Efficient construction of diverse 3-cyanoindoles under novel tandem catalysis

Article abstract of DOI:10.1039/d0cc05439a

A novel and rapid construction of 3-cyanoindoles by palladium-catalyzed tandem reactions has been developed. "N-H"free unprotected, N-alkyl and N-aryl 3-cyanoindoles are obtained with good to excellent yields. The usefulness of this synthetic approach is further demonstrated by the successful synthesis of practical compounds such as the therapeutic estrogen receptor ligand A precursor. Mechanism study shows that the tandem catalysis exploits a Suzuki cross-coupling with subsequent base-induced isoxazole fragmentation, followed by the aldimine condensation.

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DOI: 10.1039/D0CC05439A
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Efficient Construction of Diverse 3-cyanoindoles Under Novel
Tandem Catalysis
Received 00th January 20xx,
Accepted 00th January 20xx
Jun Wu,a Jiabin Liu,a Kerui Zhou,a Zhenni He,a Qian Wang,a Fen Wu,a Tingting Miao,*a Jinjie Qian*a
and Qian Shi*a
DOI: 10.1039/x0xx00000x
A novel and rapid construction of 3-cyanoindoles by Palladium- some specific substrates, this strategy remains relatively
catalyzed tandem reactions has been developed. “N−H” free unexplored. While above-mentioned methods have been
unprotected, N-alkyl and N-aryl 3-cyanoindoles are obtained with proved reliable and efficient in the synthesis of 3-
good to excellent yields. The usefulness of this synthetic approach cyanoindoles, in most cases, for a particular method, only N-
is further demonstrated by the successful synthesis of practical protected indoles or 3-cyanoindoles with free –NH units are
compounds such as the therapeutic estrogen receptor ligand A obtained. Therefore, development of a new methodology
precursor. Mechanism study shows that the tandem catalysis leading to an economical, safe and feasible preparation of
exploits a Suzuki cross-coupling with subsequent base-induced both N-protected indoles and 3-cyanoindoles with free –NH
isoxazole fragmentation, followed by the aldimine condensation.
units is still challenging and urgently needed.
In recent years, more efficient and environmentally benign
procedures for valuable target products are needed. Tandem
catalysis suits these demands well in virtue of its overall
process simplicity, effective utilization of organic reagents and
diversiform transformation possibilities [13-14]. Such reactions
decrease the reaction time and the loss in yield by avoiding the
isolation and purification of intermediate compounds in
multistep reactions. In continuation of our interest on tandem
Aryl and heteroaryl nitriles have attracted much attention due
[1]
to their wide applications in medical science and functional
materials [2]. The nitrile group could also be effectively
converted into other useful functional groups, such as
aldehydes, ketones, carboxylic acids, amines and amides [3], or
[6]
transferred into tetrazoles [4], pyrazoles [5], triazoles
and
other heterocycles. Therefore, efficient synthesis of various
aryl and heteroaryl nitriles with diverse structures has been
widely studied in recent years. Among these structures, 3-
[15]
[16]
catalysis
and the synthesis of heterocyclic compounds
,
herein we report a novel one-pot protocol for the synthesis of
3-cyanoindoles, which obtains N-protected indoles and 3-
cyanoindoles with free –NH units in good to excellent yields.
The mechanism of this tandem reaction is also carefully
studied.
cyanoindoles and their derivatives are important structural
[7]
motifs of many biologically active compounds
as well as
[8]
versatile precursors of a broad range of pharmaceuticals
(Scheme 1). The importance of this framework has led to the
development of numerous synthetic methods. Direct C(sp2)−H
As an initial examination on the tandem catalysis, 2-bromo-
on the 3-position of indoles represents one of 4-methylaniline 2a and boronate 1 were chosen as model
[9-10]
cyanation
substrates. Under typical Suzuki reaction conditions (using
DMSO as solvent, PdCl2(PPh3)2 as the catalyst, and aqueous KF
as the base), a complex mixture was obtained from which 3a
the most straightforward approaches, however, toxic cyano
sources (e.g., KCN or CuCN) or harsh reaction conditions (e.g.,
POCl3 and high temperature) are frequently used. Functional
transformations of 3-substituted indoles (e.g., 3-carbonyl-,
CN
CN
MeO
[11]
oximido-, hydroxymethyl-, or halide-substituted indoles)
S
CN
HOOC
tBu
O
N
N
also remains a powerful tool to synthesize 3-cyanoindoles. In
these cases, multiple synthetic steps are always needed from
commercial reagents to the substrates bearing particular
functional groups. In addition, cyclization of nonindole
substrates has also been employed to prepare 3-cyanoindoles
and their derivatives [12]. However, due to the requirement of
NH
NH
N
O
O
N
S
N
O
H
OH
estrogen receptor ligand
IMPDH inhibitor
Hepatitis C virus (HCV) inhibitor
CN
N
N
F
O
CF3
N
X
N
N
S
NH
NH
nBu
N
N
N
H
nBu
N
N
O
a. College of Chemistry & Materials Engineering, Wenzhou University, Wenzhou
325035, P. R. China. E-mail: miaott@wzu.edu.cn; jinjieqian@wzu.edu.cn;
shiq@wzu.edu.cn
N
N
N
N
N
H
X= -, CH2, (CH2
)2S
HCV NS4B inhibitor
anticancer immunomodulators
angiotensin II receptor antagonist
† Electronic Supplementary Information (ESI) available: Experimental procedures
and compound characterization data, and 1H and 13C NMR spectra of new
compounds. See DOI: 10.1039/x0xx00000x
Scheme 1 Representative biologically active compounds.
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could be isolated in a respectable yield of 56%. The Suzuki LiOH or Na3PO4 (Table 1, entries 11 and 12). VTiehweArtticalenOdnelimne
DOI: 10.1039/D0CC05439A
coupling product 4a and the cyanomethylation product 5a catalysis was clearly affected by solvents, and DMSO turned
were not detected (Table 1, entry 1), indicating the high out to be optimal in terms of reaction activity (Table S1 in SI).
selectivity and efficiency of this tandem catalysis. To better Interestingly, increasing the reaction temperature to 150 ℃
understand the tandem catalysis, we systematically examined didn’t bring significant improvement in the yield (Table 1,
the role of each reaction component. First, several transition- entry 14). Rather low yields were observed while the
metal catalysts were examined. The expected 5-methyl-3- temperature dropped below 130 ℃ , and Suzuki coupling
cyanoindole 3a were not detected while PdCl2/dppf, product 4a was obtained under 90℃ (Table 1, entries 15 and
RuCl3/dppf or Ni(dppe)Cl2 were applied as catalysts (Table 1, 17). After elevating the temperature to 130 ℃ again, the
entries 4-6). 3a was also not detected when transition-metal Suzuki coupling product 4a could not be detected and 3a was
catalyst was not used (Table 1, entry 7). These results generated in 90% yield, indicating that the Suzuki coupling
indicated the importance of Palladium catalyst. Reaction that product should be intermediate of this tandem catalysis (Table
using PdCl2dppf as the catalyst proceeded smoothly, affording 1, entry 16). Furthermore, to our satisfaction, with much lower
exclusively 5-methyl-3-cyanoindole 3a in 91% yield (Table 1, catalyst loadings (0.5 mol %), this tandem catalysis could still
entry 3). Using PdCl2dppf as the catalyst, several bases were exhibit excellent reaction activities (Table 1, entry 20).
examined as well. Potassium fluoride was identified as a
Under the optimized reaction condition, a variety of 2-
suitable base although rather clean and high-yielding halogenated anilines 2 were subjected to the tandem reaction
transformations
could
also
be
obtained
using in the presence of 0.5 mol % PdCl2dppf, affording the desired
“N−H” free unprotected 3-cyanoindoles 3a-h exclusively in
excellent yields. As shown in Scheme 2, it was noteworthy to
Table 1 Optimization of Reaction Conditions in the Tandem Catalysis[a]
O
N
CN
O
O
B
Br
N
CN
O
mention that functional groups such as -NO2 and -CF3 were
well tolerated under the reaction condition. Introducing
+
+
1
NH2
N
cat., base
NH2
4a
NH2
H
2a
3a
5a
electron-donating or electron-withdrawing substituents at the
5-position or 6-position of indoles had no obvious effect on
Conv.
(%) [b]
60
Yield (%) [c]
reactivities, although the introduction of electron-withdrawing
group at the R’ position slightly decreased the yields (3a, 3b vs
3c-g).
Entry
Catalyst
Base
T (℃)
3a
4a
1
2
PdCl2(PPh3)2
Pd(PPh3)4
PdCl2dppf
PdCl2, dppf
RuCl3, dppf
Ni(dppe)Cl2
--
KF
KF
130
130
130
130
130
130
130
130
130
130
130
130
130
150
90
56
60
91
--[d]
--[d]
--[d]
--[d]
38
42
40
55
60
42
91
8
--[d]
--[d]
--[d]
--[d]
--[d]
--[d]
--[d]
--[d]
--[d]
--[d]
--[d]
--[d]
--[d]
--[d]
70
62
Following the satisfying results of 3-cyanoindoles with free -
NH units, we then extended the substrate scope of this
tandem catalysis to N-substituted 3-cyanoindoles, including a
variety of N-alkyl and N-aryl 3-cyanoindoles (Scheme 3). As for
the N-alkyl 3-cyanoindoles, significant increase in the steric
hindrance showed little impact on the reactivities and
substrates bearing linear or branched alkyl chains at the R
position could react smoothly without any decreases in yields
(3i-l). Furthermore, N-aryl protected 3-cyanoindoles were also
isolated in 79-94% yields under optimized reaction condition.
The introduction of substituents ortho, para or meta to the
Scheme 2 Substrate scope of the tandem reaction for “N−H” free
unprotected 3-cyanoindole products. Reaction conditions: 2a-h (0.15
mmol, 1.0 equiv.), 1 (1.2 equiv.), KF (3 equiv., 1 M in water), PdCl2dppf (0.5
mol %), 0.05 M solution in solvent, 16 h. [a] Data obtained by using 1.0 mol
3
KF
94
4
KF
--[d]
--[d]
--[d]
--[d]
39
5
KF
6
KF
7
KF
8
PdCl2dppf
PdCl2dppf
PdCl2dppf
PdCl2dppf
PdCl2dppf
PdCl2dppf
PdCl2dppf
PdCl2dppf
PdCl2dppf
PdCl2dppf
PdCl2dppf
PdCl2dppf
PdCl2dppf
PdCl2dppf
PdCl2dppf
Cs2CO3
K2CO3
Na2CO3
LiOH
Na3PO4
NaHCO3
KF
9
45
10
11
12
13
14
15
16
17
18[f]
19[g]
20[h]
21[h,i]
22[j]
44
57
60
43
95
KF
82
KF
130[e]
95
90
--[d]
91
92
90
90
80
--[d]
KF
70
65
57
% PdCl2dppf, stirred for 16 h.
O
KF
130
130
130
95
--[d]
--[d]
--[d]
N
CN
B
X
O
O
1
R'
KF
96
R'
0.5 mol % PdCl2dppf,
KF, DMSO
NH2
X = Cl, Br, I.
N
H
KF
93
KF
KF
130
130
92
85
--[d]
2
3
--[d]
CN
CN
CN
CN
MeO
F
Br
[a] Reaction conditions: 2a (0.15 mmol, 1.0 equiv.), 1 (1.2 equiv.), base (3
equiv., 1 M in water), Pd-cat. (10 mol %), 0.1 M solution in solvent, 16 h. 5a
N
N
N
N
H
H
H
H
3c
3d
3a
92% yield
3b
91% yield
1
was not detected for all reactions. [b] Determined by H NMR analysis of
78% yield
80% yield
the crude product with 1,3,5-trimethoxybenzene as an internal standard.
[c] Isolated yields. [d] Compound 3a, 4a or 5a was not observed. [e] The
reaction was carried out under 130℃ for another 6 h after stirring at 90℃
for 16 h. [f] 5 mol % Pd-cat. was used. [g] 1.0 mol % Pd-cat. was used. [h]
0.5 mol % Pd-cat. was used. [i] All manipulations were conducted in air. [j]
0.1 mol % Pd-cat. was used.
CN
CN
CN
CN
O2N
N
H
N
N
N
Br
F3C
H
H
H
3h
3g
89% yield[a]
3e
85% yield
3f
85% yield
X = Cl, 12% yield
X = Br, 80% yield
X = I, 81% yield
2 | J. Name., 2012, 00, 1-3
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To further demonstrate the synthetic utility of
View Article Otnhlinies
Scheme 3 Substrate cope of the tandem reaction for N-alkyl and N-aryl 3-
cyanoindole products. Reaction conditions: 2i-x (0.15 mmol, 1.0 equiv.), 1
(1.2 equiv.), KF (3 equiv., 1 M in water), PdCl2dppf (0.5 mol %), 0.05 M
methodology, this catalytic protocol was successfully applied
DOI: 10.1039/D0CC05439A
to the scale-up syntheses and synthetic transformations. With
1.0 mol % PdCl2dppf, N-aryl 3-cyanoindole 3a and 3v were
obtained with more than 85% isolated yields on the gram-scale
(Scheme 4a). Further bromination of 3v provided 6v as an
excellent precursor of therapeutic estrogen receptor ligand A
(Scheme 4b).
solution in solvent, 16 h.
O
N
CN
B
Br
O
O
1
R
0.5 mol % PdCl2dppf,
KF, DMSO
N
H
N
R
R = alkyl, aryl.
3
2
The usefulness of this tandem catalysis was also exemplified
in the practical transformations of 3-cyanoindole 3h (Scheme
4c). The N-methyl analogue 3i and the N-phenyl analogue 3m
could be easily obtained from the “N−H” free unprotected
indole 3h. While in this work, they could also be directly
synthesized through the tandem catalysis (Scheme 3). 3h could
be transferred into other valuable compounds as well, such as
carboxylic acid 7h and 2-formyl-1H-Indole-3-carbonitrile 8h
using literature methods.
CN
CN
CN
CN
CN
CN
N
N
N
N
N
N
n-Bu
3n
85% yield
3i
3l
3j
3m
3k
90% yield
89% yield
95% yield
93% yield
88% yield
CN
CN
CN
CN
N
CN
CN
N
N
N
N
Cl
N
F
F
n-Bu
As a mechanistic rationale for the observed formation of 3,
we assumed a base-induced fragmentation of the primary
cross coupling product, i.e. the isoxazole 4h, to give the
intermediate A, which in turn was converted to 3h by an
aldimine condensation process. To understand the tandem
reaction process, several control experiments were carried
out. The primary cross coupling product isoxazole 4h and 4y
were successfully synthesized and reacted with boronate 1
under reaction conditions. As expected, the yield of 3h was
similar to that achieved in the standard tandem reaction
starting from 2-bromoaniline (Scheme 5a). The result indicated
that isoxazole 4h is the intermediate of the tandem catalysis.
As for isoxazole 4y, only cyanomethylation product 5y was
obtained.
3s
89% yield
3t
3o
83% yield
3q
85% yield
3r
3p
94% yield
80% yield
89% yield
CN
CN
CN
N
CN
N
N
N
OMe
3x
90% yield
3w
80% yield
3v
91% yield
3u
81% yield
F
N-phenyl groups didn’t affect the reaction outcomes, and high
yields were still observed (3n-x).
a) Scale-up synthesis of 3a and 3v
O
O
CN
B
Br
N
1.2 equiv.
O
1
NH2
N
H
1.0 mol % PdCl2dppf,
3 equiv. KF
a) Domino Suzuki coupling-isoxazole fragmentation-aldimine condensation
2a,
1.0 g
Br
NH
3a,
85% yield
HO
H
CN
CN
O
O
CN
O
B
Br
N
N
1.2 equiv.
H
-H2O
O
1,
Pd-cat.
N
1
base
O
NH2
H
NH2
N
H
NH2
1.0 mol % PdCl2dppf,
3 equiv. KF
A
3h
4h
, 80% yield
OMe
1.0 g
OMe
2v,
3v,
86% yield
b) Domino Suzuki coupling-isoxazole fragmentation-retro-Claisen condensation
b) Synthesis of therapeutic estrogen receptor ligand A precursor
HO
CN
H
CN
OH-
CN
Cl
Cl
Br
Cl
Cl
Br
O
Br
H
O
N
N
ref 10i
N
N
N
Br
N
CN
-HCOOH
1,
base
Pd-cat.
t-BuLi, -78°C
h
, 4
CN
H
N
N
N
OMe
OMe
3v
50 mg, 0.2 mmol
OMe
4y
5y
, 85% yield
B
6v
ligand A
54% yield
c) Synthetic transformations of 3-cyanoindole 3h
Scheme 5 Proposed mechanism and control experiments for this catalysis
tandem reaction.
O
CN
OH
1) NaOH,100°C
2) HCl
1) NaH, DMF, 0°C
N
In conclusion, we have discovered, optimized, and applied a
novel methodology for the direct synthesis of 3-cyanoindoles
and their derivatives. Using commercially available 2-
halogenated anilines and isoxazole-4-boronic acid pinacol
ester as substrates, a wide range of “N−H” free unprotected,
N-alkyl and N-aryl 3-cyanoindoles and their analogues are
obtained in excellent yields. The tandem catalysis exploits a
Suzuki cross-coupling with subsequent base-induced isoxazole
2) CH3I, r.t.
CN
N
H
3i
, 80% yield
CN
7h
8h
, 89% yield
CN
N
H
POCl3, DMF
CuI, C6H5Br
CHO
toluene, reflux
K3PO4, 110°C
N
3h
N
H
Ph
3m
, 92% yield
, 84% yield
Scheme 4 Scale-up syntheses and synthetic transformations.
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 3
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opens an efficient access to a broad spectrum of heterocyclic
compounds in an operationally simple and reliable fashion.
Acknowledgements
This work was financially supported by the National Natural
Science Foundation of China (grant nos. 21801192, 21704077,
21671151, 21601137); Basic Science and Technology Research
Project of Zhejiang (grant no. LGF20B020002)
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Conflicts of interest
There are no conflicts of interest to declare.
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ChemComm
View Article Online
DOI: 10.1039/D0CC05439A
HO
H
Jun Wu,a Jiabin Liu,a Kerui Zhou,a Zhenni He,a Qian
Wang,a Fen Wu,a Tingting Miao,*a Jinjie Qian*a and
Qian Shi*a
CN
O
O
O
N
O
X
B
N
-H2O
base
R'
R'
R
H
R
Pd-cat.
N
N
H
R'
N
H
R
X = Br, I.
R = H, alkyl, aryl.
24 examples
79-94% yields
Page No. – Page No.
Title: Efficient Construction of Diverse 3-cyanoindoles Under Novel Tandem Catalysis
A novel and rapid construction of 3-cyanoindoles by Palladium-catalyzed tandem reactions has been developed.