang, Jinlin Cai, Chengkou Liu, Wei He, Jindian Duan, Ning Qin, Zhao
b
a, *
Yang, and Kai Guo
DOI: 10.1039/x0xx00000x
7
A novel and efficient approach for the high selective C-2 organic synthesis. In this process, a great deal of effort has led
difluoromethylation of indole derivatives was developed by using to remarkable progress for introducing different functional
sodium difluoromethylsulfinate (HCF
2
SO
2
Na) as the source of groups into the C-2 position of indoles with the assistance of
8
difluoromethyl and Cu (II) complex as the catalyst. Various N-directing groups via transition-metal-catalysis. However,
substrates were well tolerated in this transformation and the the high selective and direct introduction of fluorine-
desired products were obtained in moderate to good yields. containing groups into the C-2 position of indoles by C − H
Moreover, the late-stage C-2 difluoromethylation of bioactive bond functionalization was less reported and only a few
9
molecules containing indole ring was achieved in good yields. examples are available (scheme 1a). Consequently, to develop
Generally, this reaction features excellent functional group a high selective and efficient strategy for the direct
compatibility, broad substrate scope and excellent C-2 selectivity.
incorporation of difluoromethyl into the C-2 position indole is
necessary.
Recently, the addition of fluorine atoms into organic
molecules has emerged as a widely employed strategy in
pharmaceutical and agrochemical research due to the
profound impact of fluorine atoms on the chemical, physical
a) Previous work of introducing fluorine-containing groups into indoles
R
[Ni]
R
CH2CF3
N
+
CF3CH2I
N
N
N
N
N
N
1
and biological properties of organic molecules. Among many
OSO2Ar
OSO2Ar
R
[Rh]
R
fluorinated groups, the difluoromethyl group have gained
considerable attention because it can act as a more lipophilic
bioisosteres 2 of alcohols, hydroxamic acid, or amide group.
+
N
F
F
N
F
F
N
N
N
3
Moreover, compared to -CF
3
group the -CF
2
H group possesses
R
[Cu]
R
CF2CO2Et
+
BrCF2CO2Et
N
N
weakly acidic and can build the hydrogen-bonding interactions
to improve the binding selectivity of biologically active
compounds.4 Therefore, allowing the introduction of
N
N
N
N
N
b) Our work
R
O
S
R
CF2H
[Cu]
difluoromethyl groups into some natural drug precursors has
N
+ HF2C
ONa
N
5
N
attracted great interest from chemists in recent years.
N
N
Indole is ubiquitous structural motif in natural products,
marketed drugs, agrochemicals, fragrances, and materials
sciences. Therefore, the introduction of fluorine atoms into
35 examples
Up to 85 % yield
Scheme 1 The methods of introducing fluorine-containing groups into indoles.
6
indole is very meaningful and useful. Recently, the transition-
metal-catalyzed C-H bond functionalization has provided
straightforward and atom-economical method in modern
Over the past few years, the radical-participated single-
10
electron-transfer (SET) pathway
has become an effective
practice for realizing the C-2 substituted indoles via an efficient
and environmentally friendly procedure. In this way, the C-2
1
1
12
13
position benzylation , acylation , sulfonylation
cyanomethylation
and
a. College of Biotechnology and Pharmaceutical Engineering Nanjing Tech
University, 30 Puzhu Rd S., Nanjing, 211816, China Email: guok@njtech.edu.cn,
Tel +86 25 5813 9901, Fax +86 25 5813 9935.
14
of indoles have been successfully
SO Na (R =CF H,
F) were examined as excellent difluoromethyl
achieved. Remarkably, sodium sulfinates R
CF Ph, and CH
f
2
f
2
b.
College of Engineering China Pharmaceutical University, 24 Tongjiaxiang, Nanjing,
2
2
2
10003, China.
radical source in single-electron-transfer (SET) pathway, Hu
and co-workers has successfully used those sodium sulfinates
in the fluoroalkylative aryl migration of conjugated N-
†
Email: guok@njtech.edu.cn (K. Guo), fzcpu@163.com (Z. Fang), Tel +86 25 5813
9
926, Fax +86 25 5813 9935.
Electronic Supplementary Information (ESI) available: [details of any
supplementary information available should be included here]. See
DOI: 10.1039/x0xx00000x
1
5
arylsulfonylated amides. Based on the inspiring results, we
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Journal Name
herein introduce a new method to achieve the high selective reaction efficiency, and reducing the temperVaiteuwrAerticlwe Oonulinlde
C-2 difluoromethylation in indoles by utilizing pyrimidinyl as a inhibit the generation of 3a (TableDO1I:,10e.1n03tr9i/eDs0C1C803–32415)F.
directing group, sodium difluoromethylsulfinate (HCF SO Na) Therefore, the conditions used in entry 4 were selected as the
2 2
as the source of difluoromethyl, which proceeds via Cu- best reaction conditions.
catalyzed (scheme 1b).
Table 2 Substrate scope for the indoles a, b
We initiated our studies by probing various reaction
CuCl2 (10 mol%)
conditions for the desired C-H difluoromethylation at the C-2
position of N-pyrimidyl indole 1a with sodium
difluoromethylsulfinate 2 (Table 1).
O
S
K2S2O8 (3 equiv.)
R
CF2H
R
+
2
HF C
ONa
N
N
CH3CN (2 mL)
50 o
C
N
N
N
N
1
2 (1.5 equiv.)
a, R1=H, 77%
3
Table 1 Optimization of the reaction conditions a
R1
3
O
CF2H 3b, R1=Me, 85%
X-ray
structure of 3c
H
CF2H
N
3c, R =COOCH , 65%
S
Cat.,oxidant
Solvent, temp
1
3
N
+ HF2C
ONa
N
1
3d, R =CN, 57%
N
N
N
N
3k, R =Me, 79%
N
3
N
R2
3l, R3=OMe, 75%
3e, R2=Me, 81%
R3
3m, R3=OBn, 70%
1a
2
3a
3f, R =OMe, 77%
2
CF2H
CF2H 3n, R3=F, 69%
3g, R2=OBn, 71%
h, R2=F, 73%
N
N
3o, R =Cl, 72%
3
3
N
3i, R =Cl, 68%
N
3p, R3=Br, 63%
Oxidant
equiv.)
Temp.
(°C)
50
50
50
50
50
50
50
50
50
50
50
50
50
50
50
50
50
70
60
40
30
Yield b
(%, 3a)
48
N
2
N
3q
,
R3=I, 59%
r, R3=NO2, 38% c
3j, R2=Br, 61%
Entry
Catalyst
Solvent
3
3
(
s, R3=CN, 48%
1
2
3
4
5
6
7
8
9
CuI
CuBr
CuCl
CuCl
Cu(OAc)
K
K
K
K
K
2
2
2
2
2
S
S
S
S
S
2
2
2
2
2
O
O
O
O
O
8
8
8
8
(3)
(3)
(3)
(3)
(3)
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
THF
DCE
DMF
DMSO
CH
CH
CH
CH
3
3
3
3
3
3
3
3
3
3
3
3
3
CN
CN
CN
CN
CN
CN
CN
CN
CN
CN
CN
CN
CN
CF H 3t, R4=Me, 78%
2
CF H
2
3
w, X=C, R5=Me, 77%
3x, X=C, R5=Et, 79%
3y, X=N, 33%
3u, R4=Cl, 71%
N
R4
N
X
42
3v, R4=COOCH3, 67%
N
R5
N
N
N
52
O
O
O
c
O
O
2
77
O
N
N
63
65
70
51
0
O
2
8
H
O
CF2H
CF2H
N
CF2H
CuCl
CuCl
CuCl
CuCl
CuCl
CuCl
CuCl
CuCl
CuCl
CuCl
CuCl
CuCl
CuCl
CuCl
CuCl
CuCl
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
Na
(NH
2
S
)
2
O
8
(3)
(3)
N
N
4
2
S
2
O
8
N
N
N
N
N
N
H
3
K
5
O
18
S
4
3
z (76%)
3za (68%)
3zb (77%)
From auxin
TBHP (3)
DTBP (3)
PIDA (3)
From melatonin
From tryptophan
1
1
1
1
1
1
1
1
1
1
2
2
0
1
2
3
4
5
6
7
8
9
0
1
0
trace
68
47
28
37
0
trace
72
76
69
56
a
Reaction conditions: 1 (0.2 mmol), 2 (1.5 equiv.), CuCl
equiv.), CH CN (2 mL), stirred at 50 °C for 24 h in a 15 mL sealed tube.
2
(10 mol%), K
2
S
2
O
8
(3
K
K
K
K
K
K
K
K
K
K
2
2
2
2
2
2
2
2
2
2
S
S
S
S
S
S
S
S
S
S
2
2
2
2
2
2
2
2
2
2
O
O
O
O
O
O
O
O
O
O
8
8
8
8
8
8
8
8
8
8
(4)
(2)
(3)
(3)
(3)
(3)
(3)
(3)
(3)
(3)
b
Isolated
3
o
c
yield. 80 C.
With the set of optimized reaction conditions in hand, we
first investigated the scope of various indole motifs in this
direct C-2 difluoromethylation process. As shown in Table 2, a
variety of substituted N-pyrimidyl indoles which bearing both
electron-donating and -withdrawing groups were examined
under the optimized conditions, and the corresponding
products were obtained in smoothly. Notably, this
3
CN
3
CN
3
CN
3
CN
a
Reaction conditions: 1a (0.2 mmol, 1.0 equiv.), 2 (1.5 equiv.), catalyst (10 mol%), transformation was found to be highly tolerable with C-3
b
1
oxidant, Solvent (2.0 mL), stirred under air in a 15 mL sealed tube for 24 h.
NMR yield using CH
H
substituted indole 1b and furnished the desired product 3b in
5% yield. The molecular structure of compound 3c was also
c
Br
2 2
as the internal standard. Isolated yield.
8
confirmed by X-ray single crystal analysis. Additionally, the C-4,
C-5, and C-6 substituted indoles also reacted well, the C-2
difluoromethylation products were afforded in moderate to
good yields (3e-3v). Screening of the substitution effect
showed that N-pyrimidyl indoles substituted by electron-
donating groups gave the corresponding products in higher
yields. But, the reaction efficiency of the substrates with cyano
and nitro groups were significantly reduced, the corresponding
products 3d, 3r and 3s were obtained only in 57%, 38% and
Firstly, different copper catalysts including monovalent and
divalent copper were tested. The results showed that CuCl
performed better than the others, affording the desired
2
product 3a in a 77% isolated yield (Table 1, entries 1-5). Then,
2 2 8 4 2 2 8
several oxidants such as Na S O , (NH ) S O , oxone, TBHP
(tert-Butyl hydroperoxide), DTBP (di-tert-butyl peroxide) and
PIDA ((diacetoxyiodo) benzene) were examined, the results
indicated that none of them could match the efficiency of
K
2
S
2
O
8
(Table 1, entries 6–11). The effect of the K
was also investigated, but unsatisfactory yields were obtained
when the loading of K was changed (Table 1, entries 12–
3). Moreover, different solvents were screened, and
compared to these solvents CH CN was confirmed to be the
2 2 8
S O loading
4
8% yields respectively. In addition, C-7 substituted indoles
were also found to proceed well under these reaction
conditions, the corresponding products 3w and 3x were
isolated in 77% and 79% yields, mostly important the N-
pyrimidyl 7-azaindole was also react smoothly in this
transformation, the corresponding products 3y was obtained
in 33% yield. Moreover, three examples of late-stage C-2
2 2 8
S O
1
3
optimal solvent for this reaction (Table 1, entries 14–17).
Meanwhile, rising the temperature would not improve the
2
| J. Name., 2012, 00, 1-3
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difluoromethylation succeeded using N-pyrimidyl melatonin,
tryptophan, and auxin derivative as the substrates (3z-3zb).
To further demonstrate the synthetic effectiveness of this
methodology, a gram-scale reaction was carried out by using
View Article Online
DOI: 10.1039/D0CC03345F
2 2
Furthermore, we were glad to find that the Cu (II)-catalyzed 1a (6 mmol, 1.17 g) and HCF SO Na (1.5 equiv.) under the
selective C-2 difluoromethylation was not restricted to indoles standard reaction conditions (see supporting information 2.4).
as the substrate. Indeed, biologically relevant pyrrole We were pleased to discover that product 3a could be
heterocycles also underwent the reaction with good yields to obtained in a 65% isolated yield. Furthermore, the pyrimidyl
provided difluoromethylation product (Table 3, 5a-5d). moiety could be easily removed under mild conditions to
1
6
Interestingly, when substituted pyrroles were proceed as obtain free N-H indole in 68% yield. These results suggested
substrates under standard conditions, only the mono- that the methodology is an efficient and practical process for
difluoromethylation products were obtained. This is mostly introducing of difluoromethyl group into indoles (see
due to the strong electron withdrawing effect of supporting information 2.5).
difluoromethyl, making it difficult to continue the
In order to shed light on the mechanism of this reaction, a
bisdifluoromethylation. In the case of 4c and 4d as the series of control experiments were performed (Scheme 2).
substrates, difluoromethylation was found to prefer the C-2 First, the substrate 1a was examined in the absence of any
position rather than the C-5 position (5c, 5d). This showed that copper catalysts and the corresponding difluoromethylation
the ester group in C-3 position also participated in product was not found. Second, the treatment of 1a with
coordination with copper. Moreover, N-pyrimidyl carbazole Tempo (3 equiv.) was tested under the standard reaction
was also subjected to the optimized reaction conditions, to our conditions and the result showed that the formation of 3a was
delight the mono-difluoromethylation product 5e was completely suppressed, suggesting the involvement of a
obtained in 65% yield.
radical pathway in the reaction.
Table 3 Substrate scope for the pyrroles a, b
O
CF2H
N
S
K2S2O8 (3 equiv.)
CH3CN, 50 o
N
+
CuCl2 (10 mol%)
HF C
ONa
ONa
R
R
2
O
S
N
C
N
K2S2O8 (3 equiv.)
CF2H
N
N
N
N
F
H
ONa
1a
3a (0%)
CH3CN (2 mL)
CuCl2 (10 mol%)
K2S2O8 (3 equiv.)
N
N
F
N
N
0 o
O
S
5
C
CF2H
+
N
HF2C
N
4
2 (1.5 equiv.)
5
CH CN, 50 oC
3
O
O
N
Tempo (3 equiv.)
N
N
N
O
O
C-5
1a
3a
(0%)
N
CF2H
N
CF2H
N
2
CF H
Scheme 2 Control experiments.
CF2H
N
C-2
C-5
C-2
N
CF2H
N
N
N
N
N
N
N
N
N
N
e (65%)
Finally, a kinetic isotope effect (KIE) was observed in an
intermolecular experiment using 1a and 1a-D as substrates
see supporting information 2.6). The k /k ratio was 1.3 for
5
a (71%)
5b (73%)
5c (61%)
5d (70%)
5
3
(
H
D
a
Reaction conditions: 4 (0.2 mmol), 2 (1.5 equiv.), CuCl
2
(10 mol%), K
CN (2 mL), stirred at 50 °C for 24 h in a 15 mL sealed tube. b Isolated
3
2 2 8
S O (3
the experiment between 1a and 1a-D
isotope effect suggested that the cleavage of the C(sp )–H
bond was not the rate-determining step of this
3
. The significant kinetic
equiv.), CH
yield.
2
Then, several N-protecting groups on indoles were transformation.17
examined for the C-2 difluoromethylation under the optimal
conditions (Table 4, 6a-10a). When the directing group was
changed from N-pyrimidyl to N-pyridyl or N-thiazolyl the
desired products 6a and 7a were obtained in much lower yield
N
N
CuCl2
N
K2S2O8
1a
4
0% and 53% respectively. Furthermore, indole 8 with N-acetyl
CF2HSO2Na
K2S2O8 SET
CF2H Cu (I)
Cu (II)
N
N
was less reactive for this transformation. Meanwhile, N-methyl
protected indole 9 and unprotected N-H indole 10 could not
afford the target product. These results suggested that a
strong coordination directing group is necessary for the high
efficiency in this reaction.
N
N
N
N
CF2H
A
3
a
CF2H
Cu
N
(III)
N
N
B
Table 4 Substrate scope for the N-protecting indoles a, b
Scheme 3 Plausible mechanism.
CF2H
According to the experimental results and previous
literature reports, a plausible mechanistic pathway for the
formation of 3a is depicted in Scheme 3. Initially, the Cu (II)
coordinated with 1a to provide the metallacycle intermediate
CF2H
2
CF H
CF2H
2
CF H
N
N
N
N
N
H
N
N
O
S
6
a (40%)
7a (53%)
8a (31%)
9a (0%)
10a (0%)
1
8
a
A. Meanwhile, potassium peroxydisulphate may decompose
Reaction conditions: 6-10 (0.2 mmol), 2 (1.5 equiv.), CuCl
2
(10 mol%), K
2 2 8
S O (3
1
9
to the sulfate radical anion upon heating. Then, HCF SO Na
2
2
equiv.), CH
yield.
3
CN (2 mL), stirred at 50 °C for 24 h in a 15 mL sealed tube. b Isolated
reacts with the sulfate radical anion to form a difluoromethyl
radical by single-electron-transfer (SET) pathway. After this,
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 3
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Journal Name
Y.-L. Xiao, S. Zhang, and X. Zhang, Angew. ChVeiemw A.rtIinclte.OEnldin.e,
2018, 57, 6921-6925.
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Yamada, Nat. Prod. Rep., 2005, 22, 73-103.
the difluoromethyl radical reacts with intermediate A to form
2
0
DOI: 10.1039/D0CC03345F
complex B by free-radical addition. Finally, with the reductive
elimination the difluoromethylated product 3a and Cu(I)
species were obtained. The Cu(I) species will oxidized by
6
7
2 2 8
K S O then takes part in the next catalytic cycle.
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In conclusion, we have developed a simple and efficient Cu
(
II) catalyzed method for the high selective C-2
difluoromethylation of N-pyrimidyl protected indoles and
pyrroles using K as the oxidant and HCF SO Na as ideal
S O
2 2 8
2
2
difluoromethyl source. This novel method tolerates various
important and useful functional groups, and the reaction
proceeds smoothly to provide the corresponding products
from moderate to good yields. Moreover, this approach is also
successfully used for the late-stage C-2 difluoromethylation of
bioactive compounds such as auxin, tryptophan, and
melatonin derivatives with good yields.
8
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Conflicts of interest
There are no conflicts of interest to declare.
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Acknowledgements
The research has been supported by the National Key Research
and Development Program of China (2016YFB0301501), the
National Natural Science Foundation of China (Grant No.
1
7, 4094-4097.
(a) S.-Y. Yan, Z.-Z. Zhang and B.-F. Shi, Chem. Commun., 2017,
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DOI: 10.1039/D0CC03345F
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35 examples