Catalyst-controlled regioselective approach to 1-aminoisoquinolines and/or 1-aminoisoindolines through aminative domino cyclization of 2-alkynylbenzonitriles

Article abstract of DOI:10.1002/ejoc.201501390

A metal-catalyzed regioselective approach towards the synthesis of 1-aminoisoquinolines and/or 1-aminoisindolines through aminative domino cyclization of 2-alkynylbenzonitriles with secondary amines has been developed under solvent-free conditions. It was

Full text of DOI:10.1002/ejoc.201501390

DOI: 10.1002/ejoc.201501390
Communication
Nitrogen Heterocycles
Catalyst-Controlled Regioselective Approach to
-Aminoisoquinolines and/or 1-Aminoisoindolines through
Aminative Domino Cyclization of 2-Alkynylbenzonitriles
1
[a]
[a]
[a]
Virsinha Reddy, Abhijeet S. Jadhav, and Ramasamy Vijaya Anand*
Abstract: A metal-catalyzed regioselective approach towards the reaction was greatly influenced by the choice of the metal
the synthesis of 1-aminoisoquinolines and/or 1-aminoisind- catalyst. Copper-based catalysts favored 6-endo-dig cyclization
olines through aminative domino cyclization of 2-alkynylbenzo- leading to 1-aminoisoquinolines, whereas other catalysts such
nitriles with secondary amines has been developed under sol- as triflates of Zn, Ag, Bi, Sc and Yb favored the formation of 1-
vent-free conditions. It was found that the regioselectivity of aminoisoindolines through 5-exo-dig cyclization.
Introduction
In recent years, significant efforts have been made for the syn-
thesis of amino-substituted isoquinoline and isoindoline deriva-
tives due to their applications in the area of medicinal chemis-
[
1,2]
try (Figure 1).
For example, the therapeutic potential of 1-
aminoisoquinolines has been well explored in the area of drug
discovery due to their intrinsic medicinal properties such as
[
3]
[4]
antimalarial and antitumor activity. They also possess re-
[
5a]
markable inhibition activities toward adenosine A3 receptor,
topoisomerase I, mutant B-Raf enzyme and PDE4B. One
of the 1-aminoisoquinoline derivatives showed potent in vivo
activity towards Parkinson disease in animal model, in addi-
tion to that 1-aminoisoquinoline derivatives serve as valuable
precursors for the synthesis of other benzo-fused hetero-
cycles. Although the utility of 1-aminoisoindoline derivatives
in medicinal chemistry is limited, they serve as valuable syn-
[
5b]
[5c]
[5d]
[
6]
[
7]
Figure 1. Some important 1-aminoisoquinolines and 1-aminoisoindoline.
[
8]
thons to prepare modified porphyrin hybrids and aza-BODIPY
[
9]
analogues. Some of the 1-aminoisoindoline derivatives have
[
10]
found application as ligands in transition-metal catalysis.
perspective. In order to overcome this drawback, a few alterna-
The traditional strategy, adopted by medicinal chemists, to tive methods have been developed.[13] In recent years, several
access 1-aminoisoquinolines involves direct installation of methods based on domino electrophilic cyclization of 2-alkynyl-
[
14]
[15]
amino substituents in the 1-haloisoquinoline core through nu- benzamides
or 2-alkynylbenzaldoximes
have been devel-
cleophilic aromatic substitution reaction either under metal- oped to access 1-aminoisoquinoline derivatives. High atom
[
11]
[12]
free
or under transition-metal-catalyzed conditions.
Al- economy and broad substrate scope made these methods at-
though the above-mentioned methods showed a wide sub- tractive and dominant for the synthesis of a wide range of 1-
strate scope and good functional-group tolerance, the synthesis aminoisoquinolines. Apart from the above-mentioned reports,
of 1-haloisoquinolines involves the use of toxic reagents such another interesting and unique approach has been developed
[
16]
as POCl , which may be a concern in terms of a green chemistry for the synthesis of 1-aminoisoquinolines based on rhodium-
3
[
17]
or ruthenium-catalyzed oxidative annulation of benzamidine
derivatives with internal alkynes. Unlike 1-aminoisoquinolines,
only a few protocols are available for the synthesis of 1-amino-
isoindoline derivatives, and most of those reported methods
involve either metal-catalyzed Sonogashira coupling of 2-
bromobenzamidines with terminal alkynes followed by 5-exo-
dig electrophilic cyclization in a one-pot manner under micro-
[
a] Department of Chemical Sciences, Indian Institute of Science Education
and Research (IISER) Mohali,
Sector 81, Knowledge City, S. A. S. Nagar, Manauli (PO),
Punjab 140306, India
E-mail: rvijayan@iisermohali.ac.in
http://14.139.227.202/faculty/vijay/
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/ejoc.201501390.
[
18]
wave-assisted conditions or the direct addition of organome-
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tallic reagents to 1,2-dicyanobenzene derivatives.[19] Another
recently developed approach involves ruthenium-catalyzed oxi-
dative annulation of benzamidines with α,β-unsaturated olefins
Table 1. Catalyst screening and optimization studies.[a]
[
17]
through C–H functionalization.
In our continued efforts toward the synthesis of biologically
[
20]
important heterocyclic systems by annulation reactions,
herein report an atom-efficient protocol for the synthesis of 1-
aminoisoquinolines and/or 1-aminoisoindolines through
we
a
metal-catalyzed aminative annulation of 2-alkynylbenzonitriles.
Although 2-alkynylbenzonitriles have been utilized for the syn-
Entry
Catalyst
Cu(OTf)2
T [h]
Ratio[b]
6/7
Yield [%][c]
[
21a,21b]
6/7
thesis of 1-aminonaphthalene
and 1-oxyisoquinoline de-
[
21c]
[d]
rivatives,
surprisingly, they have not been explored as pre-
1
24
24
24
24
40
30
42
24
40
30
42
24
–
–
0
[e]
cursors for the synthesis of 1-aminoisoquinolines so far. In the
case of the 1-aminoisoindoline synthesis, only a very few re-
ports are available using 2-alkynylbenzonitriles as precursors.
One of the reports involves the titanium amide catalyzed ami-
native cyclization of 2-alkynylbenzonitriles; however, the sub-
2
Cu(OTf)
Cu(OTf)
2
trace
43:28
62:20
32:27
6:50
8:52
8:76
6:64
7:62
14:50
0
3
4
5
6
7
8
9
2
1.7:1
3.3:1
1.5:1
1:4.2
1:5.3
1:5.3
1:4.0
1:2.2
1:3.5
–
CuOTf·PhMe
CuBr
AgOTf
Bi(OTf)
Zn(OTf)2
Yb(OTf)
Sc(OTf)
3
[
22a]
strate scope was very limited.
Another related report deals
3
with the synthesis of 1-oxoisoindoline derivatives by Pd-cata-
lyzed oxygenative domino cyclization of 2-alkynylbenzonitriles
1
1
0
1
3
Ce(OTf)
–
3
[
22b]
followed by arylative coupling.
12
[
a] Reaction conditions: 4 (0.1 mmol), 5a (0.15 mmol), catalyst (0.01 mmol)
1
at 120 °C. [b] The regioisomeric ratio was determined by H NMR analysis of
the crude reaction mixture. [c] Isolated yield. [d] The reaction was carried out
in toluene or 1,4-dioxane at room temp. or 60 °C. [e] The reaction was carried
out in toluene or 1,4-dioxane at 120 °C.
Results and Discussion
We have chosen 2-alkynylbenzonitriles as precursors, because
it is possible to access both 1-aminoisoquinolines and 1-amino-
isoindolines from this precursor through aminative 6-endo-dig be inferior to effect this transformation in terms of yield and
and 5-exo-dig cyclization, respectively, by altering the reaction selectivity when compared to Zn(OTf) (Entries 9–11). No prod-
conditions. Moreover, this precursor would lead to the products ucts were formed in the absence of any catalyst (Entry 12).
without elimination or generation of any by-products; there-
Having optimized conditions in hand for the regioselective
2
fore, it is possible to attain 100 % atom economy in this case. synthesis of 1-aminoisoquinolines (Table 1, Entry 4) and 1-
Keeping these motives in mind, we started the optimization aminoisoindolines (Table 1, Entry 8), we examined the substrate
studies using 2-alkynylbenzonitrile 4 and N-phenylpiperazine scope of this transformation under both reaction conditions.
[
23]
5
a
as model substrates (Table 1).
Table 2 summarizes the substrate scope of the reaction using
Our initial attempts using Cu(OTf) as a catalyst in toluene CuOTf·PhMe as a catalyst. For this purpose, a wide range of 2-
2
or 1,4-dioxane did not give any fruitful results as no products alkynylbenzonitriles as well as secondary amines were sub-
(
neither 6 nor 7) were observed at room temperature or 60 °C jected to the optimized conditions (Table 1, Entry 4).
(Entry 1). Even raising the temperature to 120 °C did not help It is evident from Table 2 that 2-alkynylbenzonitriles having
in effecting the reaction (Entry 2). Surprisingly, when the same electron-rich aryl substituents (4a–4e, 4h, 4i) attached to the
reaction was carried out under solvent-free conditions at alkyne part underwent aminative cyclization reaction with 5a
120 °C, 6 and 7 were obtained in a ratio of 1.7:1 (Entry 3). In and provided the corresponding 1-aminoisoquinolines (6a–6e,
this case, the products 6 and 7 were obtained in 43 and 28 % 6h, 6i) as a major product in moderate to good yields, and the
yields, respectively, after isolation. The isolated yield of 6 (62 %) regioselectivities in those cases varied from 3.8:1 to 1.6:1. In the
as well as the regioisomeric ratio (6/7 = 3.3:1) have been im- cases of 4f and 4g, derived from alkynes with electron-poor aryl
proved when CuOTf·PhMe complex was used as a catalyst in- substituents, the 1-aminoisoquinolines 6f, 6g were obtained in
stead of Cu(OTf) (Entry 4). CuBr was found to be inefficient for lower yields, and regioselectivities were found to be 1.7:1 and
2
this transformation as the yield and the regioisomeric ratio were 1:1, respectively. This transformation worked well in the case of
found to be lower (Entry 5). To our surprise, when the reaction 3-ethynylthiophene-derived precursor 4j, and the product 6j
was conducted with AgOTf as a catalyst, the regioselectivity was obtained in 66 % isolated yield with good regioselectivity
was reversed (6/7 = 1:4.2), and 7 was isolated in 50 % yield (6j/7j = 6.7:1). This methodology was also extended to other 2-
(
Entry 6). Other catalysts such as Bi(OTf) favored the formation alkynylbenzonitrile precursors derived from 3- and 4-methyl-
3
of 7 and also did help in improving the regioselectivity consid- substituted o-bromobenzonitriles (4k, 4l), and in those cases
erably (Entry 7). The maximum yield (76 %) of 7 was realized the products 6k and 6l were obtained in 50 and 70 % yields,
when Zn(OTf) was used as a catalyst without much change in respectively. Further elaboration of this transformation was car-
2
the regioselectivity (6/7 = 1:5.3) (Entry 8). Other Lewis acids ried out using other secondary amines (5b–5h), and almost in
such as ytterbium, scandium and cerium triflates were found to all these cases the required 1-aminoisoquinolines (6m–6o, 6q–
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Table 2. Substrate scope for the CuOTf·PhMe-catalyzed reaction.[a]
[
a] Reaction conditions: 4 (0.1 mmol), 5 (0.15 mmol), CuOTf·PhMe (0.01 mmol) at 120 °C. [b] 3 equiv. of 5 with respect to 4 was used. The regioisomeric ratio
1
was determined by H NMR analysis of the crude reaction mixture. Yields reported are isolated yields of the major product. Yields reported in parentheses
are isolated yields of the minor product.
6
s) were obtained in moderate yields and regioselectivities. did not work in the cases of aliphatic primary amines as well as
When pyrrolidine was used as a substrate, the products 6p and aromatic secondary amines, such as benzylamine and diphenyl-
7
6
p were obtained in a 1.1:1 ratio, and the 1-aminoisoquinoline amine, as a complex mixture of products was obtained in those
p was obtained in only 22 % yield. Unfortunately, the reaction cases.
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Communication
The substrate scope of the Zn(OTf) -catalyzed reaction was alkyne, 2-alkynylbenzonitriles (4a–4g, 4h, 4i) underwent amin-
2
evaluated with the same set of 2-alkynylbenzonitriles and sec- ative 5-exo-dig cyclization reaction to provide the corresponding
ondary amines under the standard reaction conditions (Table 1, 1-aminoisoindoline derivatives (7a–7g, 7h, 7i) in moderate to
Entry 8), and the results are summarized in Table 3. Irrespective good yields with the variations in regioselectivity from 1.9:1 to
of the electronic nature of the aryl group attached to the 13.3:1. In the case of precursor 4j, the product 7j was obtained
Table 3. Substrate scope for the Zn(OTf)
2
-catalyzed reaction.[a]
[
2
a] Reaction conditions: 1 (0.1 mmol), 5 (0.15 mmol), Zn(OTf) (0.01 mmol) at 120 °C. [b] 3 equiv. of amine with respect to 1 was used. The regioisomeric ratio
1
was determined by H NMR analysis of the crude reaction mixture. Yields reported are isolated yields of the major product. Yields reported in parentheses
are isolated yields of the minor product.
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in 66 % isolated yield, and the regioselectivity of 7j/6j was of EtOAc/hexane as eluent to obtain the pure 1-aminoisoquinoline
and/or 1-aminoisoindoline derivatives.
found to be 4.1:1. The reaction also worked rather well in the
cases of 4k and 4l, derived from methyl-substituted o-bromo-
benzonitriles; the products 7k and 7l were obtained in good
yields and regioselectivities. Extension of the substrate scope
was performed using other secondary amines, and the required
Acknowledgments
The authors gratefully acknowledge the Indian Institute of Sci-
ence Education and Research (IISER) Mohali for financial sup-
products 7m–7s were obtained in low to moderate yields with
port and infrastructure. V. R. and A. S. J. thank the Council of
the regioselectivities varying from 1.6:1 to 6.7:1 in those cases.
1
Scientific and Industrial Research (CSIR), New Delhi for a re-
search fellowship. The authors thank Mr. Hareram Yadav (IISER
Mohali) for his help in solving the crystal structure. The NMR
and HRMS facilities at IISER Mohali are gratefully acknowledged.
Interestingly, in all the examples presented in Table 3, the H
NMR analysis of the crude mixture revealed that only one
stereoisomer of olefin was present, although there is a possibil-
ity of the formation of both (E) and (Z) isomers. Fortunately, one
of the products (7p) was crystallized, and the X-ray structure of
7
p revealed that the absolute stereochemistry at the exocyclic Keywords: Amination · Heterocycles · Isoquinolines ·
double bond was cis (Z). Based on this observation, the abso- Isoindolines · Domino reactions
lute stereochemistry of all other products was assigned to be
(
Z).
To portray the application potential, this transformation was
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[
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Conclusions
A
catalyst-controlled regioselective and atom-economical
method has been developed for the synthesis of 1-aminoiso-
quinoline as well as 1-aminoisoindoline derivatives under sol-
vent-free conditions. Further studies to elucidate the exact
mechanism, especially the role of the metal catalyst in control-
ling the regioselectivity outcome of the reaction, is currently
under investigation.
[
Experimental Section
General Procedure for the Synthesis of 1-Aminoisoquinolines
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amine 5 (0.15 mmol) was heated to 120 °C in a closed vial for
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Received: November 3, 2015
Published Online: December 4, 2015
Eur. J. Org. Chem. 2016, 453–458
www.eurjoc.org
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