Visible-light-induced radical isocyanide insertion protocol for the synthesis of difluoromethylated spiro[indole-3,3′-quinoline] derivatives

Article abstract of DOI:10.1039/d0cc06645a

Herein, we report the first protocol for visible-light-induced radical isocyanide insertion reactions between 3-(2-isocyanobenzyl)-indoles and bromodifluoroacetates or bromodifluoroacetamides. The protocol, which has good functional group tolerance and a broad substrate scope, constitutes an efficient and general route to difluoromethylated spiro[indole-3,3′-quinoline] derivatives. This journal is

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DOI: 10.1039/D0CC06645A
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Visible-Light-Induced Radical Isocyanide Insertion Protocol for
Synthesis of Difluoromethylated Spiro[indole-3,3'-quinoline]
Derivatives
Received 00th January 20xx,
Accepted 00th January 20xx
Jingjing Zhang,a,b,‡Wentao Xu,a,‡ Yi Qu,a Yuxiu Liu,a Yongqiang Li, a Hongjian Song,a,* and Qingmin
Wanga,*
DOI: 10.1039/x0xx00000x
Herein, we report the first protocol for visible-light-induced radical methods for introducing fluorine-containing groups, such as the
isocyanide insertion reactions between 3-(2-isocyanobenzyl)- difluoroalkyl group, into molecules.3 The difluoroalkyl group,
indoles and bromodifluoroacetates or bromodifluoroacetamides. which is an isostere of oxygen, can improve the lipotropy and
The protocol, which has good functional group tolerance and a absorption of drugs and has been widely used in drug and
broad substrate scope, constitutes an efficient and general route to pesticide design. The groups of Zhang, Fan, Wang, Liang, Zhu,
difluoromethylated spiro[indole-3,3'-quinoline] derivatives.
Yu, and Buchwald etc. have reported excellent work in this
area.4
Radical isocyanide insertion reactions of 2-isocyanobiphenyls with difluoroalkyl radicals
3-Spiroindole and spiroindolenine moieties are present in the
core skeletons of many naturally occurring and synthetic
molecules (Figure 1).1 These compounds and their derivatives
show a wide range of pharmacological activities, including
antitumor,1e,1f antithrombotic,1g and insecticidal1h activities. In
addition, they are versatile intermediates for the synthesis of
tetrahydrocarbolines and tetrahydrocarbazoles.2
CF
2CO2Et (X = Br, TMS)
X
R2
R2
CF
Ar 2COOK
R1
R1
N
CF2Y
NC
CF
PhSO2 2H
Y = CO2Et, PhSO2, Ar, H
This work
R1
CF
Br 2COXR
CN
R1
fac-Ir(ppy)3 (1 mol %)
NaHCO3 (2 equiv)
blue LED,
N
N
O
Me
OH
F
N
N
Me
H
F
R2
R3
R2
R3
O
DMSO, rt, 24 h
H
X = O, N
H
N
H
N
N
X
R
H
H
N
N
H
O
OH
H
N
H
O
(+)-aspidospermidine
26 examples
up to 91% yield
(-)-tubifoline
(-)-strychnine
spirobacillene B
Scheme 1. Radical isocyanide insertion reactions for the synthesis of
difluoromethylated nitrogen heterocycles
N
N
NH
N
O
N
Cl
Me
F
F
Cl
O
N
N
H
N
H
N
Isocyanides are important building blocks in multicomponent
reactions.5 Recently, reactions involving insertion of radicals
into isocyano groups have emerged as an efficient and powerful
strategy for the construction of azaheterocycles such as
phenanthridines,6 indoles,7 quinolines,8 quinoxalines,9 and
isoquinolines.10 Isocyanides have also been widely used for the
construction of molecules with fluorine-containing heterocyclic
rings, but most of the reported difluoroalkylation reactions of
isocyanides yield phenanthridine derivatives (Scheme 1). For
example, Yu et al. synthesized 6-alkylated phenanthridine
derivatives by means of photoredox-neutral somophilic
isocyanide insertion reactions,11 and Dolbier et al. used
difluoromethylation and 1,1-difluoroalkylation reactions of
biphenyl isocyanides to synthesize 6-(difluoromethyl)- and 6-
N
N
O
Cl
N
O
O
HN
H
OCF3
antitumor activity
insecticide
inhibitor of SYK kinase
P2Y1 antagonist
Figure 1. Representative naturally occurring and synthetic molecules bearing a 3-
spiroindole or 3-spiroindolenine skeleton
Because of the special bioactivities of fluorine-containing
pharmaceuticals, much research effort has been directed at
a State Key Laboratory of Elemento-Organic Chemistry, College of Chemistry,
Collaborative Innovation Center of Chemical Science and Engineering (Tianjin),
Nankai University, Tianjin 300071, People’s Republic of China.E-mail:
songhongjian@nankai.edu.cn (H. S.);wangqm@nankai.edu.cn (Q. W.)
b Tianjin Agricultural University, Tianjin 300384, People’s Republic of China.
‡ These authors contributed equally
Electronic Supplementary Information (ESI) available: General experimental
procedures, characterization data, free radical capture experiments, light on/off
experiments, and 1H 19F, and 13C NMR spectra of new compounds. See
DOI: 10.1039/x0xx00000x
(1,1-difluoroalkyl)phenanthridines via
a strategy involving
tandem addition/cyclization/oxidation reactions.12 Hao et al.
developed a protocol for C–CF2 bond formation by means of
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silver-catalyzed oxidative decarboxylation reactions of
Journal Name
We began by examining the reaction of isocyanide 1a with
View Article Online
difluoroacetates.13 In addition, these investigators performed a ethyl bromodifluoroacetate (2a) (Table 1). When fac-Ir(ppy)3 (1
similar transformation using difluoroalkyl trimethylsilane as a mol %) was used as the catalyst and K2HPO4 (2 equiv) was used
free radical precursor under oxidative conditions with silver as the base, reaction in DMF at room temperature under an Ar
DOI: 10.1039/D0CC06645A
catalysis.14
Hu
et
al.
reported
radical atmosphere for 24 h with irradiation by a 3 W blue LED
(phenylsulfonyl)difluoromethylation reactions of isocyanides (approximately 2 cm away from the reaction vessel) afforded
with PhSO2CF2H as a radical precursor under transition-metal- desired product 3a in 59% isolated yield (entry 1). Attempting
free conditions; in these reactions, a proton acts as a leaving to improve the yield, we evaluated other bases (entries 2−11)
group, which makes them more atom-economical than and found that NaHCO3 was the most effective, increasing the
reactions involving previously reported free radical yield of 3a to 77% (entry 6). The other photoredox catalysts that
precursors.15
we tested failed to catalyze the desired reaction (entries 12−
In contrast, there have been relatively few reports on the use 15). We then evaluated solvents other than DMF (entries 16−
of difluoroalkylation reactions of isocyanides to construct other 18) and found that DMSO increased the yield of 3a to 86% (entry
heterocyclic skeletons.16 Visible-light promoted spirocylizations 16). The catalyst, the argon atmosphere, and the blue LED were
of indole derivatives have been reported in the literature.17 necessary for the reaction (entries 19–21). These experiments
However, the difluoromethylation of these skeletons has rarely revealed the best reaction conditions to be as follows: 1 mol %
been reported. Herein, we report the first protocol for visible- fac-Ir(ppy)3 as the photocatalyst, NaHCO3 (2 equiv) as the base,
light-induced radical isocyanide insertion reactions that afford DMSO as the solvent, 3 W LED as the light source, room
molecules with
a
difluoromethylated spiro[indole-3,3'- temperature, Ar atmosphere, 24 h.
quinoline] skeleton, which has never been reported any in
naturally occurring or synthetic compounds.
R1
CN
fac-Ir(ppy)3 (1 mol %)
NaHCO3 (2 equiv)
blue LED
R1
N
BrCF2CO2Et
Table 1. Optimization of Reaction Conditionsa
+
R2
R3
DMSO, rt, 24 h
CF2CO2Et
R3
N
R2
CN
H
N
catalyst (1 mol %)
1
2a
3
base (2.0 equiv)
blue LED
N
BrCF2CO2Et
+
R1
Me
solvent, rt, 24 h
CF2CO2Et
Me
N
H
3b, R1 = F, 44%
3c
Me
N
, R1 = Cl, 67%
1a
2a
3a
N
N
N
N
, R1 = Br, 72%
3d
CF2CO2Et
, R1 = Me, 87%
CF2CO2Et
3e
CF2CO2Et
CF2CO2Et
, R1 = OMe, 91%
N
N
3f
N
N
entry
1
catalyst (1 mol %)
fac-Ir(ppy)3
fac-Ir(ppy)3
fac-Ir(ppy)3
fac-Ir(ppy)3
fac-Ir(ppy)3
fac-Ir(ppy)3
fac-Ir(ppy)3
fac-Ir(ppy)3
fac-Ir(ppy)3
fac-Ir(ppy)3
fac-Ir(ppy)3
[Ir(dtppy)(ppy)2]PF6
Ru(bpy)3PF6
Ru(bpy)3Cl2·6H2O
Eosin Y
baseb
K2HPO4
Na2HPO4
Cs2CO3
solvent
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMSO
DME
DCE
yield (%)c
59
3a
, 86%
3g
, 84%
3h
, 88%
CF3
2
51
F
R2 = Me, 81%
3k
,
N
N
R2 = OMe, 80%
, R2 = F, 77%
R2 = Cl, 78%
R2 = Br, 82%
N
3l
,
3
22
N
CF2CO2Et
3m
CF2CO2Et
2
CF2CO2Et
Ph
R
3n
,
N
4
K2CO3
63
CF2CO2Et
N
N
3o
,
N
3i
, 42%
3j
, 34%
3p
, 74%
5
Na2CO3
NaHCO3
NaOAc
73
Scheme 2. Reaction scope with respect to the isocyanide
6
77
7
37
With the optimized conditions in hand (Table 1, entry 16), we
explored the substrate scope of the reaction with respect to the
isocyanide (Scheme 2). First, we evaluated the effect of the R1
substituent on the benzene ring. These experiments showed
that a variety of substituents were suitable for constructing
difluoromethylated spiro[indole-3,3'-quinolines] in moderate
to excellent yields. Substrates with an electron-donating group
at R1 (3e–3h) gave higher yields than those with an electron-
withdrawing group (3b–3d, 3i, 3j). The position of the
substituent had no influence on the yield (3b versus 3i, 3e
versus 3g). Next, we investigated the effect of the R2 substituent
and found that all of the tested substituents gave good yields of
the corresponding products (3k–3o) and that the electronic
properties of the substituent had little effect on the product
yield. But when R2 was a CN or OH group, no products can be
obtained. Finally, we found that the yield of the products
decreased when R3 was changed from methyl (3a) to phenyl
(3p).
8
PhCOONa
NEt3
29
9
56
10
11
12
13
14
15
16
17
18
19
20d
21e
DABCO
4-DMAP
NaHCO3
NaHCO3
NaHCO3
NaHCO3
NaHCO3
NaHCO3
NaHCO3
NaHCO3
NaHCO3
NaHCO3
5
53
N.R.
N.R.
N.R.
N.R.
86
fac-Ir(ppy)3
fac-Ir(ppy)3
fac-Ir(ppy)3
none
53
35
DMSO
DMSO
DMSO
N.R.
N.R.
N.R.
fac-Ir(ppy)3
fac-Ir(ppy)3
aReaction conditions, unless otherwise noted: 1a (0.20 mmol), 2a (0.30 mmol), fac-
Ir(ppy)3 (0.002 mmol), base (0.40 mmol), anhydrous solvent (2 mL), 3 W blue LED
(approximately 2 cm away from the reaction vessel), room temperature, under an
Ar atmosphere. bDABCO, 1,4-diazabicyclo[2.2.2]octane; 4-DMAP, 4-
dimethylaminopyridine. cIsolated yields are provided; N.R., no reaction. dThe
reaction was carried out in air. eThe reaction was carried out in the dark.
Next, we carried out reactions between isocyanides 1 and
various bromodifluoroacetamides 2 (Scheme 3). Under the
optimized conditions, difluoromethylated spiro[indole-3,3'-
2 | J. Name., 2012, 00, 1-3
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a) radical inhibition experiments
quinoline] derivatives 3q–3z were obtained in moderate to
good yields. When R was a cyclic amine, the ring size had no
effect on the yield (3q–3s). Molecules with other azacyclic
View Article Online
DOI: 10.1039/D0CC06645A
CN
standard condition
N
BrCF2CO2Et
+
radical inhibitors (1.0 equiv)
CF2CO2Et
substituents
(morpholinyl,
piperazinyl,
and
3,4-
TEMPO: 10% yield
or BHT: 20% yield
N
H
N
dihydroisoquinolin-2-yl) were also suitable substrates (3t–3x).
Finally, we evaluated the effect of a methyl substituent on the
benzene ring of the isocyanide and found that it had no effect
on the yield of reactions with bromodifluoroacetamides with
cyclic amine substituents (3y and 3z). We then tried to prepare
the 5- or 7-membered spirocyclic compound, but we could not
get the target compound under the current experimental
conditions.
1a
2a
3a
O
N
O
O
O
O
F
F
H+
H+
O
F
F
+
+
Chemical Formula: C13H24F2NO3
Chemical Formula: C19H29F2O3
Exact Mass: 280.1719 found 280.1720
Exact Mass: 343.2079 found 343.2082
b) light on/off experiments
MeO
CN
standard condition
N
BrCF2CO2Et
+
R1
OMe
CN
Ir(ppy)3 (1 mol %)
NaHCO3 (2 equiv)
CF2CO2Et
N
blue LED
N
H
BrCF2COR
+
R1
N
3f
F
DMSO, rt, 24 h
1f
2a
F
N
H
N
O
R
1
2
3
N
N
N
N
F
F
F
F
F
F
F
F
N
O
N
N
N
O
N
O
N
N
O
N
O
3s
, 72%
3t
, 74%
3q
, 71%
3r
, 71%
N
N
N
N
F
Scheme 4. Mechanistic experiments
F
F
F
F
F
F
F
N
O
N
N
O
N
N
N
O
O
N
N
N
N
N
N
On the basis of these experiments, we propose the
mechanism outlined in Scheme 5. Irradiation of fac-IrIII(ppy)3
with visible light generates excited-state [fac-IrIII(ppy)3]*, which
is oxidized by ethyl bromoacetate 2a to generate radical A.11
Radical A inserts into the isocyanide to produce intermediate B,
which undergoes a 6-exo-trig cyclization to form intermediate
C. Oxidization of C by fac-IrIV(ppy)3 generates intermediate D,
Ph
N
3u
3v
3w
3x
, 69%
, 58%
, 51%
, 52%
N
N
F
F
F
F
N
O
N
N
O
N
3z
, 72%
3y
, 77%
which loses a proton to afford final product 3a.
Scheme 3. Reactions between isocyanides and bromodifluoroacetamides
O
*IrIII(ppy)3
F
F
O
Br
To elucidate the mechanism of the reaction, we carried out
two free radical inhibition experiments (Scheme 4a). When 1
equiv of free radical inhibitor BHT (2,6-di-tert-butyl-4-
methylphenol) was added to a reaction mixture containing 1a
under the optimal conditions, the yield of 3a (20%) was
dramatically lower than in the absence of the inhibitor. In
addition, when TEMPO (2,2,6,6-tetramethylpiperidine-1-oxyl)
was present in the reaction mixture, the yield of 3a was even
lower (10%). Furthermore, BHT and TEMPO adducts of ethyl 2-
fluoroacetate radical (generated in situ) were detected by liquid
chromatography–mass spectrometry (see the Supporting
Information for details). These results suggest that the reaction
proceeded by means of a radical pathway. To determine
whether radical propagation was involved, we performed light
on/off experiments with 1f as a substrate; these experiments
showed the irradiation dependence of the reaction yield and
thus ruled out the involvement of a radical chain pathway
(Scheme 4b).
2a
IrIII(ppy)3
- Br
SET
-H+
N
3a
CF2CO2Et
O
N
SET
F
H
F
O
D
IrIV(ppy)3
A
1a
EtO2CF2C
N
N
CF2CO2Et
N
N
H
H
B
C
Scheme 5. Proposed mechanism
In conclusion, we have developed a protocol for visible-light-
induced radical isocyanide insertion reactions of 3-(2-
isocyanobenzyl)-indoles and bromodifluoroacetates or
bromodifluoroacetamides
for
the
synthesis
of
difluoromethylated spiro[indole-3,3'-quinoline] derivatives.
The protocol has good functional group tolerance, a broad
substrate scope, and high yields. Mechanistic experiments
indicated that a radical isocyanide insertion and 6-exo-trig
cyclization processes are involved in the transformation.
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 3
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Journal Name
670; (f) J. Huang, F. Li, L. Cui, S. K. Su, X. S. Jia, J. Li, Chem.
We are grateful to the National Natural Science Foundation
of China (21977056, 21732002) and the Fundamental Research
Funds for the Central Universities, Nankai University
View Article Online
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the
Tianjin
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(19JCTPJC57800), for generous financial support for our
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6
Conflicts of interest
There are no conflicts to declare.
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DOI: 10.1039/D0CC06645A
R1
CF
Br 2COXR
CN
R1
fac-Ir(ppy)3 (1 mol %)
NaHCO3 (2 equiv)
blue LED
N
F
F
R2
R3
R2
R3
O
DMSO, rt, 24 h
X = O, N
N
N
X
R
H
26 examples
up to 91% yield
A protocol for visible-light-induced radical isocyanide insertion reactions for the
synthesis of difluoromethylated spiro[indole-3,3'-quinoline] derivatives was
developed.